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Sample records for primary amphipathic cell-penetrating

  1. Coexistence of a two-states organization for a cell-penetrating peptide in lipid bilayer.

    Science.gov (United States)

    Plénat, Thomas; Boichot, Sylvie; Dosset, Patrice; Milhiet, Pierre-Emmanuel; Le Grimellec, Christian

    2005-12-01

    Primary amphipathic cell-penetrating peptides transport cargoes across cell membranes with high efficiency and low lytic activity. These primary amphipathic peptides were previously shown to form aggregates or supramolecular structures in mixed lipid-peptide monolayers, but their behavior in lipid bilayers remains to be characterized. Using atomic force microscopy, we have examined the interactions of P(alpha), a primary amphipathic cell-penetrating peptide which remains alpha-helical whatever the environment, with dipalmitoylphosphatidylcholine (DPPC) bilayers. Addition of P(alpha) at concentrations up to 5 mol % markedly modified the supported bilayers topography. Long and thin filaments lying flat at the membrane surface coexisted with deeply embedded peptides which induced a local thinning of the bilayer. On the other hand, addition of P(alpha) only exerted very limited effects on the corresponding liposome's bilayer physical state, as estimated from differential scanning calorimetry and diphenylhexatriene fluorescence anisotropy experiments. The use of a gel-fluid phase separated supported bilayers made of a dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine mixture confirmed both the existence of long filaments, which at low peptide concentration were preferentially localized in the fluid phase domains and the membrane disorganizing effects of 5 mol % P(alpha). The simultaneous two-states organization of P(alpha), at the membrane surface and deeply embedded in the bilayer, may be involved in the transmembrane carrier function of this primary amphipathic peptide.

  2. Cell-penetrating peptide-driven Cre recombination in porcine primary cells and generation of marker-free pigs.

    Science.gov (United States)

    Kang, Qianqian; Sun, Zhaolin; Zou, Zhiyuan; Wang, Ming; Li, Qiuyan; Hu, Xiaoxiang; Li, Ning

    2018-01-01

    Cell-penetrating peptides (CPPs) have been increasingly used to deliver various molecules, both in vitro and in vivo. However, there are no reports of CPPs being used in porcine fetal fibroblasts (PFFs). The increased use of transgenic pigs for basic research and biomedical applications depends on the availability of technologies for efficient genetic-modification of PFFs. Here, we report that three CPPs (CPP5, TAT, and R9) can efficiently deliver active Cre recombinase protein into PFFs via an energy-dependent endocytosis pathway. The three CPP-Cre proteins can enter PFFs and subsequently perform recombination with different efficiencies. The recombination efficacy of CPP5-Cre was found to be nearly 90%. The rate-limiting step for CPP-Cre-mediated recombination was the step of endosome escape. HA2 and chloroquine were found to improve the recombination efficiency of TAT-Cre. Furthermore, we successfully obtained marker-free transgenic pigs using TAT-Cre and CPP5-Cre. We provide a framework for the development of CPP-based farm animal transgenic technologies that would be beneficial to agriculture and biomedicine.

  3. Cell-penetrating recombinant peptides for potential use in agricultural pest control applications.

    Science.gov (United States)

    Hughes, Stephen R; Dowd, Patrick F; Johnson, Eric T

    2012-09-28

    Several important areas of interest intersect in a class of peptides characterized by their highly cationic and partly hydrophobic structure. These molecules have been called cell-penetrating peptides (CPPs) because they possess the ability to translocate across cell membranes. This ability makes these peptides attractive candidates for delivery of therapeutic compounds, especially to the interior of cells. Compounds with characteristics similar to CPPs and that, in addition, have antimicrobial properties are being investigated as antibiotics with a reduced risk of causing resistance. These CPP-like membrane-acting antimicrobial peptides (MAMPs) are α-helical amphipathic peptides that interact with and perturb cell membranes to produce their antimicrobial effects. One source of MAMPs is spider venom. Because these compounds are toxic to insects, they also show promise for development as biological agents for control of insecticide-resistant agricultural pests. Spider venom is a potential source of novel insect-specific peptide toxins. One example is the small amphipathic α-helical peptide lycotoxin-1 (Lyt-1 or LCTX) from the wolf spider (Lycosa carolinensis). One side of the α-helix has mostly hydrophilic and the other mainly hydrophobic amino acid residues. The positive charge of the hydrophilic side interacts with negatively charged prokaryotic membranes and the hydrophobic side associates with the membrane lipid bilayer to permeabilize it. Because the surface of the exoskeleton, or cuticle, of an insect is highly hydrophobic, to repel water and dirt, it would be expected that amphipathic compounds could permeabilize it. Mutagenized lycotoxin 1 peptides were produced and expressed in yeast cultures that were fed to fall armyworm (Spodoptera frugiperda) larvae to identify the most lethal mutants. Transgenic expression of spider venom toxins such as lycotoxin-1 in plants could provide durable insect resistance.

  4. Analysis of in vitro toxicity of five cell-penetrating peptides by metabolic profiling

    International Nuclear Information System (INIS)

    Kilk, Kalle; Mahlapuu, Riina; Soomets, Ursel; Langel, Ulo

    2009-01-01

    Cell-penetrating peptides (CPPs) are promising candidates for safe and efficient delivery vectors for a wide range of cargoes. However, any compound that is internalized into cells may affect the cell homeostasis. The plethora of possible biological responses makes large scale 'omics' studies appealing approaches for hunting any unsuspected side-effects and evaluate the toxicity of drug candidates. Here we have compared the alterations in cytosolic metabolome of CHO cells caused by five representatives of the most common CPPs: transportan (TP), penetratin (pAntp), HIV Tat derived peptide (pTat), nonaarginine (R 9 ) and model amphipathic peptide (MAP). Analysis was done by liquid chromatography-mass spectrometry techniques, principal component analysis and heatmap displays. Results showed that the intracellular metabolome was the most affected by TP followed by pTat and MAP. Only minor changes could be associated with pAntp or R 9 treatment. The cells could recover from a treatment with 5 μM TP, but no recovery was observed at higher concentration. Both metabolomic and control experiments showed that TP affected cellular redox potential, depleted energy and the pools of purines and pyrimidines. In conclusion, we have performed a metabolomic analysis comparing the safety of cell-penetrating peptides and demonstrate the toxicity of one of them.

  5. The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures.

    Science.gov (United States)

    Meloni, Bruno P; Craig, Amanda J; Milech, Nadia; Hopkins, Richard M; Watt, Paul M; Knuckey, Neville W

    2014-03-01

    Cell-penetrating peptides (CPPs) are small peptides (typically 5-25 amino acids), which are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids, or drugs into cells. However, several recent studies have demonstrated that the TAT CPP has neuroprotective properties. Therefore, in this study, we assessed the TAT and three other CPPs (penetratin, Arg-9, Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose deprivation). Arg-9, penetratin, and TAT-D displayed consistent and high level neuroprotective activity in both the glutamic acid (IC50: 0.78, 3.4, 13.9 μM) and kainic acid (IC50: 0.81, 2.0, 6.2 μM) injury models, while Pep-1 was ineffective. The TAT-D isoform displayed similar efficacy to the TAT-L isoform in the glutamic acid model. Interestingly, Arg-9 was the only CPP that displayed efficacy when washed-out prior to glutamic acid exposure. Neuroprotection following in vitro ischemia was more variable with all peptides providing some level of neuroprotection (IC50; Arg-9: 6.0 μM, TAT-D: 7.1 μM, penetratin/Pep-1: >10 μM). The positive control peptides JNKI-1D-TAT (JNK inhibitory peptide) and/or PYC36L-TAT (AP-1 inhibitory peptide) were neuroprotective in all models. Finally, in a post-glutamic acid treatment experiment, Arg-9 was highly effective when added immediately after, and mildly effective when added 15 min post-insult, while the JNKI-1D-TAT control peptide was ineffective when added post-insult. These findings demonstrate that different CPPs have the ability to inhibit neurodamaging events/pathways associated with excitotoxic and ischemic injuries. More importantly, they highlight the need to interpret neuroprotection studies when using CPPs as delivery agents with caution. On a positive note, the cytoprotective properties of CPPs suggests they are ideal carrier molecules to

  6. Nanocarriers Conjugated with Cell Penetrating Peptides: New Trojan Horses by Modern Ulysses.

    Science.gov (United States)

    Zappavigna, Silvia; Misso, Gabriella; Falanga, Annarita; Perillo, Emiliana; Novellino, Ettore; Galdiero, Massimiliano; Grieco, Paolo; Caraglia, Michele; Galdiero, Stefania

    Nanomedicine has opened the way to the design of more efficient diagnostics and therapeutics. Moreover, recent literature has illustrated the use of short cationic and/or amphipathic peptides, known as cell-penetrating peptides (CPPs), for mediating advanced drug delivery. CPPs exploit their ability to enter cells and enhance the uptake of many cargoes ranging from small molecules to proteins. The distinctive properties of nanocarriers (NC) based systems provide unforeseen benefits over pure drugs for biomedical applications and constitute a challenging research field particularly focused on imaging and delivery; nonetheless, several problems have to be overcome to make them a viable option in clinic. The use of CPPs improves significantly their delivery to specific intracellular targets and thus readily contributes to their use both for effective tumor therapy and gene therapy. A key issue is related to their mechanism of uptake, because although classical CPPs enhance NCs' uptake, the entry mechanism involves the endocytic pathway, which means that the delivered material is sequestered within vesicles and only a small amount will escape from this environment and reach the desired target. In this review, we will summarize recent advances in the use of CPP for enhanced delivery of nanocarriers, nucleic acids, and drugs, we will discuss their uptake mechanisms and we will describe novel approaches to improve endosomal escape of internalized nanosystems.

  7. Cell-penetrating peptides for drug delivery across membrane barriers

    DEFF Research Database (Denmark)

    Foged, Camilla; Nielsen, Hanne Moerck

    2008-01-01

    During the last decade, cell-penetrating peptides have been investigated for their ability to overcome the plasma membrane barrier of mammalian cells for the intracellular or transcellular delivery of cargoes as diverse as low molecular weight drugs, imaging agents, oligonucleotides, peptides......, proteins and colloidal carriers such as liposomes and polymeric nanoparticles. Their ability to cross biological membranes in a non-disruptive way without apparent toxicity is highly desired for increasing drug bioavailability. This review provides an overview of the application of cell......-penetrating peptides as transmembrane drug delivery agents, according to the recent literature, and discusses critical issues and future challenges in relation to fully understanding the fundamental principles of the cell-penetrating peptide-mediated membrane translocation of cargoes and the exploitation...

  8. Adsorption of amphipathic dendrons on polystyrene nanoparticles.

    Science.gov (United States)

    Sakthivel, T; Florence, A T

    2003-03-18

    Adsorption of dendrons onto nanoparticles may provide new model structures which may be useful in drug and gene delivery. Tritiated amphipathic dendrons having three lipidic (C(14)) chains coupled to branched (dendritic) lysine head groups with 8, 16 or 32 free terminal amino groups have been synthesised by solid phase peptide techniques. The interaction between these tritiated dendrons and 200 nm polystyrene latex nanoparticles was investigated in phosphate buffered saline. The amount of dendron adsorbed increased with increasing concentration of dendrons and then decreased. Maximum adsorption of dendrons per gram of nanoparticles was found to be between 8.2 and 84 x 10(-6)M, the amounts adsorbed being inversely proportional to the number of amino groups present in the molecule. The number of dendron molecules adsorbed per nanoparticle was found to be between 430 and 4421. The degree of adsorption was found to be slightly altered by the temperature. Copyright 2002 Elsevier Science B.V.

  9. Bioportide: an emergent concept of bioactive cell-penetrating peptides

    Czech Academy of Sciences Publication Activity Database

    Howl, J.; Matou-Nasri, S.; West, D. C.; Farquhar, M.; Slaninová, Jiřina; Ostenson, C. G.; Zorko, M.; Ostlund, P.; Kumar, S.; Langel, U.; McKeating, J.; Jones, S.

    2012-01-01

    Roč. 69, č. 17 (2012), s. 2951-2966 ISSN 1420-682X Institutional research plan: CEZ:AV0Z40550506 Keywords : angiogenesis * bioportide * cell-penetrating peptide * second messenger * insulin secretion Subject RIV: CE - Biochemistry Impact factor: 5.615, year: 2012

  10. Interaction of 18-residue peptides derived from amphipathic helical ...

    Indian Academy of Sciences (India)

    Madhsudhan

    interaction of proteins and peptides with membranes (Segrest ... favour surface activity have been described by Eisenberg et ... amphipathicity and propensity for α-helical conformation ..... Membrane destabilisation occurs due to electrostatic.

  11. IFITM3 requires an amphipathic helix for antiviral activity.

    Science.gov (United States)

    Chesarino, Nicholas M; Compton, Alex A; McMichael, Temet M; Kenney, Adam D; Zhang, Lizhi; Soewarna, Victoria; Davis, Matthew; Schwartz, Olivier; Yount, Jacob S

    2017-10-01

    Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that blocks virus fusion with cell membranes. IFITM3 has been suggested to alter membrane curvature and fluidity, though its exact mechanism of action is unclear. Using a bioinformatic approach, we predict IFITM3 secondary structures and identify a highly conserved, short amphipathic helix within a hydrophobic region of IFITM3 previously thought to be a transmembrane domain. Consistent with the known ability of amphipathic helices to alter membrane properties, we show that this helix and its amphipathicity are required for the IFITM3-dependent inhibition of influenza virus, Zika virus, vesicular stomatitis virus, Ebola virus, and human immunodeficiency virus infections. The homologous amphipathic helix within IFITM1 is also required for the inhibition of infection, indicating that IFITM proteins possess a conserved mechanism of antiviral action. We further demonstrate that the amphipathic helix of IFITM3 is required to block influenza virus hemagglutinin-mediated membrane fusion. Overall, our results provide evidence that IFITM proteins utilize an amphipathic helix for inhibiting virus fusion. © 2017 The Authors.

  12. Cell-penetrating antimicrobial peptides - prospectives for targeting intracellular infections

    DEFF Research Database (Denmark)

    Bahnsen, Jesper S; Franzyk, Henrik; Sayers, Edward J

    2015-01-01

    PURPOSE: To investigate the suitability of three antimicrobial peptides (AMPs) as cell-penetrating antimicrobial peptides. METHODS: Cellular uptake of three AMPs (PK-12-KKP, SA-3 and TPk) and a cell-penetrating peptide (penetratin), all 5(6)-carboxytetramethylrhodamine-labeled, were tested in He......La WT cells and analyzed by flow cytometry and confocal microscopy. Furthermore, the effects of the peptides on eukaryotic cell viability as well as their antimicrobial effect were tested. In addition, the disrupting ability of the peptides in the presence of bilayer membranes of different composition...... the cellular viability to an unacceptable degree. TPk showed acceptable uptake efficiency, high antimicrobial activity and relatively low toxicity, and it is the best potential lead peptide for further development....

  13. Antimicrobial and cell-penetrating properties of penetratin analogs

    DEFF Research Database (Denmark)

    Bahnsen, Jesper Søborg; Franzyk, Henrik; Sandberg-Schaal, Anne

    2013-01-01

    Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) show great potential as drug delivery vectors and new antibiotic drug entities, respectively. The current study deals with the properties of a variety of peptide analogs derived from the well-known CPP penetratin as well as octaar......Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) show great potential as drug delivery vectors and new antibiotic drug entities, respectively. The current study deals with the properties of a variety of peptide analogs derived from the well-known CPP penetratin as well...... as octaarginine and different Tat sequences. The effects of peptide length, guanidinium content, and sequence of non-cationic residues were assessed in mammalian and bacterial cells. The arginine (Arg) content in the penetratin analogs was found to influence eukaryotic cell uptake efficiency, antimicrobial...... was similar, the eukaryotic cellular uptake of the shuffled analogs was noticeably lower than for native penetratin. Moreover, a point substitution of Met to Leu in native penetratin had no influence on eukaryotic cellular uptake and antimicrobial effect, and only a minor effect on cytotoxicity, in contrast...

  14. Enhanced mitochondrial degradation of yeast cytochrome c with amphipathic structures.

    Science.gov (United States)

    Chen, Xi; Moerschell, Richard P; Pearce, David A; Ramanan, Durga D; Sherman, Fred

    2005-02-01

    The dispensable N-terminus of iso-1-cytochrome c (iso-1) in the yeast Saccharomyces cerevisiae was replaced by 11 different amphipathic structures. Rapid degradation of the corresponding iso-1 occurred, with the degree of degradation increasing with the amphipathic moments; and this amphipathic-dependent degradation was designated ADD. ADD occurred with the holo-forms in the mitochondria but not as the apo-forms in the cytosol. The extreme mutant type degraded with a half-life of approximately 12 min, whereas the normal iso-1 was stable over hours. ADD was influenced by the rho+/rho- state and by numerous chromosomal genes. Most importantly, ADD appeared to be specifically suppressed to various extents by deletions of any of the YME1, AFG3, or RCA1 genes encoding membrane-associated mitochondrial proteases, probably because the amphipathic structures caused a stronger association with the mitochondrial inner membrane and its associated proteases. The use of ADD assisted in the differentiation of substrates of different mitochondrial degradation pathways.

  15. [Potential of cell penetrating peptides for cell drug delivery].

    Science.gov (United States)

    Poillot, Cathy; De Waard, Michel

    2011-05-01

    The interest of the scientific community for cell penetrating peptides (CPP) has been growing exponentially for these last years, and the list of novel CPP is increasing. These peptides are powerful tools for the delivery of cargoes to their site of action. Indeed, several drugs that cannot translocate through the cell plasma membrane have been successfully delivered into cells when grafted to a CPP. Various cargoes have been linked to CPP, such as oligonucleotides, pharmacologically active drugs, contrast agents for imaging, or nanoparticles as platforms for multigrafting purposes… This review illustrates the fabulous potential of CPP and the diversity of their use, but their most interesting application appears their future clinical use for the treatment of various pathological conditions. © 2011 médecine/sciences - Inserm / SRMS.

  16. Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by fluorescence correlation spectroscopy.

    Science.gov (United States)

    Vasconcelos, Luís; Lehto, Tõnis; Madani, Fatemeh; Radoi, Vlad; Hällbrink, Mattias; Vukojević, Vladana; Langel, Ülo

    2018-02-01

    Peptides able to translocate cell membranes while carrying macromolecular cargo, as cell-penetrating peptides (CPPs), can contribute to the field of drug delivery by enabling the transport of otherwise membrane impermeable molecules. Formation of non-covalent complexes between amphipathic peptides and oligonucleotides is driven by electrostatic and hydrophobic interactions. Here we investigate and quantify the coexistence of distinct molecular species in multiple equilibria, namely peptide monomer, peptide self-aggregates and peptide/oligonucleotide complexes. As a model for the complexes, we used a stearylated peptide from the PepFect family, PF14 and siRNA. PF14 has a cationic part and a lipid part, resembling some characteristics of cationic lipids. Fluorescence correlation spectroscopy (FCS) and fluorescence cross-correlation spectroscopy (FCCS) were used to detect distinct molecular entities in solution and at the plasma membrane of live cells. For that, we labeled the peptide with carboxyrhodamine 6G and the siRNA with Cyanine 5. We were able to detect fluorescent entities with diffusional properties characteristic of the peptide monomer as well as of peptide aggregates and peptide/oligonucleotide complexes. Strategies to avoid peptide adsorption to solid surfaces and self-aggregation were developed and allowed successful FCS measurements in solution and at the plasma membrane. The ratio between the detected molecular species was found to vary with pH, peptide concentration and the proximity to the plasma membrane. The present results suggest that the diverse cellular uptake mechanisms, often reported for amphipathic CPPs, might result from the synergistic effect of peptide monomers, self-aggregates and cargo complexes, distributed unevenly at the plasma membrane. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Electrochemistry of a ferrocene-grafted cell-penetrating peptide

    International Nuclear Information System (INIS)

    Messina, Pierluca; Hallais, Géraldine; Labbé, Eric; Béranger, Marie; Chassaing, Gérard; Lavielle, Solange; Mansuy, Christelle; Buriez, Olivier

    2012-01-01

    A cationic cell-penetrating peptide (CPP) labeled with both a ferrocenyl (Fc) moiety and a biotin (B) was successfully synthesized and investigated by electrochemistry. This original CPP derivative noted as Fc-CPP-B could be electrochemically detected, at a micromolar concentration, at a naked gold bead electrode. The presence of a biotin tag in the Fc-CPP-B complex allowed its complexation with avidin, which was itself tethered to a thiolated self-assembled monolayer. Such an avidin-modified gold surface, characterized by atomic force microscopy (AFM), allowed the immobilization of Fc-CPP-B onto the electrode surface, which greatly enhanced its electrochemical detection. Nevertheless, under these conditions the electrogenerated ferrocenium cation could not be reduced during the backward scan, indicating its unexpected reactivity when tethered within the avidin environment. In terms of detection and redox probe regeneration the best results were obtained at a glassy carbon electrode modified with a cation-exchange polymer. Ion-exchange voltammetry, performed under these conditions, allowed the pre-concentration of the peptide at the electrode surface thanks to the net positive charge of the CPP derivative. Interestingly, the anionic character of the polymer contributed to retain the electrogenerated cation Fc + in the film so that it could be reduced back to its original neutral form during the reverse voltammetric scans.

  18. Internalisation of cell-penetrating peptides into tobacco protoplasts.

    Science.gov (United States)

    Mäe, Maarja; Myrberg, Helena; Jiang, Yang; Paves, Heiti; Valkna, Andres; Langel, Ulo

    2005-05-20

    Cells are protected from the surrounding environment by plasma membrane which is impenetrable for most hydrophilic molecules. In the last 10 years cell-penetrating peptides (CPPs) have been discovered and developed. CPPs enter mammalian cells and carry cargo molecules over the plasma membrane with a molecular weight several times their own. Known transformation methods for plant cells have relatively low efficiency and require improvement. The possibility to use CPPs as potential delivery vectors for internalisation in plant cells has been studied in the present work. We analyse and compare the uptake of the fluorescein-labeled CPPs, transportan, TP10, penetratin and pVEC in Bowes human melanoma cells and Nicotiana tabacum cultivar (cv.) SR-1 protoplasts (plant cells without cell wall). We study the internalisation efficiency of CPPs with fluorescence microscopy, spectrofluorometry and fluorescence-activated cell sorter (FACS). All methods indicate, for the first time, that these CPPs can internalise into N. tabacum cv. SR-1 protoplasts. Transportan has the highest uptake efficacy among the studied peptides, both in mammalian cells and plant protoplast. The internalisation of CPPs by plant protoplasts may open up a new effective method for transfection in plants.

  19. In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides.

    Science.gov (United States)

    Bolhassani, Azam; Jafarzade, Behnaz Sadat; Mardani, Golnaz

    2017-01-01

    The failure of proteins to penetrate mammalian cells or target tumor cells restricts their value as therapeutic tools in a variety of diseases such as cancers. Recently, protein transduction domains (PTDs) or cell penetrating peptides (CPPs) have been shown to promote the delivery of therapeutic proteins or peptides into live cells. The successful delivery of proteins mainly depends on their physicochemical properties. Although, linear cell penetrating peptides are one of the most effective delivery vehicles; but currently, cyclic CPPs has been developed to potently transport bioactive full-length proteins into cells. Up to now, several small protein transduction domains from viral proteins including Tat or VP22 could be fused to other peptides or proteins to entry them in various cell types at a dose-dependent approach. A major disadvantage of PTD-fusion proteins is primary uptake into endosomal vesicles leading to inefficient release of the fusion proteins into the cytosol. Recently, non-covalent complex formation (Chariot) between proteins and CPPs has attracted a special interest to overcome some delivery limitations (e.g., toxicity). Many preclinical and clinical trials of CPP-based delivery are currently under evaluation. Generally, development of more efficient protein transduction domains would significantly increase the potency of protein therapeutics. Moreover, the synergistic or combined effects of CPPs with other delivery systems for protein/peptide drug delivery would promote their therapeutic effects in cancer and other diseases. In this review, we will describe the functions and implications of CPPs for delivering the therapeutic proteins or peptides in preclinical and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Conformational Plasticity of the Cell-Penetrating Peptide SAP As Revealed by Solid-State 19F-NMR and Circular Dichroism Spectroscopies.

    Science.gov (United States)

    Afonin, Sergii; Kubyshkin, Vladimir; Mykhailiuk, Pavel K; Komarov, Igor V; Ulrich, Anne S

    2017-07-13

    The cell-penetrating peptide SAP, which was designed as an amphipathic poly-l-proline helix II (PPII), was suggested to self-assemble into regular fibrils that are relevant for its internalization. Herein we have analyzed the structure of SAP in the membrane-bound state by solid-state 19 F-NMR, which revealed other structural states, in addition to the expected surface-aligned PPII. Trifluoromethyl-bicyclopentyl-glycine (CF 3 -Bpg) and two rigid isomers of trifluoromethyl-4,5-methanoprolines (CF 3 -MePro) were used as labels for 19 F-NMR analysis. The equilibria between different conformations of SAP were studied and were found to be shifted by the substituents at Pro-11. Synchrotron-CD results suggested that substituting Pro-11 by CF 3 -MePro governed the coil-to-PPII equilibrium in solution and in the presence of a lipid bilayer. Using CD and 19 F-NMR, we examined the slow kinetics of the association of SAP with membranes and the dependence of the SAP conformational dynamics on the lipid composition. The peptide did not bind to lipids in the solid ordered phase and aggregated only in the liquid ordered "raft"-like bilayers. Self-association could not be detected in solution or in the presence of liquid disordered membranes. Surface-bound amphipathic SAP in a nonaggregated state was structured as a mixture of nonideal extended conformations reflecting the equilibrium already present in solution, i.e., before binding to the membrane.

  1. Translocation of Cell Penetrating Peptide Engrafted Nanoparticles Across Skin Layers

    Science.gov (United States)

    Patlolla, Ram R; Desai, Pinaki; Belay, Kalayu; Singh, Mandip

    2010-01-01

    The objective of the current study was to evaluate the ability of cell penetrating peptides (CPP) to translocate the lipid payload into the skin layers. Fluorescent dye (DID-oil) encapsulated nano lipid crystal nanoparticles (FNLCN) were prepared using Compritol, Miglyol and DOGS-NTA-Ni lipids by hot melt homogenization technique. The FNLCN surface was coated with TAT peptide (FNLCNT) or control YKA peptide (FNLCNY) and in vitro rat skin permeation studies were performed using Franz diffusion cells. Observation of lateral skin sections obtained using cryotome with a confocal microscope demonstrated that skin permeation of FNLCNT was time dependent and after 24 h, fluorescence was observed upto a depth of 120 µm which was localized in the hair follicles and epidermis. In case of FNLCN and FNLCNY formulations fluorescence was mainly observed in the hair follicles. This observation was further supported by confocal Raman spectroscopy where higher fluorescence signal intensity was observed at 80 and 120 µm depth with FNLCNT treated skin and intensity of fluorescence peaks was in the ratio of 2:1:1 and 5:3:1 for FNLCNT, FNLCN, and FNLCNY treated skin sections, respectively. Furthermore, replacement of DID-oil with celecoxib (Cxb), a model lipophilic drug showed similar results and after 24 h, the CXBNT formulation increased the Cxb concentration in SC by 3 and 6 fold and in epidermis by 2 and 3 fold as compared to CXBN and CXBNY formulations respectively. Our results strongly suggest that CPP can translocate nanoparticles with their payloads into deeper skin layers. PMID:20413152

  2. Translocation of cell-penetrating peptides into Candida fungal pathogens.

    Science.gov (United States)

    Gong, Zifan; Karlsson, Amy J

    2017-09-01

    Cell-penetrating peptides (CPPs) are small peptides capable of crossing cellular membranes while carrying molecular cargo. Although they have been widely studied for their ability to translocate nucleic acids, small molecules, and proteins into mammalian cells, studies of their interaction with fungal cells are limited. In this work, we evaluated the translocation of eleven fluorescently labeled peptides into the important human fungal pathogens Candida albicans and C. glabrata and explored the mechanisms of translocation. Seven of these peptides (cecropin B, penetratin, pVEC, MAP, SynB, (KFF) 3 K, and MPG) exhibited substantial translocation (>80% of cells) into both species in a concentration-dependent manner, and an additional peptide (TP-10) exhibiting strong translocation into only C. glabrata. Vacuoles were involved in translocation and intracellular trafficking of the peptides in the fungal cells and, for some peptides, escape from the vacuoles and localization in the cytosol were correlated to toxicity toward the fungal cells. Endocytosis was involved in the translocation of cecropin B, MAP, SynB, MPG, (KFF) 3 K, and TP-10, and cecropin B, penetratin, pVEC, and MAP caused membrane permeabilization during translocation. These results indicate the involvement of multiple translocation mechanisms for some CPPs. Although high levels of translocation were typically associated with toxicity of the peptides toward the fungal cells, SynB was translocated efficiently into Candida cells at concentrations that led to minimal toxicity. Our work highlights the potential of CPPs in delivering antifungal molecules and other bioactive cargo to Candida pathogens. © 2017 The Protein Society.

  3. Two functional motifs define the interaction, internalization and toxicity of the cell-penetrating antifungal peptide PAF26 on fungal cells.

    Directory of Open Access Journals (Sweden)

    Alberto Muñoz

    Full Text Available The synthetic, cell penetrating hexapeptide PAF26 (RKKWFW is antifungal at low micromolar concentrations and has been proposed as a model for cationic, cell-penetrating antifungal peptides. Its short amino acid sequence facilitates the analysis of its structure-activity relationships using the fungal models Neurospora crassa and Saccharomyces cerevisiae, and human and plant pathogens Aspergillus fumigatus and Penicillium digitatum, respectively. Previously, PAF26 at low fungicidal concentrations was shown to be endocytically internalized, accumulated in vacuoles and then actively transported into the cytoplasm where it exerts its antifungal activity. In the present study, two PAF26 derivatives, PAF95 (AAAWFW and PAF96 (RKKAAA, were designed to characterize the roles of the N-terminal cationic and the C-terminal hydrophobic motifs in PAF26's mode-of-action. PAF95 and PAF96 exhibited substantially reduced antifungal activity against all the fungi analyzed. PAF96 localized to fungal cell envelopes and was not internalized by the fungi. In contrast, PAF95 was taken up into vacuoles of N. crassa, wherein it accumulated and was trapped without toxic effects. Also, the PAF26 resistant Δarg1 strain of S. cerevisiae exhibited increased PAF26 accumulation in vacuoles. Live-cell imaging of GFP-labelled nuclei in A. fumigatus showed that transport of PAF26 from the vacuole to the cytoplasm was followed by nuclear breakdown and dissolution. This work demonstrates that the amphipathic PAF26 possesses two distinct motifs that allow three stages in its antifungal action to be defined: (i its interaction with the cell envelope; (ii its internalization and transport to vacuoles mediated by the aromatic hydrophobic domain; and (iii its transport from vacuoles to the cytoplasm. Significantly, cationic residues in PAF26 are important not only for the electrostatic attraction and interaction with the fungal cell but also for transport from the vacuole to the

  4. Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytes

    KAUST Repository

    Haidar, Malak; de Laté , Perle Latré ; Kennedy, Eileen J.; Langsley, Gordon

    2017-01-01

    One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way

  5. Neutron diffraction studies of amphipathic helices in phospholipid bilayers

    Energy Technology Data Exchange (ETDEWEB)

    Bradshaw, J.P.; Gilchrist, P.J. [Univ. of Edinburgh (United Kingdom); Duff, K.C. [Univ. of Edinburgh Medical School (United Kingdom); Saxena, A.M. [Brookhaven National Laboratory, Upton, NY (United States)

    1994-12-31

    The structural feature which is thought to facilitate the interaction of many peptides with phospholipid bilayers is the ability to fold into an amphipathic helix. In most cases the exact location and orientation of this helix with respect to the membrane is not known, and may vary with factors such as pH and phospholipid content of the bilayer. The growing interest in this area is stimulated by indications that similar interactions can contribute to the binding of certain hormones to their cell-surface receptors. We have been using the techniques of neutron diffraction from stacked phospholipid bilayers in an attempt to investigate this phenomenon with a number of membrane-active peptides. Here we report some of our findings with three of these: the bee venom melittin; the hormone calcitonin; and a synthetic peptide representing the ion channel fragment of influenza A M2 protein.

  6. Neutron diffraction studies of amphipathic helices in phospholipid bilayers

    International Nuclear Information System (INIS)

    Bradshaw, J.P.; Gilchrist, P.J.; Duff, K.C.; Saxena, A.M.

    1994-01-01

    The structural feature which is thought to facilitate the interaction of many peptides with phospholipid bilayers is the ability to fold into an amphipathic helix. In most cases the exact location and orientation of this helix with respect to the membrane is not known, and may vary with factors such as pH and phospholipid content of the bilayer. The growing interest in this area is stimulated by indications that similar interactions can contribute to the binding of certain hormones to their cell-surface receptors. We have been using the techniques of neutron diffraction from stacked phospholipid bilayers in an attempt to investigate this phenomenon with a number of membrane-active peptides. Here we report some of our findings with three of these: the bee venom melittin; the hormone calcitonin; and a synthetic peptide representing the ion channel fragment of influenza A M2 protein

  7. Characterization of the cell penetrating properties of a human salivary proline-rich peptide.

    Science.gov (United States)

    Radicioni, Giorgia; Stringaro, Annarita; Molinari, Agnese; Nocca, Giuseppina; Longhi, Renato; Pirolli, Davide; Scarano, Emanuele; Iavarone, Federica; Manconi, Barbara; Cabras, Tiziana; Messana, Irene; Castagnola, Massimo; Vitali, Alberto

    2015-11-01

    Saliva contains hundreds of small proline-rich peptides most of which derive from the post-translational and post-secretory processing of the acidic and basic salivary proline-rich proteins. Among these peptides we found that a 20 residue proline-rich peptide (p1932), commonly present in human saliva and patented for its antiviral activity, was internalized within cells of the oral mucosa. The cell-penetrating properties of p1932 have been studied in a primary gingival fibroblast cell line and in a squamous cancer cell line, and compared to its retro-inverso form. We observed by mass-spectrometry, flow cytometry and confocal microscopy that both peptides were internalized in the two cell lines on a time scale of minutes, being the natural form more efficient than the retro-inverso one. The cytosolic localization was dependent on the cell type: both peptide forms were able to localize within nuclei of tumoral cells, but not in the nuclei of gingival fibroblasts. The uptake was shown to be dependent on the culture conditions used: peptide internalization was indeed effective in a complete medium than in a serum-free one allowing the hypothesis that the internalization could be dependent on the cell cycle. Both peptides were internalized likely by a lipid raft-mediated endocytosis mechanism as suggested by the reduced uptake in the presence of methyl-ß-cyclodextrin. These results suggest that the natural peptide may play a role within the cells of the oral mucosa after its secretion and subsequent internalization. Furthermore, lack of cytotoxicity of both peptide forms highlights their possible application as novel drug delivery agents.

  8. Role of Cell-Penetrating Peptides in Intracellular Delivery of Peptide Nucleic Acids Targeting Hepadnaviral Replication

    DEFF Research Database (Denmark)

    Ndeboko, Benedicte; Ramamurthy, Narayan; Lemamy, Guy Joseph

    2017-01-01

    Peptide nucleic acids (PNAs) are potentially attractive antisense agents against hepatitis B virus (HBV), although poor cellular uptake limits their therapeutic application. In the duck HBV (DHBV) model, we evaluated different cell-penetrating peptides (CPPs) for delivery to hepatocytes of a PNA...

  9. Self-association of a highly charged arginine-rich cell-penetrating peptide

    Czech Academy of Sciences Publication Activity Database

    Tesei, G.; Vazdar, M.; Jensen, M. R.; Cragnell, C.; Mason, Philip E.; Heyda, J.; Skepö, M.; Jungwirth, Pavel; Lund, M.

    2017-01-01

    Roč. 114, č. 43 (2017), s. 11428-11433 ISSN 0027-8424 R&D Projects: GA ČR(CZ) GA16-01074S Institutional support: RVO:61388963 Keywords : cell-penetrating peptide * self-association * MD simulations * SAXS * NMR Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 9.661, year: 2016

  10. Metabolic cleavage of cell-penetrating peptides in contact with epithelial models

    DEFF Research Database (Denmark)

    Tréhin, Rachel; Nielsen, Hanne Mørck; Jahnke, Heinz-Georg

    2004-01-01

    We assessed the metabolic degradation kinetics and cleavage patterns of some selected CPP (cell-penetrating peptides) after incubation with confluent epithelial models. Synthesis of N-terminal CF [5(6)-carboxyfluorescein]-labelled CPP, namely hCT (human calcitonin)-derived sequences, Tat(47-57) a...

  11. Translocation of cell penetrating peptides and calcium-induced membrane fusion share same mechanism

    Czech Academy of Sciences Publication Activity Database

    Magarkar, Aniket; Allolio, Christoph; Jurkiewicz, Piotr; Baxová, Katarína; Šachl, Radek; Horinek, D.; Heinz, V.; Rachel, R.; Ziegler, C.; Jungwirth, Pavel

    2017-01-01

    Roč. 46, Suppl 1 (2017), S386 ISSN 0175-7571. [IUPAB congress /19./ and EBSA congress /11./. 16.07.2017-20.07.2017, Edinburgh] Institutional support: RVO:61388963 ; RVO:61388955 Keywords : membrane interactions * membrane fusion * cell penetration Subject RIV: BO - Biophysics

  12. Improving cell penetration of helical peptides stabilized by N-terminal crosslinked aspartic acids.

    Science.gov (United States)

    Zhao, Hui; Jiang, Yanhong; Tian, Yuan; Yang, Dan; Qin, Xuan; Li, Zigang

    2017-01-04

    Cell penetration and nucleus translocation efficiency are important for the cellular activities of peptide therapeutics. For helical peptides stabilized by N-terminal crosslinked aspartic acid, correlations between their penetration efficiency/nucleus translocation and physicochemical properties were studied. An increase in hydrophobicity and isoelectric point will promote cellular uptake and nucleus translocation of stabilized helices.

  13. The uptake of arginine-rich cell-penetrating peptides: putting the puzzle together

    NARCIS (Netherlands)

    Brock, R.E.

    2014-01-01

    Over the past 20 years, cell-penetrating peptides (CPPs) have captured the attention of biomedical researchers, biophysicists, and (bio)organic chemists. These molecules efficiently enter cells and mediate entry of (macro)molecules that by themselves do not cross the plasma membrane. Since their

  14. Polymeric pH nanosensor with extended measurement range bearing octaarginine as cell penetrating peptide

    DEFF Research Database (Denmark)

    Ke, Peng; Sun, Honghao; Liu, Mingxing

    2016-01-01

    A synthetic peptide octaarginine which mimics human immunodeficiency virus-1, Tat protein is used as cell penetrating moiety for new pH nanosensors which demonstrate enhanced cellular uptake and expanded measurement range from pH 3.9 to pH 7.3 by simultaneously incorporating two complemental pH-s......H-sensitive fluorophores in a same nanoparticle. The authors believe that this triple fluorescent pH sensor provides a new tool to pH measurements that can have application in cellular uptake mechanism study and new nanomedicine design.......A synthetic peptide octaarginine which mimics human immunodeficiency virus-1, Tat protein is used as cell penetrating moiety for new pH nanosensors which demonstrate enhanced cellular uptake and expanded measurement range from pH 3.9 to pH 7.3 by simultaneously incorporating two complemental p...

  15. Conformational analysis of Infectious bursal disease virus (IBDV derived cell penetrating peptide (CPP analogs

    Directory of Open Access Journals (Sweden)

    Vinay G. Joshi

    2013-12-01

    Full Text Available Aim: This study was designed to develop peptide analogs of Infectious Bursal Disease (IBD virus VP5 protein segment having cell penetrating ability to improve their interaction with cargo molecule (Nucleic acid without affecting the backbone conformation. Materials and Methods: IBDV VP5 protein segment designated as RATH peptide were synthesized using solid phase peptide synthesis and their solution conformation was elucidated using CD spectroscopy in polar (water and apolar (TFE solvents. Cell penetrating ability of RATH-CONH2 was observed using FITC labeled peptide internalization in to HeLa cells under fluorescent microscopy. The efficacy of RATH analog interactions with nucleic acids was evaluated using FITC labeled oligonucleotides by fluorescence spectroscopy and plasmid constructs in gel retardation assay. Results: CD spectra of RATH analogs in water and apolar trifluroethanol (TFE helped to compare their secondary structures which were almost similar with dominant beta conformations suggesting successful induction of positive charge in the analogs without affecting back bone conformation of CPP designed. Cell penetrating ability of RATH CONH2 in HeLa cell was more than 90%. The fluorescence spectroscopy and plasmid constructs in gel retardation assay demonstrated successful interaction of amide analogs with nucleic acid. Conclusion: Intentional changes made in IBDV derived peptide RATH COOH to RATH CONH2 did not showed major changes in backbone conformation and such modifications may help to improve the cationic charge in most CPPs to interact with nucleic acid. [Vet World 2013; 6(6.000: 307-312

  16. Role of amphipathic helix of a herpesviral protein in membrane deformation and T cell receptor downregulation.

    Directory of Open Access Journals (Sweden)

    Chan-Ki Min

    2008-11-01

    Full Text Available Lipid rafts are membrane microdomains that function as platforms for signal transduction and membrane trafficking. Tyrosine kinase interacting protein (Tip of T lymphotropic Herpesvirus saimiri (HVS is targeted to lipid rafts in T cells and downregulates TCR and CD4 surface expression. Here, we report that the membrane-proximal amphipathic helix preceding Tip's transmembrane (TM domain mediates lipid raft localization and membrane deformation. In turn, this motif directs Tip's lysosomal trafficking and selective TCR downregulation. The amphipathic helix binds to the negatively charged lipids and induces liposome tubulation, the TM domain mediates oligomerization, and cooperation of the membrane-proximal helix with the TM domain is sufficient for localization to lipid rafts and lysosomal compartments, especially the mutivesicular bodies. These findings suggest that the membrane-proximal amphipathic helix and TM domain provide HVS Tip with the unique ability to deform the cellular membranes in lipid rafts and to downregulate TCRs potentially through MVB formation.

  17. Potent inhibition of late stages of hepadnavirus replication by a modified cell penetrating peptide

    DEFF Research Database (Denmark)

    Abdul, Fabien; Ndeboko, Bénédicte; Buronfosse, Thierry

    2012-01-01

    Cationic cell-penetrating peptides (CPPs) and their lipid domain-conjugates (CatLip) are agents for the delivery of (uncharged) biologically active molecules into the cell. Using infection and transfection assays we surprisingly discovered that CatLip peptides were able to inhibit replication...... by confocal laser scanning microscopy indicating severe structural changes of preS/S. Sucrose gradient analysis of supernatants from Deca-(Arg)8-treated cells showed unaffected naked viral nucleocapsids release, which was concomitant with a complete arrest of virion and surface protein-containing subviral...

  18. Cell-Penetrating Ability of Peptide Hormones: Key Role of Glycosaminoglycans Clustering

    Directory of Open Access Journals (Sweden)

    Armelle Tchoumi Neree

    2015-11-01

    Full Text Available Over the last two decades, the potential usage of cell-penetrating peptides (CPPs for the intracellular delivery of various molecules has prompted the identification of novel peptidic identities. However, cytotoxic effects and unpredicted immunological responses have often limited the use of various CPP sequences in the clinic. To overcome these issues, the usage of endogenous peptides appears as an appropriate alternative approach. The hormone pituitary adenylate-cyclase-activating polypeptide (PACAP38 has been recently identified as a novel and very efficient CPP. This 38-residue polycationic peptide is a member of the secretin/glucagon/growth hormone-releasing hormone (GHRH superfamily, with which PACAP38 shares high structural and conformational homologies. In this study, we evaluated the cell-penetrating ability of cationic peptide hormones in the context of the expression of cell surface glycosaminoglycans (GAGs. Our results indicated that among all peptides evaluated, PACAP38 was unique for its potent efficiency of cellular uptake. Interestingly, the abilities of the peptides to reach the intracellular space did not correlate with their binding affinities to sulfated GAGs, but rather to their capacity to clustered heparin in vitro. This study demonstrates that the uptake efficiency of a given cationic CPP does not necessarily correlate with its affinity to sulfated GAGs and that its ability to cluster GAGs should be considered for the identification of novel peptidic sequences with potent cellular penetrating properties.

  19. Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytes

    KAUST Repository

    Haidar, Malak

    2017-09-08

    One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets. Theileria-transformed leukocytes display high PKA activity, but PKAis an enzyme that plays key roles in multiple cellular processes; consequently genetic ablation of kinase activity gives rise to a myriad of confounding phenotypes. By contrast, ablation of a specific kinase-substrate interaction has the potential to give more refined information and we illustrate this here by describing how surgically ablating PKA interactions with BAD gives precise information on the type of glycolysis performed by Theileria-transformed leukocytes. In addition, we provide two other examples of how ablating specific protein-protein interactions in Theileria-infected leukocytes leads to precise phenotypes and argue that constrained penetrating peptides have great therapeutic potential to combat infectious diseases in general.

  20. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

    Institute of Scientific and Technical Information of China (English)

    Tingting Lin; Ergang Liu; Huining He; Meong Cheol Shin; Cheol Moon; Victor C.Yang; Yongzhuo Huang

    2016-01-01

    Brain delivery of macromolecular therapeutics(e.g., proteins) remains an unsolved problem because of the formidable blood–brain barrier(BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs,new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways(e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine(LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides(CPP)have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP–proteins are able to effectively penetrate into the brain after intranasal administration.The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

  1. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

    Directory of Open Access Journals (Sweden)

    Tingting Lin

    2016-07-01

    Full Text Available Brain delivery of macromolecular therapeutics (e.g., proteins remains an unsolved problem because of the formidable blood–brain barrier (BBB. Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs, new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways (e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion, a low molecular weight protamine (LMWP cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides (CPP have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP–proteins are able to effectively penetrate into the brain after intranasal administration. The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

  2. Selective mono-radioiodination and characterization of a cell-penetrating peptide. L-Tyr-maurocalcine

    Energy Technology Data Exchange (ETDEWEB)

    Ahmadi, Mitra; Bacot, Sandrine; Perret, Pascale; Riou, Laurent; Ghezzi, Catherine [Universite Joseph Fourier, Grenoble (France); INSERM U1039, Grenoble (France). Radiopharmaceutiques Biocliniques; Poillot, Cathy; Cestele, Sandrine [INSERM U836, Grenoble (France). Grenoble Inst. of Neuroscience; Universite Joseph Fourier, Grenoble (France); Desruet, Marie-Dominique [INSERM U1039, Grenoble (France). Radiopharmaceutiques Biocliniques; Couvet, Morgane; Bourgoin, Sandrine; Seve, Michel [CRI-INSERM U823, Grenoble (France). Inst. of Albert Bonniot; Universite Joseph Fourier, Grenoble (France); Waard, Michel de [INSERM U836, Grenoble (France). Grenoble Inst. of Neuroscience; Universite Joseph Fourier, Grenoble (France); Smartox Biotechnologies, Grenoble (France)

    2014-07-01

    Mono-and poly-iodinated peptides form frequently during radioiodination procedures. However, the formation of a single species in its mono-iodinated form is essential for quantitative studies such as determination of tissue concentration or image quantification. Therefore, the aim of the present study was to define the optimal experimental conditions in order to exclusively obtain the mono-iodinated form of L-maurocalcine (L-MCa). L-MCa is an animal venom toxin which was shown to act as a cell-penetrating peptide. In order to apply the current direct radioiodination technique using oxidative agents including chloramine T, Iodo-Gen {sup registered} or lactoperoxidase, an analogue of this peptide containing a tyrosine residue (Tyr-L-MCa) was synthesized and was shown to fold/oxidize properly. The enzymatic approach using lactoperoxidase/H{sub 2}O{sub 2} was found to be the best method for radioiodination of Tyr-L-MCa. MALDI-TOF mass spectrometry analyses were then used for identification of the chromatographic eluting components of the reaction mixtures. We observed that the production of different radioiodinated species depended upon the reaction conditions. Our results successfully described the experimental conditions of peptide radioiodination allowing the exclusive production of the mono-iodinated form with high radiochemical purity and without the need for a purification step. Mono-radioiodination of L-Tyr-MCa will be crucial for future quantitative studies, investigating the mechanism of cell penetration and in vivo biodistribution.

  3. Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate.

    Science.gov (United States)

    Wang, Julie T-W; Giuntini, Francesca; Eggleston, Ian M; Bown, Stephen G; MacRobert, Alexander J

    2012-01-30

    Photochemical internalisation (PCI) is a site-specific technique for improving cellular delivery of macromolecular drugs. In this study, a cell penetrating peptide, containing the core HIV-1 Tat 48-57 sequence, conjugated with a porphyrin photosensitiser has been shown to be effective for PCI. Herein we report an investigation of the photophysical and photobiological properties of a water soluble bioconjugate of the cationic Tat peptide with a hydrophobic tetraphenylporphyrin derivative. The cellular uptake and localisation of the amphiphilic bioconjugate was examined in the HN5 human head and neck squamous cell carcinoma cell line. Efficient cellular uptake and localisation in endo/lysosomal vesicles was found using fluorescence detection, and light-induced, rupture of the vesicles resulting in a more diffuse intracellular fluorescence distribution was observed. Conjugation of the Tat sequence with a hydrophobic porphyrin thus enables cellular delivery of an amphiphilic photosensitiser which can then localise in endo/lysosomal membranes, as required for effective PCI treatment. PCI efficacy was tested in combination with a protein toxin, saporin, and a significant reduction in cell viability was measured versus saporin or photosensitiser treatment alone. This study demonstrates that the cell penetrating peptide-photosensitiser bioconjugation strategy is a promising and versatile approach for enhancing the therapeutic potential of bioactive agents through photochemical internalisation. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease.

    Science.gov (United States)

    Dinca, Ana; Chien, Wei-Ming; Chin, Michael T

    2016-02-22

    Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects.

  5. Harnessing the capacity of cell-penetrating peptides for drug delivery to the central nervous system.

    Science.gov (United States)

    Kang, Ting; Gao, Xiaoling; Chen, Jun

    2014-01-01

    The existence of blood-brain barrier (BBB) represents the most formidable challenge for drug delivery to the central nervous system (CNS). Modern breakthrough in biology offers multiple choices for overcoming this barrier but yields modest outcomes for clinical application due to various problems such as safety concerns, insufficient delivery efficiency and poor penetration. Cell penetrating peptides (CPPs) possessing powerful transmembrane capacity have been shown to be effective transport vectors for bioactive molecules and an attractive alternative to traditional active targeting approaches. However, the non-specificity of CPPs has hindered them from targeting a desired site of action. Promisingly, design of novel CPP-mediated nanoparticulate delivery systems with specific targeting property may extricate CPPs from the dilemma. In this review, both the traditional and novel applications of CPPs-based strategies for CNS drug delivery will be discussed.

  6. Visualization of the Nucleolus in Living Cells with Cell-Penetrating Fluorescent Peptides.

    Science.gov (United States)

    Martin, Robert M; Herce, Henry D; Ludwig, Anne K; Cardoso, M Cristina

    2016-01-01

    The nucleolus is the hallmark of nuclear compartmentalization and has been shown to exert multiple roles in cellular metabolism besides its main function as the place of ribosomal RNA synthesis and assembly of ribosomes. The nucleolus plays also a major role in nuclear organization as the largest compartment within the nucleus. The prominent structure of the nucleolus can be detected using contrast light microscopy providing an approximate localization of the nucleolus, but this approach does not allow to determine accurately the three-dimensional structure of the nucleolus in cells and tissues. Immunofluorescence staining with antibodies specific to nucleolar proteins albeit very useful is time consuming, normally antibodies recognize their epitopes only within a small range of species and is applicable only in fixed cells. Here, we present a simple method to selectively and accurately label this ubiquitous subnuclear compartment in living cells of a large range of species using a fluorescently labeled cell-penetrating peptide.

  7. Cell-Penetrating Peptides as Carriers for Oral Delivery of Biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-01-01

    Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa, to a large extent limiting the mode of administration to injections, which is not favouring...... patient compliance. Nevertheless, cell-penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this minireview highlights recent knowledge gained within the field of CPP-mediated transepithelial delivery of therapeutic peptides and proteins from the intestine...... is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP-mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed...

  8. Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-01-01

    Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary...... routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging. CPPs act as transepithelial delivery vectors, but the mechanism...... understanding, documentation of CPP-mediated delivery in higher animal species than rodent as well as extensive toxicological studies are necessary for CPP-containing non-injectable DDSs to reach the clinic....

  9. Sensing lymphoma cells based on a cell-penetrating/apoptosis-inducing/electron-transfer peptide probe

    International Nuclear Information System (INIS)

    Sugawara, Kazuharu; Shinohara, Hiroki; Kadoya, Toshihiko; Kuramitz, Hideki

    2016-01-01

    To electrochemically sense lymphoma cells (U937), we fabricated a multifunctional peptide probe that consists of cell-penetrating/apoptosis-inducing/electron-transfer peptides. Electron-transfer peptides derive from cysteine residue combined with the C-terminals of four tyrosine residues (Y_4). A peptide whereby Y_4C is bound to the C-terminals of protegrin 1 (RGGRLCYCRRRFCVCVGR-NH_2) is known to be an apoptosis-inducing agent against U937 cells, and is referred to as a peptide-1 probe. An oxidation response of the peptide-1 probe has been observed due to a phenolic hydroxyl group, and this response is decreased by the uptake of the peptide probe into the cells. To improve the cell membrane permeability against U937 cells, the RGGR at the N-terminals of the peptide-1 probe was replaced by RRRR (peptide-2 probe). In contrast, RNRCKGTDVQAWY_4C (peptide-3 probe), which recognizes ovalbumin, was constructed as a control. Compared with the other probes, the change in the peak current of the peptide-2 probe was the greatest at low concentrations and occurred in a short amount of time. Therefore, the cell membrane permeability of the peptide-2 probe was increased based on the arginine residues and the apoptosis-inducing peptides. The peak current was linear and ranged from 100 to 1000 cells/ml. The relative standard deviation of 600 cells/ml was 5.0% (n = 5). Furthermore, the membrane permeability of the peptide probes was confirmed using fluorescent dye. - Highlights: • We constructed a multifunctional peptide probe for the electrochemical sensing of lymphoma cells. • The peptide probe consists of cell-penetrating/apoptosis-inducing/electron-transfer peptides. • The electrode response of the peptide probe changes due to selective uptake into the cells.

  10. Sensing lymphoma cells based on a cell-penetrating/apoptosis-inducing/electron-transfer peptide probe

    Energy Technology Data Exchange (ETDEWEB)

    Sugawara, Kazuharu, E-mail: kzsuga@maebashi-it.ac.jp [Maebashi Institute of Technology, Gunma 371-0816 (Japan); Shinohara, Hiroki; Kadoya, Toshihiko [Maebashi Institute of Technology, Gunma 371-0816 (Japan); Kuramitz, Hideki [Department of Environmental Biology and Chemistry, Graduate School of Science and Engineering for Research, University of Toyama, Toyama 930-8555 (Japan)

    2016-06-14

    To electrochemically sense lymphoma cells (U937), we fabricated a multifunctional peptide probe that consists of cell-penetrating/apoptosis-inducing/electron-transfer peptides. Electron-transfer peptides derive from cysteine residue combined with the C-terminals of four tyrosine residues (Y{sub 4}). A peptide whereby Y{sub 4}C is bound to the C-terminals of protegrin 1 (RGGRLCYCRRRFCVCVGR-NH{sub 2}) is known to be an apoptosis-inducing agent against U937 cells, and is referred to as a peptide-1 probe. An oxidation response of the peptide-1 probe has been observed due to a phenolic hydroxyl group, and this response is decreased by the uptake of the peptide probe into the cells. To improve the cell membrane permeability against U937 cells, the RGGR at the N-terminals of the peptide-1 probe was replaced by RRRR (peptide-2 probe). In contrast, RNRCKGTDVQAWY{sub 4}C (peptide-3 probe), which recognizes ovalbumin, was constructed as a control. Compared with the other probes, the change in the peak current of the peptide-2 probe was the greatest at low concentrations and occurred in a short amount of time. Therefore, the cell membrane permeability of the peptide-2 probe was increased based on the arginine residues and the apoptosis-inducing peptides. The peak current was linear and ranged from 100 to 1000 cells/ml. The relative standard deviation of 600 cells/ml was 5.0% (n = 5). Furthermore, the membrane permeability of the peptide probes was confirmed using fluorescent dye. - Highlights: • We constructed a multifunctional peptide probe for the electrochemical sensing of lymphoma cells. • The peptide probe consists of cell-penetrating/apoptosis-inducing/electron-transfer peptides. • The electrode response of the peptide probe changes due to selective uptake into the cells.

  11. Amphipathic motifs in BAR domains are essential for membrane curvature sensing

    DEFF Research Database (Denmark)

    Bhatia, Vikram K; Madsen, Kenneth L; Bolinger, Pierre-Yves

    2009-01-01

    BAR (Bin/Amphiphysin/Rvs) domains and amphipathic alpha-helices (AHs) are believed to be sensors of membrane curvature thus facilitating the assembly of protein complexes on curved membranes. Here, we used quantitative fluorescence microscopy to compare the binding of both motifs on single...... nanosized liposomes of different diameters and therefore membrane curvature. Characterization of members of the three BAR domain families showed surprisingly that the crescent-shaped BAR dimer with its positively charged concave face is not able to sense membrane curvature. Mutagenesis on BAR domains showed...... that membrane curvature sensing critically depends on the N-terminal AH and furthermore that BAR domains sense membrane curvature through hydrophobic insertion in lipid packing defects and not through electrostatics. Consequently, amphipathic motifs, such as AHs, that are often associated with BAR domains...

  12. Alternative Mechanisms for the Interaction of the Cell-Penetrating Peptides Penetratin and the TAT Peptide with Lipid Bilayers

    NARCIS (Netherlands)

    Yesylevskyy, Semen; Marrink, Siewert-Jan; Mark, Alan E.

    2009-01-01

    Cell-penetrating peptides (CPPs) have recently attracted much interest due to their apparent ability to penetrate cell membranes in an energy-independent manner. Here molecular-dynamics simulation techniques were used to study the interaction of two CPPs: penetratin and the TAT peptide with

  13. Recent in vivo advances in cell-penetrating peptide-assisted drug delivery.

    Science.gov (United States)

    Kurrikoff, Kaido; Gestin, Maxime; Langel, Ülo

    2016-01-01

    Delivery of macromolecular drugs is an important field in medical research. However, macromolecules are usually unable to cross the cell membrane without the assistance of a delivery system. Cell penetrating peptides (CPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into the cytosol or nucleus. In addition to macromolecular delivery, CPPs have been used to deliver smaller bioactive molecules. Therefore CPPs have become an intensive field of research for medical treatment. In this review, we highlight studies that include CPP in vivo disease models. We review different strategies and approaches that have been used, with specific attention on recent publications. The approaches that have been used include CPP-cargo covalent conjugation strategies and nanoparticle strategies. Various additional strategies have been used to achieve disease targeting, including active targeting, passive targeting, and combined active/passive strategies. As a result, delivery of various types of molecule has been achieved, including small drug molecules, proteins and nucleic acid-based macromolecules (e.g. siRNA, antisense nucleotides and plasmid DNA). Despite recent advances in the field, confusions surrounding CPP internalization mechanisms and intracellular trafficking are hindering the development of new and more efficient vectors. Nevertheless, the recent increase in the number of publications containing in vivo CPP utilization looks promising that the number of clinical trials would also increase in the near future.

  14. Brain delivery of insulin boosted by intranasal coadministration with cell-penetrating peptides.

    Science.gov (United States)

    Kamei, Noriyasu; Takeda-Morishita, Mariko

    2015-01-10

    Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape.

    Science.gov (United States)

    Salomone, Fabrizio; Cardarelli, Francesco; Di Luca, Mariagrazia; Boccardi, Claudia; Nifosì, Riccardo; Bardi, Giuseppe; Di Bari, Lorenzo; Serresi, Michela; Beltram, Fabio

    2012-11-10

    Efficient endocytosis into a wide range of target cells and low toxicity make the arginine-rich Tat peptide (Tat(11): YGRKKRRQRRR, residues 47-57 of HIV-1 Tat protein) an excellent transporter for delivery purposes. Unfortunately, molecules taken up by endocytosis undergo endosomal entrapment and possible metabolic degradation. Escape from the endosome is therefore actively researched. In this context, antimicrobial peptides (AMPs) provide viable templates for the design of new membrane-disruptive motifs. In particular the Cecropin-A and Melittin hybrids (CMs) are among the smallest and most effective peptides with membrane-perturbing abilities. Here we present a novel chimeric peptide in which the Tat(11) motif is fused to the CM(18) hybrid (KWKLFKKIGAVLKVLTTG, residues 1-7 of Cecropin-A and 2-12 of Melittin). When administered to cells, CM(18)-Tat(11) combines the two desired functionalities: efficient uptake and destabilization of endocytotic-vesicle membranes. We show that this chimeric peptide effectively increases cargo-molecule cytoplasm availability and allows the subsequent intracellular localization of diverse membrane-impermeable molecules (i.e. Tat(11)-EGFP fusion protein, calcein, dextrans, and plasmidic DNA) with no detectable cytotoxicity. The present results open the way to the rational engineering of "modular" cell-penetrating peptides (CPPs) that combine (i) efficient translocation from the extracellular milieu into vesicles and (ii) efficient release of molecules from vesicles into the cytoplasm. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Xue; Lin, Congcong; Lu, Aiping; Lin, Ge; Chen, Huoji; Liu, Qiang; Yang, Zhijun; Zhang, Hongqi

    2017-11-01

    A main hurdle for the success of tumor-specific liposomes is their inability to penetrate tumors efficiently. In this study, we incorporated a cell-penetrating peptide BR2 onto the surface of a liposome loaded with the anticancer drug cantharidin (CTD) to create a system targeting hepatocellular carcinoma (HCC) cells more efficiently and effectively. The in vitro cytotoxicity assay comparing the loaded liposomes' effects on hepatocellular cancer HepG2 and the control Miha cells showed that CTD-loaded liposomes had a stronger anticancer effect after BR2 modification. The cellular uptake results of HepG2 and Miha cells further confirmed the superior ability of BR2-modified liposomes to penetrate cancer cells. The colocalization study revealed that BR2-modified liposomes could enter tumor cells and subsequently release drugs. A higher efficiency of delivery by BR2 liposomes as compared to unmodified liposomes was evident by evaluation of the HepG2 tumor spheroids penetration and inhibition. The biodistribution studies and anticancer efficacy results in vivo showed the significant accumulation of BR2-modified liposomes into tumor sites and an enhanced tumor inhibition. In conclusion, BR2-modified liposomes improve the anticancer potency of drugs for HCC.

  17. Biofunctionalized nanoparticles with pH-responsive and cell penetrating blocks for gene delivery

    International Nuclear Information System (INIS)

    Gaspar, V M; Marques, J G; Sousa, F; Queiroz, J A; Correia, I J; Louro, R O

    2013-01-01

    Bridging the gap between nanoparticulate delivery systems and translational gene therapy is a long sought after requirement in nanomedicine-based applications. However, recent developments regarding nanoparticle functionalization have brought forward the ability to synthesize materials with biofunctional moieties that mimic the evolved features of viral particles. Herein we report the versatile conjugation of both cell penetrating arginine and pH-responsive histidine moieties into the chitosan polymeric backbone, to improve the physicochemical characteristics of the native material. Amino acid coupling was confirmed by 2D TOCSY NMR and Fourier transform infrared spectroscopy. The synthesized chitosan–histidine–arginine (CH–H–R) polymer complexed plasmid DNA biopharmaceuticals, and spontaneously assembled into stable 105 nm nanoparticles with spherical morphology and positive surface charge. The functionalized delivery systems were efficiently internalized into the intracellular compartment, and exhibited remarkably higher transfection efficiency than unmodified chitosan without causing any cytotoxic effect. Additional findings regarding intracellular trafficking events reveal their preferential escape from degradative lysosomal pathways and nuclear localization. Overall, this assembly of nanocarriers with bioinspired moieties provides the foundations for the design of efficient and customizable materials for cancer gene therapy. (paper)

  18. Manipulation of Cell Cycle and Chromatin Configuration by Means of Cell-Penetrating Geminin.

    Directory of Open Access Journals (Sweden)

    Yoshinori Ohno

    Full Text Available Geminin regulates chromatin remodeling and DNA replication licensing which play an important role in regulating cellular proliferation and differentiation. Transcription of the Geminin gene is regulated via an E2F-responsive region, while the protein is being closely regulated by the ubiquitin-proteasome system. Our objective was to directly transduce Geminin protein into cells. Recombinant cell-penetrating Geminin (CP-Geminin was generated by fusing Geminin with a membrane translocating motif from FGF4 and was efficiently incorporated into NIH 3T3 cells and mouse embryonic fibroblasts. The withdrawal study indicated that incorporated CP-Geminin was quickly reduced after removal from medium. We confirmed CP-Geminin was imported into the nucleus after incorporation and also that the incorporated CP-Geminin directly interacted with Cdt1 or Brahma/Brg1 as the same manner as Geminin. We further demonstrated that incorporated CP-Geminin suppressed S-phase progression of the cell cycle and reduced nuclease accessibility in the chromatin, probably through suppression of chromatin remodeling, indicating that CP-Geminin constitutes a novel tool for controlling chromatin configuration and the cell cycle. Since Geminin has been shown to be involved in regulation of stem cells and cancer cells, CP-Geminin is expected to be useful for elucidating the role of Geminin in stem cells and cancer cells, and for manipulating their activity.

  19. Antibacterial Effects of a Cell-Penetrating Peptide Isolated from Kefir.

    Science.gov (United States)

    Miao, Jianyin; Guo, Haoxian; Chen, Feilong; Zhao, Lichao; He, Liping; Ou, Yangwen; Huang, Manman; Zhang, Yi; Guo, Baoyan; Cao, Yong; Huang, Qingrong

    2016-04-27

    Kefir is a traditional fermented milk beverage used throughout the world for centuries. A cell-penetrating peptide, F3, was isolated from kefir by Sephadex G-50 gel filtration, DEAE-52 ion exchange, and reverse-phase high-performance liquid chromatography. F3 was determined to be a low molecular weight peptide containing one leucine and one tyrosine with two phosphate radicals. This peptide displayed antimicrobial activity across a broad spectrum of organisms including several Gram-positive and Gram-negative bacteria as well as fungi, with minimal inhibitory concentration (MIC) values ranging from 125 to 500 μg/mL. Cellular penetration and accumulation of F3 were determined by confocal laser scanning microscopy. The peptide was able to penetrate the cellular membrane of Escherichia coli and Staphylococcus aureus. Changes in cell morphology were observed by scanning electron microscopy (SEM). The results indicate that peptide F3 may be a good candidate for use as an effective biological preservative in agriculture and the food industry.

  20. Efficient Cargo Delivery into Adult Brain Tissue Using Short Cell-Penetrating Peptides.

    Directory of Open Access Journals (Sweden)

    Caghan Kizil

    Full Text Available Zebrafish brains can regenerate lost neurons upon neurogenic activity of the radial glial progenitor cells (RGCs that reside at the ventricular region. Understanding the molecular events underlying this ability is of great interest for translational studies of regenerative medicine. Therefore, functional analyses of gene function in RGCs and neurons are essential. Using cerebroventricular microinjection (CVMI, RGCs can be targeted efficiently but the penetration capacity of the injected molecules reduces dramatically in deeper parts of the brain tissue, such as the parenchymal regions that contain the neurons. In this report, we tested the penetration efficiency of five known cell-penetrating peptides (CPPs and identified two- polyR and Trans - that efficiently penetrate the brain tissue without overt toxicity in a dose-dependent manner as determined by TUNEL staining and L-Plastin immunohistochemistry. We also found that polyR peptide can help carry plasmid DNA several cell diameters into the brain tissue after a series of coupling reactions using DBCO-PEG4-maleimide-based Michael's addition and azide-mediated copper-free click reaction. Combined with the advantages of CVMI, such as rapidness, reproducibility, and ability to be used in adult animals, CPPs improve the applicability of the CVMI technique to deeper parts of the central nervous system tissues.

  1. Cell penetrating peptide-modified poly(lactic-co-glycolic acid) nanoparticles with enhanced cell internalization.

    Science.gov (United States)

    Steinbach, Jill M; Seo, Young-Eun; Saltzman, W Mark

    2016-01-01

    The surface modification of nanoparticles (NPs) can enhance the intracellular delivery of drugs, proteins, and genetic agents. Here we studied the effect of different surface ligands, including cell penetrating peptides (CPPs), on the cell binding and internalization of poly(lactic-co-glycolic) (PLGA) NPs. Relative to unmodified NPs, we observed that surface-modified NPs greatly enhanced cell internalization. Using one CPP, MPG (unabbreviated notation), that achieved the highest degree of internalization at both low and high surface modification densities, we evaluated the effect of two different NP surface chemistries on cell internalization. After 2h, avidin-MPG NPs enhanced cellular internalization by 5 to 26-fold relative to DSPE-MPG NP formulations. Yet, despite a 5-fold increase in MPG density on DSPE compared to Avidin NPs, both formulations resulted in similar internalization levels (48 and 64-fold, respectively) after 24h. Regardless of surface modification, all NPs were internalized through an energy-dependent, clathrin-mediated process, and became dispersed throughout the cell. Overall both Avidin- and DSPE-CPP modified NPs significantly increased internalization and offer promising delivery options for applications in which internalization presents challenges to efficacious delivery. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  2. The uptake of arginine-rich cell-penetrating peptides: putting the puzzle together.

    Science.gov (United States)

    Brock, Roland

    2014-05-21

    Over the past 20 years, cell-penetrating peptides (CPPs) have captured the attention of biomedical researchers, biophysicists, and (bio)organic chemists. These molecules efficiently enter cells and mediate entry of (macro)molecules that by themselves do not cross the plasma membrane. Since their discovery, models on the mechanism by which uptake occurs have seen major revisions. Starting from direct penetration across the plasma membrane, it later became apparent that for large molecular weight cargos in particular, endocytosis plays a role in uptake and furthermore that the route of uptake is a function of CPP, cell-type, cargo, and concentration. For the class of arginine-rich CPPs, this dependence on conditions has been elucidated in particular. As I will discuss here for this class of CPPs, a downside of this multitude of possibilities has been a lack of attention for commonalities in the observation of apparently distinct phenomena. At the same time, differences of apparently similar observations were not appreciated sufficiently. In addition, there has been insufficient acknowledgment of observations that are incompatible with the proposed models. Nevertheless, a considerable amount of data can be assembled into a quite coherent picture and the data that is left creates the basis for concrete future lines of research to resolve the questions that remain. Moreover, any uptake mechanism has its distinct structure-activity relationship for uptake giving room for the molecular design of molecules to preferentially direct uptake to either of them.

  3. Effects of Tryptophan Content and Backbone Spacing on the Uptake Efficiency of Cell-Penetrating Peptides

    KAUST Repository

    Rydberg, Hanna A.; Matson, Maria; Å mand, Helene L.; Esbjö rner, Elin K.; Nordé n, Bengt

    2012-01-01

    Cell-penetrating peptides (CPPs) are able to traverse cellular membranes and deliver macromolecular cargo. Uptake occurs through both endocytotic and nonendocytotic pathways, but the molecular requirements for efficient internalization are not fully understood. Here we investigate how the presence of tryptophans and their position within an oligoarginine influence uptake mechanism and efficiency. Flow cytometry and confocal fluorescence imaging are used to estimate uptake efficiency, intracellular distribution and toxicity in Chinese hamster ovarian cells. Further, membrane leakage and lipid membrane affinity are investigated. The peptides contain eight arginine residues and one to four tryptophans, the tryptophans positioned either at the N-terminus, in the middle, or evenly distributed along the amino acid sequence. Our data show that the intracellular distribution varies among peptides with different tryptophan content and backbone spacing. Uptake efficiency is higher for the peptides with four tryptophans in the middle, or evenly distributed along the peptide sequence, than for the peptide with four tryptophans at the N-terminus. All peptides display low cytotoxicity except for the one with four tryptophans at the N-terminus, which was moderately toxic. This finding is consistent with their inability to induce efficient leakage of dye from lipid vesicles. All peptides have comparable affinities for lipid vesicles, showing that lipid binding is not a decisive parameter for uptake. Our results indicate that tryptophan content and backbone spacing can affect both the CPP uptake efficiency and the CPP uptake mechanism. The low cytotoxicity of these peptides and the possibilities of tuning their uptake mechanism are interesting from a therapeutic point of view. © 2012 American Chemical Society.

  4. Effects of Tryptophan Content and Backbone Spacing on the Uptake Efficiency of Cell-Penetrating Peptides

    KAUST Repository

    Rydberg, Hanna A.

    2012-07-10

    Cell-penetrating peptides (CPPs) are able to traverse cellular membranes and deliver macromolecular cargo. Uptake occurs through both endocytotic and nonendocytotic pathways, but the molecular requirements for efficient internalization are not fully understood. Here we investigate how the presence of tryptophans and their position within an oligoarginine influence uptake mechanism and efficiency. Flow cytometry and confocal fluorescence imaging are used to estimate uptake efficiency, intracellular distribution and toxicity in Chinese hamster ovarian cells. Further, membrane leakage and lipid membrane affinity are investigated. The peptides contain eight arginine residues and one to four tryptophans, the tryptophans positioned either at the N-terminus, in the middle, or evenly distributed along the amino acid sequence. Our data show that the intracellular distribution varies among peptides with different tryptophan content and backbone spacing. Uptake efficiency is higher for the peptides with four tryptophans in the middle, or evenly distributed along the peptide sequence, than for the peptide with four tryptophans at the N-terminus. All peptides display low cytotoxicity except for the one with four tryptophans at the N-terminus, which was moderately toxic. This finding is consistent with their inability to induce efficient leakage of dye from lipid vesicles. All peptides have comparable affinities for lipid vesicles, showing that lipid binding is not a decisive parameter for uptake. Our results indicate that tryptophan content and backbone spacing can affect both the CPP uptake efficiency and the CPP uptake mechanism. The low cytotoxicity of these peptides and the possibilities of tuning their uptake mechanism are interesting from a therapeutic point of view. © 2012 American Chemical Society.

  5. Secondary structure of cell-penetrating peptides during interaction with fungal cells.

    Science.gov (United States)

    Gong, Zifan; Ikonomova, Svetlana P; Karlsson, Amy J

    2018-03-01

    Cell-penetrating peptides (CPPs) are peptides that cross cell membranes, either alone or while carrying molecular cargo. Although their interactions with mammalian cells have been widely studied, much less is known about their interactions with fungal cells, particularly at the biophysical level. We analyzed the interactions of seven CPPs (penetratin, Pep-1, MPG, pVEC, TP-10, MAP, and cecropin B) with the fungal pathogen Candida albicans using experiments and molecular simulations. Circular dichroism (CD) of the peptides revealed a structural transition from a random coil or weak helix to an α-helix occurs for all peptides when the solvent is changed from aqueous to hydrophobic. However, CD performed in the presence of C. albicans cells showed that proximity to the cell membrane is not necessarily sufficient to induce this structural transition, as penetratin, Pep-1, and MPG did not display a structural shift in the presence of cells. Monte Carlo simulations were performed to further probe the molecular-level interaction with the cell membrane, and these simulations suggested that pVEC, TP-10, MAP, and cecropin B strongly penetrate into the hydrophobic domain of the membrane lipid bilayer, inducing a transition to an α-helical conformation. In contrast, penetratin, Pep-1 and MPG remained in the hydrophilic region without a shift in conformation. The experimental data and MC simulations combine to explain how peptide structure affects their interaction with cells and their mechanism of translocation into cells (direct translocation vs. endocytosis). Our work also highlights the utility of combining biophysical experiments, biological experiments, and molecular modeling to understand biological phenomena. © 2017 The Protein Society.

  6. Conjugation to the cell-penetrating peptide TAT potentiates the photodynamic effect of carboxytetramethylrhodamine.

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    Divyamani Srinivasan

    2011-03-01

    Full Text Available Cell-penetrating peptides (CPPs can transport macromolecular cargos into live cells. However, the cellular delivery efficiency of these reagents is often suboptimal because CPP-cargo conjugates typically remain trapped inside endosomes. Interestingly, irradiation of fluorescently labeled CPPs with light increases the release of the peptide and its cargos into the cytosol. However, the mechanism of this phenomenon is not clear. Here we investigate the molecular basis of the photo-induced endosomolytic activity of the prototypical CPPs TAT labeled to the fluorophore 5(6-carboxytetramethylrhodamine (TMR.We report that TMR-TAT acts as a photosensitizer that can destroy membranes. TMR-TAT escapes from endosomes after exposure to moderate light doses. However, this is also accompanied by loss of plasma membrane integrity, membrane blebbing, and cell-death. In addition, the peptide causes the destruction of cells when applied extracellularly and also triggers the photohemolysis of red blood cells. These photolytic and photocytotoxic effects were inhibited by hydrophobic singlet oxygen quenchers but not by hydrophilic quenchers.Together, these results suggest that TAT can convert an innocuous fluorophore such as TMR into a potent photolytic agent. This effect involves the targeting of the fluorophore to cellular membranes and the production of singlet oxygen within the hydrophobic environment of the membranes. Our findings may be relevant for the design of reagents with photo-induced endosomolytic activity. The photocytotoxicity exhibited by TMR-TAT also suggests that CPP-chromophore conjugates could aid the development of novel Photodynamic Therapy agents.

  7. The synthesis of amphipathic prodrugs of 1,2-diol drugs with saccharide conjugates by high regioselective enzymatic protocol.

    Science.gov (United States)

    Quan, Jing; Chen, Zhichun; Han, Chengyou; Lin, Xianfu

    2007-02-15

    A facile, high regioselective enzymatic synthesis approach for the preparation of amphipathic prodrugs with saccharides of mephenesin and chlorphenesin was developed. Firstly, transesterification of two drugs with divinyl dicarboxylates with different carbon chain length was performed under the catalysis of Candida antarctica lipase acrylic resin and Lipozyme in anhydrous acetone at 50 degrees C, respectively. A series of lipophilic derivatives with vinyl groups of mephenesin and chlorphenesin were prepared. The influences of different organic solvents, enzyme sources, reaction time, and the acylation reagents on the synthesis of vinyl esters were investigated. And then, protease-catalyzed high regioselective acylation of D-glucose and D-mannose with vinyl esters of mephenesin and chlorphenesin gave drug-saccharide derivatives in good yields. The studies of lipophilicity and hydrolysis in vitro of prodrugs verified that drug-saccharide derivatives had amphipathic properties, and both lipophilic and amphipathic drug derivatives had obvious controlled release characteristics.

  8. Paramagnetic particles carried by cell-penetrating peptide tracking of bone marrow mesenchymal stem cells, a research in vitro

    International Nuclear Information System (INIS)

    Liu Min; Guo Youmin; Wu Qifei; Yang Junle; Wang Peng; Wang Sicen; Guo Xiaojuan; Qiang Yongqian; Duan Xiaoyi

    2006-01-01

    The ability to track the distribution and differentiation of stem cells by high-resolution imaging techniques would have significant clinical and research implications. In this study, a model cell-penetrating peptide was used to carry gadolinium particles for magnetic resonance imaging of the mesenchymal stem cells. The mesenchymal stem cells were isolated from rat bone marrow by Percoll and identified by osteogenic differentiation in vitro. The cell-penetrating peptides labeled with fluorescein-5-isothiocyanate and gadolinium were synthesized by a solid-phase peptide synthesis method and the relaxivity of cell-penetrating peptide-gadolinium paramagnetic conjugate on 400 MHz nuclear magnetic resonance was 5.7311 ± 0.0122 mmol -1 s -1 , higher than that of diethylenetriamine pentaacetic acid gadolinium (p < 0.05). Fluorescein imaging confirmed that this new peptide could internalize into the cytoplasm and nucleus. Gadolinium was efficiently internalized into mesenchymal stem cells by the peptide in a time- or concentration-dependent fashion, resulting in intercellular T1 relaxation enhancement, which was obviously detected by 1.5 T magnetic resonance imaging. Cytotoxicity assay and flow cytometric analysis showed the intercellular contrast medium incorporation did not affect cell viability and membrane potential gradient. The research in vitro suggests that the newly constructed peptides could be a vector for tracking mesenchymal stem cells

  9. Lipid Binding of the Amphipathic Helix Serving as Membrane Anchor of Pestivirus Glycoprotein Erns.

    Science.gov (United States)

    Aberle, Daniel; Oetter, Kay-Marcus; Meyers, Gregor

    2015-01-01

    Pestiviruses express a peculiar protein named Erns representing envelope glycoprotein and RNase, which is important for control of the innate immune response and persistent infection. The latter functions are connected with secretion of a certain amount of Erns from the infected cell. Retention/secretion of Erns is most likely controlled by its unusual membrane anchor, a long amphipathic helix attached in plane to the membrane. Here we present results of experiments conducted with a lipid vesicle sedimentation assay able to separate lipid-bound from unbound protein dissolved in the water phase. Using this technique we show that a protein composed of tag sequences and the carboxyterminal 65 residues of Erns binds specifically to membrane vesicles with a clear preference for compositions containing negatively charged lipids. Mutations disturbing the helical folding and/or amphipathic character of the anchor as well as diverse truncations and exchange of amino acids important for intracellular retention of Erns had no or only small effects on the proteins membrane binding. This result contrasts the dramatically increased secretion rates observed for Erns proteins with equivalent mutations within cells. Accordingly, the ratio of secreted versus cell retained Erns is not determined by the lipid affinity of the membrane anchor.

  10. Lipid Binding of the Amphipathic Helix Serving as Membrane Anchor of Pestivirus Glycoprotein Erns.

    Directory of Open Access Journals (Sweden)

    Daniel Aberle

    Full Text Available Pestiviruses express a peculiar protein named Erns representing envelope glycoprotein and RNase, which is important for control of the innate immune response and persistent infection. The latter functions are connected with secretion of a certain amount of Erns from the infected cell. Retention/secretion of Erns is most likely controlled by its unusual membrane anchor, a long amphipathic helix attached in plane to the membrane. Here we present results of experiments conducted with a lipid vesicle sedimentation assay able to separate lipid-bound from unbound protein dissolved in the water phase. Using this technique we show that a protein composed of tag sequences and the carboxyterminal 65 residues of Erns binds specifically to membrane vesicles with a clear preference for compositions containing negatively charged lipids. Mutations disturbing the helical folding and/or amphipathic character of the anchor as well as diverse truncations and exchange of amino acids important for intracellular retention of Erns had no or only small effects on the proteins membrane binding. This result contrasts the dramatically increased secretion rates observed for Erns proteins with equivalent mutations within cells. Accordingly, the ratio of secreted versus cell retained Erns is not determined by the lipid affinity of the membrane anchor.

  11. DNA-interactive properties of crotamine, a cell-penetrating polypeptide and a potential drug carrier.

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    Pei-Chun Chen

    Full Text Available Crotamine, a 42-residue polypeptide derived from the venom of the South American rattlesnake Crotalus durissus terrificus, has been shown to be a cell-penetrating protein that targets chromosomes, carries plasmid DNA into cells, and shows specificity for actively proliferating cells. Given this potential role as a nucleic acid-delivery vector, we have studied in detail the binding of crotamine to single- and double-stranded DNAs of different lengths and base compositions over a range of ionic conditions. Agarose gel electrophoresis and ultraviolet spectrophotometry analysis indicate that complexes of crotamine with long-chain DNAs readily aggregate and precipitate at low ionic strength. This aggregation, which may be important for cellular uptake of DNA, becomes less likely with shorter chain length. 25-mer oligonucleotides do not show any evidence of such aggregation, permitting the determination of affinities and size via fluorescence quenching experiments. The polypeptide binds non-cooperatively to DNA, covering about 5 nucleotide residues when it binds to single (ss or (ds double stranded molecules. The affinities of the protein for ss- vs. ds-DNA are comparable, and inversely proportional to salt levels. Analysis of the dependence of affinity on [NaCl] indicates that there are a maximum of ∼3 ionic interactions between the protein and DNA, with some of the binding affinity attributable to non-ionic interactions. Inspection of the three-dimensional structure of the protein suggests that residues 31 to 35, Arg-Trp-Arg-Trp-Lys, could serve as a potential DNA-binding site. A hexapeptide containing this sequence displayed a lower DNA binding affinity and salt dependence as compared to the full-length protein, likely indicative of a more suitable 3D structure and the presence of accessory binding sites in the native crotamine. Taken together, the data presented here describing crotamine-DNA interactions may lend support to the design of more

  12. BAR domains, amphipathic helices and membrane-anchored proteins use the same mechanism to sense membrane curvature

    DEFF Research Database (Denmark)

    Madsen, Kenneth Lindegaard; Bhatia, V K; Gether, U

    2010-01-01

    /ensemble liposome samples of different mean diameter. Next, we describe two different MCS protein motifs (amphipathic helices and BAR domains) and suggest that in both cases curvature sensitive membrane binding results from asymmetric insertion of hydrophobic amino acids in the lipid membrane. This mechanism can...

  13. Amphipathic lignin derivatives to accelerate simultaneous saccharification and fermentation of unbleached softwood pulp for bioethanol production.

    Science.gov (United States)

    Cheng, Ningning; Yamamoto, Yoko; Koda, Keiichi; Tamai, Yutaka; Uraki, Yasumitsu

    2014-12-01

    Amphipathic lignin derivatives (A-LDs) were already demonstrated to improve enzymatic saccharification of lignocellulose. Based on this knowledge, two kinds of A-LDs prepared from black liquor of soda pulping of Japanese cedar were applied to a fed-batch simultaneous saccharification and fermentation (SSF) process for unbleached soda pulp of Japanese cedar to produce bioethanol. Both lignin derivatives slightly accelerated yeast fermentation of glucose but not inhibited it. In addition, ethanol yields based on the theoretical maximum ethanol production in the fed-batch SSF process was increased from 49% without A-LDs to 64% in the presence of A-LDs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

    Science.gov (United States)

    Suh, Jin Sook; Lee, Jue Yeon; Choi, Yoon Jung; You, Hyung Keun; Hong, Seong-Doo; Chung, Chong Pyoung; Park, Yoon Jeong

    2014-01-01

    Protein-transduction technology has been attempted to deliver macromolecular materials, including protein, nucleic acids, and polymeric drugs, for either diagnosis or therapeutic purposes. Herein, fusion protein composed of an arginine-rich cell-penetrating peptide, termed low-molecular-weight protamine (LMWP), and a transcriptional coactivator with a PDZ-binding motif (TAZ) protein was prepared and applied in combination with biomaterials to increase bone-forming capacity. TAZ has been recently identified as a specific osteogenic stimulating transcriptional coactivator in human mesenchymal stem cell (hMSC) differentiation, while simultaneously blocking adipogenic differentiation. However, TAZ by itself cannot penetrate the cells, and thus needs a transfection tool for translocalization. The LMWP-TAZ fusion proteins were efficiently translocalized into the cytosol of hMSCs. The hMSCs treated with cell-penetrating LMWP-TAZ exhibited increased expression of osteoblastic genes and protein, producing significantly higher quantities of mineralized matrix compared to free TAZ. In contrast, adipogenic differentiation of the hMSCs was blocked by treatment of LMWP-TAZ fusion protein, as reflected by reduced marker-protein expression, adipocyte fatty acid-binding protein 2, and peroxisome proliferator-activated receptor-γ messenger ribonucleic acid levels. LMWP-TAZ was applied in alginate gel for the purpose of localization and controlled release. The LMWP-TAZ fusion protein-loaded alginate gel matrix significantly increased bone formation in rabbit calvarial defects compared with alginate gel matrix mixed with free TAZ protein. The protein transduction of TAZ fused with cell-penetrating LMWP peptide was able selectively to stimulate osteogenesis in vitro and in vivo. Taken together, this fusion protein-transduction technology for osteogenic protein can thus be applied in combination with biomaterials for tissue regeneration and controlled release for tissue

  15.   Cell Penetrating Peptoids (CPPos: Synthesis of a Small Combinatorial Library by Using IRORI MiniKans

    Directory of Open Access Journals (Sweden)

    Dominik K. Kölmel

    2012-11-01

    Full Text Available Cell penetrating peptoids (CPPos are potent mimics of the corresponding cell penetrating peptides (CPPs. The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a “proof of principle” peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached.

  16. A versatile palindromic amphipathic repeat coding sequence horizontally distributed among diverse bacterial and eucaryotic microbes

    Directory of Open Access Journals (Sweden)

    Glass John I

    2010-07-01

    Full Text Available Abstract Background Intragenic tandem repeats occur throughout all domains of life and impart functional and structural variability to diverse translation products. Repeat proteins confer distinctive surface phenotypes to many unicellular organisms, including those with minimal genomes such as the wall-less bacterial monoderms, Mollicutes. One such repeat pattern in this clade is distributed in a manner suggesting its exchange by horizontal gene transfer (HGT. Expanding genome sequence databases reveal the pattern in a widening range of bacteria, and recently among eucaryotic microbes. We examined the genomic flux and consequences of the motif by determining its distribution, predicted structural features and association with membrane-targeted proteins. Results Using a refined hidden Markov model, we document a 25-residue protein sequence motif tandemly arrayed in variable-number repeats in ORFs lacking assigned functions. It appears sporadically in unicellular microbes from disparate bacterial and eucaryotic clades, representing diverse lifestyles and ecological niches that include host parasitic, marine and extreme environments. Tracts of the repeats predict a malleable configuration of recurring domains, with conserved hydrophobic residues forming an amphipathic secondary structure in which hydrophilic residues endow extensive sequence variation. Many ORFs with these domains also have membrane-targeting sequences that predict assorted topologies; others may comprise reservoirs of sequence variants. We demonstrate expressed variants among surface lipoproteins that distinguish closely related animal pathogens belonging to a subgroup of the Mollicutes. DNA sequences encoding the tandem domains display dyad symmetry. Moreover, in some taxa the domains occur in ORFs selectively associated with mobile elements. These features, a punctate phylogenetic distribution, and different patterns of dispersal in genomes of related taxa, suggest that the

  17. A proline-hinge alters the characteristics of the amphipathic α-helical AMPs.

    Science.gov (United States)

    Lee, Jong Kook; Gopal, Ramamourthy; Park, Seong-Cheol; Ko, Hyun Sook; Kim, Yangmee; Hahm, Kyung-Soo; Park, Yoonkyung

    2013-01-01

    HP (2-20) is a 19-aa, amphipathic, α-helical peptide with antimicrobial properties that was derived from the N-terminus of Helicobacter pylori ribosomal protein L1. We previously showed that increasing the net hydrophobicity of HP (2-20) by substituting Trp for Gln(17) and Asp(19) (Anal 3) increased the peptide's antimicrobial activity. In hydrophobic medium, Anal 3 forms an amphipathic structure consisting of an N-terminal random coil region (residues 2-5) and an extended helical region (residues 6-20). To investigate the structure-activity relationship of Anal 3, we substituted Pro for Glu(9) (Anal 3-Pro) and then examined the new peptide's three-dimensional structure, antimicrobial activity and mechanism of action. Anal 3-Pro had an α-helical structure in the presence of trifluoroethanol (TFE) and sodium dodecyl sulfate (SDS). NMR spectroscopic analysis of Anal 3-Pro's tertiary structure in SDS micelles confirmed that the kink potential introduced by Pro(10) was responsible for the helix distortion. We also found that Anal 3-Pro exhibited about 4 times greater antimicrobial activity than Anal 3. Fluorescence activated flow cytometry and confocal fluorescence microscopy showed that incorporating a Pro-hinge into Anal 3 markedly reduced its membrane permeability so that it accumulated in the cytoplasm without remaining in the cell membrane. To investigate the translocation mechanism, we assessed its ability to release of FITC-dextran. The result showed Anal 3-Pro created a pore Candida albicans revealed that Anal 3-Pro and buforin II exert similar effects on cell membranes, whereas magainin 2 exerts a different, more damaging, effect. In addition, Anal 3-Pro assumed a helix-hinge-helix structure in the presence of biological membranes and formed micropores in both bacterial and fungal membranes, through which it entered the cytoplasm and tightly bound to DNA. These results indicate that the bending region of Anal 3- Pro peptide is prerequisite for effective

  18. A proline-hinge alters the characteristics of the amphipathic α-helical AMPs.

    Directory of Open Access Journals (Sweden)

    Jong Kook Lee

    Full Text Available HP (2-20 is a 19-aa, amphipathic, α-helical peptide with antimicrobial properties that was derived from the N-terminus of Helicobacter pylori ribosomal protein L1. We previously showed that increasing the net hydrophobicity of HP (2-20 by substituting Trp for Gln(17 and Asp(19 (Anal 3 increased the peptide's antimicrobial activity. In hydrophobic medium, Anal 3 forms an amphipathic structure consisting of an N-terminal random coil region (residues 2-5 and an extended helical region (residues 6-20. To investigate the structure-activity relationship of Anal 3, we substituted Pro for Glu(9 (Anal 3-Pro and then examined the new peptide's three-dimensional structure, antimicrobial activity and mechanism of action. Anal 3-Pro had an α-helical structure in the presence of trifluoroethanol (TFE and sodium dodecyl sulfate (SDS. NMR spectroscopic analysis of Anal 3-Pro's tertiary structure in SDS micelles confirmed that the kink potential introduced by Pro(10 was responsible for the helix distortion. We also found that Anal 3-Pro exhibited about 4 times greater antimicrobial activity than Anal 3. Fluorescence activated flow cytometry and confocal fluorescence microscopy showed that incorporating a Pro-hinge into Anal 3 markedly reduced its membrane permeability so that it accumulated in the cytoplasm without remaining in the cell membrane. To investigate the translocation mechanism, we assessed its ability to release of FITC-dextran. The result showed Anal 3-Pro created a pore <1.8 nm in diameter, which is similar to buforin II. Notably, scanning electron microscopic observation of Candida albicans revealed that Anal 3-Pro and buforin II exert similar effects on cell membranes, whereas magainin 2 exerts a different, more damaging, effect. In addition, Anal 3-Pro assumed a helix-hinge-helix structure in the presence of biological membranes and formed micropores in both bacterial and fungal membranes, through which it entered the cytoplasm and tightly

  19. Molecular imaging of a cell-penetrating peptide labeled fluorescein-5-isothiocyanate and MR contrast agents: gadopentetate dimeglumine

    International Nuclear Information System (INIS)

    Liu Min; Guo Youmin; Duan Xiaoyi; Guo Xiaojuan; Yang Junle; Xu Min

    2006-01-01

    Objective: To study the value of a new intracellular contrast agent--cell penetrating peptide labeled Fluorescein-5-isothiocyanate (FITC) and MRI contrast agent, Gadopentetate dimeglumine in molecular imaging. Methods: A new cell penetration peptides (CPPs)sequence LAGRRRRRRRRRK were synthesized in solid phase on the base of arginine (9) and were labelled with FITC (CPP 13 -FITC) and Gd - DTPA (CPP 13 -DTPA-Gd). Hepatic carcinoma cell line-HEPG 2 and mouse bone marrow stem cell was respectively stained by CPP 13 -FITC for different time intervals for observing the uptake and intracellular distribution. HEPG 2 in three l00 mm 2 culture plates was respectively incubated with CPP 13 -DTPA-Gd, Gd- DTPA and Dulbecco minimum essential medium for 30 min and imaged by 1.5 T MRI for studying the intracellular uptake and T 1 WI signal characteristics. Results: The peptide was synthesized by the manual solid-phase method successfully. The calculated molecular weight was 1792.78 and the chemical purity was over 95%. By inverted fluorescence microscope, HEPG 2 and mouse stem cell could transport CPP-FITC in cytoplasm and nuclear in 10 min. By MR imaging, CPP-DTPA-Gd could be uptake by HEPG 2 in 30 min and had a short T 1 short T 2 signal, furthermore. T 1 WI signal intensity ratio between in-tube (Ii) and out-tube (Io) in three groups of three scan slices were shown below: Iil/Io of group 1 (Group 1 was the cell incubated by CPP 13 -DTPA-Gd ) respectively was 2.84, 2.60, 2. 48; Iil/Io of group 2 (Group 2 was the cell incubated by DTPA-Gd) respectively is 1.15, 1.11, 1.12; Iil/Io of group 3 (Group 3 was the controled cell ) respectively was 1.15, 1.11, 1.11. By ANVOA analysis, the signal intensity among group 1, group 2 and group 3 had significant difference(F (1,2) = 201.88 P (1,3) =206.37 P (2,3) =0.529 P=0.507). Conclusion: The new constructed cell penetration peptide on the base of the polyargnine can translocate cell by carting FITC and MRI contrast agent-DTPA-Gd and the

  20. Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

    Directory of Open Access Journals (Sweden)

    Suh JS

    2014-03-01

    Full Text Available Jin Sook Suh,1,* Jue Yeon Lee,2,* Yoon Jung Choi,1 Hyung Keun You,3 Seong-Doo Hong,4 Chong Pyoung Chung,2 Yoon Jeong Park1,2 1Dental Regenerative Biotechnology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, 2Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC, Seoul, 3Department of Periodontology, College of Dentistry, Wonkwang University, Iksan, 4Department of Oral Pathology, School of Dentistry, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Protein-transduction technology has been attempted to deliver macromolecular materials, including protein, nucleic acids, and polymeric drugs, for either diagnosis or therapeutic purposes. Herein, fusion protein composed of an arginine-rich cell-penetrating peptide, termed low-molecular-weight protamine (LMWP, and a transcriptional coactivator with a PDZ-binding motif (TAZ protein was prepared and applied in combination with biomaterials to increase bone-forming capacity. TAZ has been recently identified as a specific osteogenic stimulating transcriptional coactivator in human mesenchymal stem cell (hMSC differentiation, while simultaneously blocking adipogenic differentiation. However, TAZ by itself cannot penetrate the cells, and thus needs a transfection tool for translocalization. The LMWP-TAZ fusion proteins were efficiently translocalized into the cytosol of hMSCs. The hMSCs treated with cell-penetrating LMWP-TAZ exhibited increased expression of osteoblastic genes and protein, producing significantly higher quantities of mineralized matrix compared to free TAZ. In contrast, adipogenic differentiation of the hMSCs was blocked by treatment of LMWP-TAZ fusion protein, as reflected by reduced marker-protein expression, adipocyte fatty acid-binding protein 2, and peroxisome proliferator-activated receptor-γ messenger ribonucleic acid levels. LMWP-TAZ was applied in

  1. Cell-Penetrating Peptide as a Means of Directing the Differentiation of Induced-Pluripotent Stem Cells.

    Science.gov (United States)

    Kaitsuka, Taku; Tomizawa, Kazuhito

    2015-11-06

    Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS) cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies.

  2. Peptide nucleic acid (PNA) cell penetrating peptide (CPP) conjugates as carriers for cellular delivery of antisense oligomers

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Nielsen, Peter E

    2012-01-01

    We have explored the merits of a novel delivery strategy for the antisense oligomers based on cell penetrating peptide (CPP) conjugated to a carrier PNA with sequence complementary to part of the antisense oligomer. The effect of these carrier CPP-PNAs was evaluated by using antisense PNA targeting......-PNA (cPNA1(7)-(D-Arg)8) and hexamer carrier decanoyl-CPP-PNA (Deca-cPNA1(6)-(D-Arg)8), respectively, without showing significant additional cellular toxicity. Most interestingly, the activity reached the same level obtained by enhancement with endosomolytic chloroquine (CQ) treatment, suggesting...... that the carrier might facilitate endosomal escape. Furthermore, 50% downregulation of luciferase expression at 60 nM siRNA was obtained using this carrier CPP-PNA delivery strategy (with CQ co-treatment) for a single stranded antisense RNA targeting normal luciferase mRNA. These results indicated that CPP...

  3. Cell-Penetrating Peptide as a Means of Directing the Differentiation of Induced-Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Taku Kaitsuka

    2015-11-01

    Full Text Available Protein transduction using cell-penetrating peptides (CPPs is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies.

  4. Deep Subseafloor Fungi as an Untapped Reservoir of Amphipathic Antimicrobial Compounds.

    Science.gov (United States)

    Navarri, Marion; Jégou, Camille; Meslet-Cladière, Laurence; Brillet, Benjamin; Barbier, Georges; Burgaud, Gaëtan; Fleury, Yannick

    2016-03-10

    The evolving global threat of antimicrobial resistance requires a deep renewal of the antibiotic arsenal including the isolation and characterization of new drugs. Underexplored marine ecosystems may represent an untapped reservoir of novel bioactive molecules. Deep-sea fungi isolated from a record-depth sediment core of almost 2000 m below the seafloor were investigated for antimicrobial activities. This antimicrobial screening, using 16 microbial targets, revealed 33% of filamentous fungi synthesizing bioactive compounds with activities against pathogenic bacteria and fungi. Interestingly, occurrence of antimicrobial producing isolates was well correlated with the complexity of the habitat (in term of microbial richness), as higher antimicrobial activities were obtained at specific layers of the sediment core. It clearly highlights complex deep-sea habitats as chemical battlefields where synthesis of numerous bioactive compounds appears critical for microbial competition. The six most promising deep subseafloor fungal isolates were selected for the production and extraction of bioactive compounds. Depending on the fungal isolates, antimicrobial compounds were only biosynthesized in semi-liquid or solid-state conditions as no antimicrobial activities were ever detected using liquid fermentation. An exception was made for one fungal isolate, and the extraction procedure designed to extract amphipathic compounds was successful and highlighted the amphiphilic profile of the bioactive metabolites.

  5. Effect of a novel amphipathic ionic liquid on lithium deposition in gel polymer electrolytes

    International Nuclear Information System (INIS)

    Choi, Nam-Soon; Koo, Bonjae; Yeon, Jin-Tak; Lee, Kyu Tae; Kim, Dong-Won

    2011-01-01

    Highlights: · Synthesis of a dimeric ionic liquid. · Gel polymer electrolytes providing uniform lithium deposit pathway. · An amphipathic ionic liquid locates at the interface between an electrolyte-rich phase and a polymer matrix in a gel polymer electrolyte. · The presence of PDMITFSI ionic liquid leads to the suppression of dendritic lithium formation on a lithium metal electrode. - Abstract: A novel dimeric ionic liquid based on imidazolium cation and bis(trifluoromethanesulfonyl) imide (TFSI) anion has been synthesized through a metathesis reaction. Its chemical shift values and thermal properties are identified via 1 H nuclear magnetic resonance (NMR) imaging and differential scanning calorimetry (DSC). The effect of the synthesized dimeric ionic liquid on the interfacial resistance of gel polymer electrolytes is described. Differences in the SEM images of lithium electrodes after lithium deposition with and without the 1,1'-pentyl-bis(2,3-dimethylimidazolium) bis(trifluoromethane-sulfonyl)imide (PDMITFSI) ionic liquid in gel polymer electrolytes are clearly discernible. This occurs because the PDMITFSI ionic liquid with hydrophobic moieties and polar groups modulates lithium deposit pathways onto the lithium metal anode. Moreover, high anodic stability for a gel polymer electrolyte with the PDMITFSI ionic liquid was clearly observed.

  6. Amphipaths Differentially Modulate Membrane Surface Deformation in Rat Peritoneal Mast Cells During Exocytosis

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    Itsuro Kazama

    2013-04-01

    Full Text Available Background/Aims: Salicylate and chlorpromazine exert differential effects on the chemokine release from mast cells. Since these drugs are amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membranes, they would induce some morphological changes in mast cells and thus affect the process of exocytosis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of salicylate and chlorpromazine on the membrane capacitance (Cm during exocytosis in rat peritoneal mast cells. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on plasma membrane deformation of the cells. Results: Salicylate dramatically accelerated the GTP-γ-S-induced increase in the Cm immediately after its application, whereas chlorpromazine significantly suppressed the increase. Treatment with salicylate increased the trapping of the dye on the cell surface, while treatment with chlorpromazine completely washed it out, indicating that both drugs induced membrane surface deformation in mast cells. Conclusion: This study demonstrated for the first time that membrane amphipaths, such as salicylate and chlorpromazine, may oppositely modulate the process of exocytosis in mast cells, as detected by the changes in the Cm. The plasma membrane deformation induced by the drugs was thought to be responsible for their differential effects.

  7. Rigid amphipathic fusion inhibitors demonstrate antiviral activity against African swine fever virus.

    Science.gov (United States)

    Hakobyan, Astghik; Galindo, Inmaculada; Nañez, Almudena; Arabyan, Erik; Karalyan, Zaven; Chistov, Alexey A; Streshnev, Philipp P; Korshun, Vladimir A; Alonso, Covadonga; Zakaryan, Hovakim

    2018-01-01

    Rigid amphipathic fusion inhibitors (RAFIs) are a family of nucleoside derivatives that inhibit the infectivity of several enveloped viruses by interacting with virion envelope lipids and inhibiting fusion between viral and cellular membranes. Here we tested the antiviral activity of two RAFIs, 5-(Perylen-3-ylethynyl)-arabino-uridine (aUY11) and 5-(Perylen-3-ylethynyl)uracil-1-acetic acid (cm1UY11) against African swine fever virus (ASFV), for which no effective vaccine is available. Both compounds displayed a potent, dose-dependent inhibitory effect on ASFV infection in Vero cells. The major antiviral effect was observed when aUY11 and cm1UY11 were added at early stages of infection and maintained during the complete viral cycle. Furthermore, virucidal assay revealed a significant extracellular anti-ASFV activity for both compounds. We also found decrease in the synthesis of early and late viral proteins in Vero cells treated with cm1UY11. Finally, the inhibitory effect of aUY11 and cm1UY11 on ASFV infection in porcine alveolar macrophages was confirmed. Overall, our study has identified novel anti-ASFV compounds with potential for future therapeutic developments.

  8. Optimization of simultaneous saccharification and fermentation conditions with amphipathic lignin derivatives for concentrated bioethanol production.

    Science.gov (United States)

    Cheng, Ningning; Koda, Keiichi; Tamai, Yutaka; Yamamoto, Yoko; Takasuka, Taichi E; Uraki, Yasumitsu

    2017-05-01

    Amphipathic lignin derivatives (A-LDs) prepared from the black liquor of soda pulping of Japanese cedar are strong accelerators for bioethanol production under a fed-batch simultaneous enzymatic saccharification and fermentation (SSF) process. To improve the bioethanol production concentration, conditions such as reaction temperature, stirring program, and A-LDs loadings were optimized in both small scale and large scale fed-batch SSF. The fed-batch SSF in the presence of 3.0g/L A-LDs at 38°C gave the maximum ethanol production and a high enzyme recovery rate. Furthermore, a jar-fermenter equipped with a powerful mechanical stirrer was designed for 1.5L-scale fed-batch SSF to achieve rigorous mixing during high substrate loading. Finally, the 1.5L fed-batch SSF with a substrate loading of 30% (w/v) produced a high ethanol concentration of 87.9g/L in the presence of A-LDs under optimized conditions. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Anti-plasmodial action of de novo-designed, cationic, lysine-branched, amphipathic, helical peptides

    Directory of Open Access Journals (Sweden)

    Kaushik Naveen K

    2012-08-01

    Full Text Available Abstract Background A lack of vaccine and rampant drug resistance demands new anti-malarials. Methods In vitro blood stage anti-plasmodial properties of several de novo-designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum using SYBR Green assay. Mechanistic details of anti-plasmodial action were examined by optical/fluorescence microscopy and FACS analysis. Results Unlike the monomeric decapeptides {(Ac-GXRKXHKXWA-NH2 (X = F,ΔF (Fm, ΔFm IC50 >100 μM}, the lysine-branched,dimeric versions showed far greater potency {IC50 (μM Fd 1.5 , ΔFd 1.39}. The more helical and proteolytically stable ΔFd was studied for mechanistic details. ΔFq, a K-K2 dendrimer of ΔFm and (ΔFm2 a linear dimer of ΔFm showed IC50 (μM of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (ΔFd, >20 (ΔFm2 and 10 (ΔFq. FITC-ΔFd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ΔFd binds DNA. Trophozoites and schizonts incubated with ΔFd (2.5 μM egressed anomalously and Band-3 immunostaining revealed them not to be associated with RBC membrane. Prematurely egressed merozoites from peptide-treated cultures were found to be invasion incompetent. Conclusion Good selectivity (>35, good resistance index (1.1 and low cytotoxicity indicate the promise of ΔFd against malaria.

  10. Enhanced Cellular Uptake of Albumin-Based Lyophilisomes when Functionalized with Cell-Penetrating Peptide TAT in HeLa Cells

    NARCIS (Netherlands)

    van Bracht, Etienne; Versteegden, Luuk R. M.; Stolle, Sarah; Verdurmen, Wouter P. R.; Woestenenk, Rob; Raave, Rene; Hafmans, Theo; Oosterwijk, Egbert; Brock, Roland; van Kuppevelt, Toin H.; Daamen, Willeke F.

    2014-01-01

    Lyophilisomes are a novel class of biodegradable proteinaceous nano/micrometer capsules with potential use as drug delivery carrier. Cell-penetrating peptides (CPPs) including the TAT peptide have been successfully implemented for intracellular delivery of a broad variety of cargos including various

  11. Amphipathic α-Helices in Apolipoproteins Are Crucial to the Formation of Infectious Hepatitis C Virus Particles

    Science.gov (United States)

    Nakamura, Shota; Ono, Chikako; Shiokawa, Mai; Yamamoto, Satomi; Motomura, Takashi; Okamoto, Toru; Okuzaki, Daisuke; Yamamoto, Masahiro; Saito, Izumu; Wakita, Takaji; Koike, Kazuhiko; Matsuura, Yoshiharu

    2014-01-01

    Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly. PMID:25502789

  12. Relationships between Cargo, Cell Penetrating Peptides and Cell Type for Uptake of Non-Covalent Complexes into Live Cells

    Directory of Open Access Journals (Sweden)

    Andrea-Anneliese Keller

    2013-02-01

    Full Text Available Modulating signaling pathways for research and therapy requires either suppression or expression of selected genes or internalization of proteins such as enzymes, antibodies, nucleotide binding proteins or substrates including nucleoside phosphates and enzyme inhibitors. Peptides, proteins and nucleotides are transported by fusing or conjugating them to cell penetrating peptides or by formation of non-covalent complexes. The latter is often preferred because of easy handling, uptake efficiency and auto-release of cargo into the live cell. In our studies complexes are formed with labeled or readily detectable cargoes for qualitative and quantitative estimation of their internalization. Properties and behavior of adhesion and suspension vertebrate cells as well as the protozoa Leishmania tarentolae are investigated with respect to proteolytic activity, uptake efficiency, intracellular localization and cytotoxicity. Our results show that peptide stability to membrane-bound, secreted or intracellular proteases varies between different CPPs and that the suitability of individual CPPs for a particular cargo in complex formation by non-covalent interactions requires detailed studies. Cells vary in their sensitivity to increasing concentrations of CPPs. Thus, most cells can be efficiently transduced with peptides, proteins and nucleotides with intracellular concentrations in the low micromole range. For each cargo, cell type and CPP the optimal conditions must be determined separately.

  13. Effect of a Fusion Peptide by Covalent Conjugation of a Mitochondrial Cell-Penetrating Peptide and a Glutathione Analog Peptide

    Directory of Open Access Journals (Sweden)

    Carmine Pasquale Cerrato

    2017-06-01

    Full Text Available Previously, we designed and synthesized a library of mitochondrial antioxidative cell-penetrating peptides (mtCPPs superior to the parent peptide, SS31, to protect mitochondria from oxidative damage. A library of antioxidative glutathione analogs called glutathione peptides (UPFs, exceptional in hydroxyl radical elimination compared with glutathione, were also designed and synthesized. Here, a follow-up study is described, investigating the effects of the most promising members from both libraries on reactive oxidative species scavenging ability. None of the peptides influenced cell viability at the concentrations used. Fluorescence microscopy studies showed that the fluorescein-mtCPP1-UPF25 (mtgCPP internalized into cells, and spectrofluorometric analysis determined the presence and extent of peptide into different cell compartments. mtgCPP has superior antioxidative activity compared with mtCPP1 and UPF25 against H2O2 insult, preventing ROS formation by 2- and 3-fold, respectively. Moreover, we neither observed effects on mitochondrial membrane potential nor production of ATP. These data indicate that mtgCPP is targeting mitochondria, protecting them from oxidative damage, while also being present in the cytosol. Our hypothesis is based on a synergistic effect resulting from the fused peptide. The mitochondrial peptide segment is targeting mitochondria, whereas the glutathione analog peptide segment is active in the cytosol, resulting in increased scavenging ability.

  14. Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide.

    Science.gov (United States)

    Brezden, Anna; Mohamed, Mohamed F; Nepal, Manish; Harwood, John S; Kuriakose, Jerrin; Seleem, Mohamed N; Chmielewski, Jean

    2016-08-31

    Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. For this significant problem to be addressed, a cleavable conjugate of the antibiotic kanamycin and a nonmembrane lytic, broad-spectrum antimicrobial peptide with efficient mammalian cell penetration, P14LRR, was prepared. This approach allows kanamycin to enter mammalian cells as a conjugate linked via a tether that breaks down in the reducing environment within cells. Potent antimicrobial activity of the P14KanS conjugate was demonstrated in vitro, and this reducible conjugate effectively cleared intracellular pathogenic bacteria within macrophages more potently than that of a conjugate lacking the disulfide moiety. Notably, successful clearance of Mycobacterium tuberculosis within macrophages was observed with the dual antibiotic conjugate, and Salmonella levels were significantly reduced in an in vivo Caenorhabditis elegans model.

  15. Synthesis and in vitro evaluation of PNA-peptide-DETA conjugates as potential cell penetrating artificial ribonucleases.

    Science.gov (United States)

    Petersen, Lene; de Koning, Martijn C; van Kuik-Romeijn, Petra; Weterings, Jimmy; Pol, Christine J; Platenburg, Gerard; Overhand, Mark; van der Marel, Gijsbert A; van Boom, Jacques H

    2004-01-01

    We report the synthesis of novel artificial ribonucleases with potentially improved cellular uptake. The design of trifunctional conjugates 1a and 1b is based on the specific RNA-recognizing properties of PNA, the RNA-cleaving abilities of diethylenetriamine (DETA), and the peptide (KFF)(3)K for potential uptake into E. coli. The conjugates were assembled in a convergent synthetic route involving native chemical ligation of a PNA, containing an N-terminal cysteine, with the C-terminal thioester of the cell-penetrating (KFF)(3)K peptide to give 12a and 12b. These hybrids contained a free cysteine side-chain, which was further functionalized with an RNA-hydrolyzing diethylenetriamine (DETA) moiety. The trifunctional conjugates (1a, 1b) were evaluated for RNA-cleaving properties in vitro and showed efficient degradation of the target RNA at two major cleavage sites. It was also established that the cleavage efficiency strongly depended on the type of spacer connecting the PNA and the peptide.

  16. Formulation of Stable and Homogeneous Cell-Penetrating Peptide NF55 Nanoparticles for Efficient Gene Delivery In Vivo

    Directory of Open Access Journals (Sweden)

    Krista Freimann

    2018-03-01

    Full Text Available Although advances in genomics and experimental gene therapy have opened new possibilities for treating otherwise incurable diseases, the transduction of nucleic acids into the cells and delivery in vivo remain challenging. The high molecular weight and anionic nature of nucleic acids require their packing into nanoparticles for the delivery. The efficacy of nanoparticle drugs necessitates the high bioactivity of constituents, but their distribution in organisms is mostly governed by the physical properties of nanoparticles, and therefore, generation of stable particles with strictly defined characteristics is highly essential. Using previously designed efficient cell-penetrating peptide NF55, we searched for strategies enabling control over the nanoparticle formation and properties to further improve transfection efficacy. The size of the NF55/pDNA nanoparticles correlates with the concentration of its constituents at the beginning of assembly, but characteristics of nanoparticles measured by DLS do not reliably predict the applicability of particles in in vivo studies. We introduce a new formulation approach called cryo-concentration, where we acquired stable and homogeneous nanoparticles for administration in vivo. The cryo-concentrated NF55/pDNA nanoparticles exhibit several advantages over standard formulation: They have long shelf-life and do not aggregate after reconstitution, have excellent stability against enzymatic degradation, and show significantly higher bioactivity in vivo.

  17. Hemocompatible poly(NIPAm-MBA-AMPS) colloidal nanoparticles as carriers of anti-inflammatory cell penetrating peptides.

    Science.gov (United States)

    Bartlett, Rush L; Medow, Matthew R; Panitch, Alyssa; Seal, Brandon

    2012-04-09

    Anionic copolymer systems containing sulfated monomers have great potential for delivery of cationic therapeutics, but N-isopropylacrylamide (NIPAm) 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) copolymer nanoparticles have seen limited characterization to date with regard to physical properties relevant to loading and release of therapeutics. Characterization of polymeric nanoparticles incorporating AMPS showed an increased size and decreased thermodynamic swelling ratios of AMPS containing particles as compared to NIPAm nanoparticles lacking AMPS. Particles with increasing AMPS addition showed an increased propensity for uniformity, intraparticle colloidal stability, and drug loading capacity. Peptide encapsulated in particles was shielded from peptide degradation in serum. Particles were shown not impede blood coagulation or to cause hemolysis. This study has demonstrated that AMPS incorporation into traditional NIPAm nanoparticles presents a tunable parameter for changing particle LCST, size, swelling ratio, ζ potential, and cationic peptide loading potential. This one-pot synthesis results in a thermosensitive anionic nanoparticle system that is a potentially useful platform to deliver cationic cell penetrating peptides.

  18. Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Juteau Jean-Marc

    2009-12-01

    Full Text Available Abstract Background Phosphorothioated oligonucleotides (PS-ONs have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV infections in vitro and in vivo was therefore investigated. Results In vitro, a 40 mer degenerate AP (REP 9 inhibited both murine CMV (MCMV and guinea pig CMV (GPCMV with an IC50 of 0.045 μM and 0.16 μM, respectively, and a 40 mer poly C AP (REP 9C inhibited MCMV with an IC50 of 0.05 μM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism in vivo. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers. Conclusion These studies indicate that APs exhibit potent, well tolerated

  19. Functionalization with C-terminal cysteine enhances transfection efficiency of cell-penetrating peptides through dimer formation

    Energy Technology Data Exchange (ETDEWEB)

    Amand, Helene L., E-mail: helene.amand@chalmers.se [Chalmers University of Technology, Department of Chemical and Biological Engineering/Physical Chemistry, SE-412 96 Gothenburg (Sweden); Norden, Bengt, E-mail: norden@chalmers.se [Chalmers University of Technology, Department of Chemical and Biological Engineering/Physical Chemistry, SE-412 96 Gothenburg (Sweden); Fant, Kristina, E-mail: kristina.fant@sp.se [Chalmers University of Technology, Department of Chemical and Biological Engineering/Physical Chemistry, SE-412 96 Gothenburg (Sweden)

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Reversible CPP dimerisation is a simple yet efficient strategy to improve delivery. Black-Right-Pointing-Pointer Dimer formation enhances peptiplex stability, resulting in increased transfection. Black-Right-Pointing-Pointer By dimerisation, the CPP EB1 even gain endosomal escape properties while lowering cytotoxicity. -- Abstract: Cell-penetrating peptides have the ability to stimulate uptake of macromolecular cargo in mammalian cells in a non-toxic manner and therefore hold promise as efficient and well tolerated gene delivery vectors. Non-covalent peptide-DNA complexes ('peptiplexes') enter cells via endocytosis, but poor peptiplex stability and endosomal entrapment are considered as main barriers to peptide-mediated delivery. We explore a simple, yet highly efficient, strategy to improve the function of peptide-based vectors, by adding one terminal cysteine residue. This allows the peptide to dimerize by disulfide bond formation, increasing its affinity for nucleic acids by the 'chelate effect' and, when the bond is reduced intracellularly, letting the complex dissociate to deliver the nucleic acid. By introducing a single C-terminal cysteine in the classical CPP penetratin and the penetratin analogs PenArg and EB1, we show that this minor modification greatly enhances the transfection capacity for plasmid DNA in HEK293T cells. We conclude that this effect is mainly due to enhanced thermodynamic stability of the peptiplexes as endosome-disruptive chloroquine is still required for transfection and the effect is more pronounced for peptides with lower inherent DNA condensation capacity. Interestingly, for EB1, addition of one cysteine makes the peptide able to mediate transfection in absence of chloroquine, indicating that dimerisation can also improve endosomal escape properties. Further, the cytotoxicity of EB1 peptiplexes is considerably reduced, possibly due to lower concentration of free peptide

  20. [Cell-penetrating chimeric apoptotic peptide AVPI-LMWP/DNA co-delivery system for cancer therapy].

    Science.gov (United States)

    Tan, Jiao; Wang, Ya-Ping; Wang, Hui-Xin; Liang, Jian-Ming; Zhang, Meng; Sun, Xun; Huang, Yong-Zhuo

    2014-12-01

    To develop a cell-penetrating chimeric apoptotic peptide AVPI-LMWP/DNA co-delivery system for cancer therapy, we prepared the AVPI-LMWP/pTRAIL self-assembled complexes containing a therapeutic combination of peptide drug AVPI and DNA drug TRAIL. The chimeric apoptotic peptide AVPI-LMWP was synthesized using the standard solid-phase synthesis. The cationic AVPI-LMWP could condense pTRAIL by electrostatic interaction. The physical-chemical properties of the AVPI-LMWP/pTRAIL complexes were characterized. The cellular uptake efficiency and the inhibitory activity of the AVPI-LMWP/pTRAIL complexes on tumor cell were also performed. The results showed that the AVPI-LMWP/pTRAIL complexes were successfully prepared by co-incubation. With the increase of mass ratio (AVPI-LMWP/DNA), the particle size was decreased and the zeta potential had few change. Agarose gel electrophoresis showed that AVPI-LMWP could fully bind and condense pTRAIL at a mass ratio above 15:1. Cellular uptake efficiency was improved along with the increased ratio of W(AVPI-LMWP)/WpTRAIL. The in vitro cytotoxicity experiments demonstrated that the AVPI-LMWP/pTRAIL (W:W = 20:1) complexes was significantly more effective than the pTRAIL, AVPI-LMWP alone or LMWP/pTRAIL complexes on inhibition of HeLa cell growth. Our studies indicated that the AVPI-LMWP/pTRAIL co-delivery system could deliver plasmid into HeLa cell and induce tumor cell apoptosis efficiently, which showed its potential in cancer therapy using combination of apoptoic peptide and gene drugs.

  1. Applications and Challenges for Use of Cell-Penetrating Peptides as Delivery Vectors for Peptide and Protein Cargos

    Directory of Open Access Journals (Sweden)

    Mie Kristensen

    2016-01-01

    Full Text Available The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs constitute a promising tool and have shown applications for peptide and protein delivery into cells as well as across various epithelia and the blood-brain barrier (BBB. CPP-mediated delivery of peptides and proteins may be pursued via covalent conjugation of the CPP to the cargo peptide or protein or via physical complexation obtained by simple bulk-mixing of the CPP with its cargo. Both approaches have their pros and cons, and which is the better choice likely relates to the physicochemical properties of the CPP and its cargo as well as the route of administration, the specific barrier and the target cell. Besides the physical barrier, a metabolic barrier must be taken into consideration when applying peptide-based delivery vectors, such as the CPPs, and stability-enhancing strategies are commonly employed to prolong the CPP half-life. The mechanisms by which CPPs translocate cell membranes are believed to involve both endocytosis and direct translocation, but are still widely investigated and discussed. The fact that multiple factors influence the mechanisms responsible for cellular CPP internalization and the lack of sensitive methods for detection of the CPP, and in some cases the cargo, further complicates the design and conduction of conclusive mechanistic studies.

  2. Vesicles mimicking normal and cancer cell membranes exhibit differential responses to the cell-penetrating peptide Pep-1.

    Science.gov (United States)

    Almarwani, Bashiyar; Phambu, Esther Nzuzi; Alexander, Christopher; Nguyen, Ha Aimee T; Phambu, Nsoki; Sunda-Meya, Anderson

    2018-06-01

    The cell-penetrating peptide (CPP) Pep-1 presents a great potential in drug delivery due to its intrinsic property to cross plasma membrane. However, its mechanism of entry into the cell remains unresolved. In this study, we compare the selectivity of Pep-1 towards vesicles mimicking normal and cancer cell membranes. The interaction was performed in a wide range of peptide-to-lipid molar ratios using infrared (IR), fluorescence, scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) techniques. At low peptide concentration, fluorescence experiments show that lipid-phosphatidylserine (PS) seems to enable Pep-1 translocation into cancer cell membrane as evidenced by the blue shift of its maximal emission wavelength. DSC data show that Pep-1 induces segregation of lipids. At high peptide concentration, IR data indicate that the interaction of Pep-1 is relatively stronger with normal cell membrane than with cancer cell membrane through the phosphate groups, while the interaction is weaker with normal cell membrane than with cancer cell membrane through the carbonyl groups. TGA and DSC data reveal that vesicles of normal cell membrane are thermally more stable than vesicles of cancer cell membrane. This suggests that the additional lipid PS included in cancer cell membrane has a destabilizing effect on the membrane structure. SEM images reveal that Pep-1 form superstructures including spherical particles and fibrils in the presence of both model membranes. PS seems to enhance peptide transport across cellular membranes. The biophysical techniques in this study provide valuable insights into the properties of CPPs in drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Current Understanding of Physicochemical Mechanisms for Cell Membrane Penetration of Arginine-rich Cell Penetrating Peptides: Role of Glycosaminoglycan Interactions.

    Science.gov (United States)

    Takechi-Haraya, Yuki; Saito, Hiroyuki

    2018-01-01

    Arginine-rich cell penetrating peptides (CPPs) are very promising drug carriers to deliver membrane-impermeable pharmaceuticals, such as siRNA, bioactive peptides and proteins. CPPs directly penetrate into cells across cell membranes via a spontaneous energy-independent process, in which CPPs appear to interact with acidic lipids in the outer leaflet of the cell membrane. However, acidic lipids represent only 10 to 20% of the total membrane lipid content and in mammalian cell membranes they are predominantly located in the inner leaflet. Alternatively, CPPs favorably bind in a charge density- dependent manner to negatively charged, sulfated glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate, which are abundant on the cell surface and are involved in many biological functions. We have recently demonstrated that the interaction of CPPs with sulfated GAGs plays a critical role in their direct cell membrane penetration: the favorable enthalpy contribution drives the high-affinity binding of arginine-rich CPPs to sulfated GAGs, initiating an efficient cell membrane penetration. The favorable enthalpy gain is presumably mainly derived from a unique property of the guanidino group of arginine residues forming multidentate hydrogen bonding with sulfate and carboxylate groups in GAGs. Such interactions can be accompanied with charge neutralization of arginine-rich CPPs, promoting their partition into cell membranes. This review summarizes the current understanding of the physicochemical mechanism for lipid membrane penetration of CPPs, and discusses the role of the GAG interactions on the cell membrane penetration of CPPs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides.

    Science.gov (United States)

    de Cogan, Felicity; Hill, Lisa J; Lynch, Aisling; Morgan-Warren, Peter J; Lechner, Judith; Berwick, Matthew R; Peacock, Anna F A; Chen, Mei; Scott, Robert A H; Xu, Heping; Logan, Ann

    2017-05-01

    To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection. CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV. CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment. CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

  5. Functionalization with C-terminal cysteine enhances transfection efficiency of cell-penetrating peptides through dimer formation

    International Nuclear Information System (INIS)

    Åmand, Helene L.; Nordén, Bengt; Fant, Kristina

    2012-01-01

    Highlights: ► Reversible CPP dimerisation is a simple yet efficient strategy to improve delivery. ► Dimer formation enhances peptiplex stability, resulting in increased transfection. ► By dimerisation, the CPP EB1 even gain endosomal escape properties while lowering cytotoxicity. -- Abstract: Cell-penetrating peptides have the ability to stimulate uptake of macromolecular cargo in mammalian cells in a non-toxic manner and therefore hold promise as efficient and well tolerated gene delivery vectors. Non-covalent peptide-DNA complexes (“peptiplexes”) enter cells via endocytosis, but poor peptiplex stability and endosomal entrapment are considered as main barriers to peptide-mediated delivery. We explore a simple, yet highly efficient, strategy to improve the function of peptide-based vectors, by adding one terminal cysteine residue. This allows the peptide to dimerize by disulfide bond formation, increasing its affinity for nucleic acids by the “chelate effect” and, when the bond is reduced intracellularly, letting the complex dissociate to deliver the nucleic acid. By introducing a single C-terminal cysteine in the classical CPP penetratin and the penetratin analogs PenArg and EB1, we show that this minor modification greatly enhances the transfection capacity for plasmid DNA in HEK293T cells. We conclude that this effect is mainly due to enhanced thermodynamic stability of the peptiplexes as endosome-disruptive chloroquine is still required for transfection and the effect is more pronounced for peptides with lower inherent DNA condensation capacity. Interestingly, for EB1, addition of one cysteine makes the peptide able to mediate transfection in absence of chloroquine, indicating that dimerisation can also improve endosomal escape properties. Further, the cytotoxicity of EB1 peptiplexes is considerably reduced, possibly due to lower concentration of free peptide dimer resulting from its stronger binding to DNA.

  6. The heparin-binding domain of HB-EGF as an efficient cell-penetrating peptide for drug delivery.

    Science.gov (United States)

    Luo, Zhao; Cao, Xue-Wei; Li, Chen; Wu, Miao-Dan; Yang, Xu-Zhong; Zhao, Jian; Wang, Fu-Jun

    2016-11-01

    Cell-penetrating peptides (CPPs) have been shown to be potential drug carriers for cancer therapy. The inherently low immunogenicity and cytotoxicity of human-derived CPPs make them more suitable for intracellular drug delivery compared to other delivery vehicles. In this work, the protein transduction ability of a novel CPP (termed HBP) derived from the heparin-binding domain of HB-EGF was evaluated. Our data shows, for the first time, that HBP possesses similar properties to typical CPPs and is a potent drug delivery vector for improving the antitumor activity of impermeable MAP30. The intrinsic bioactivities of recombinant MAP30-HBP were well preserved compared to those of free MAP30. Furthermore, HBP conjugated to the C-terminus of MAP30 promoted the cellular uptake of recombinant MAP30-HBP. Moreover, the fusion of HBP to MAP30 gave rise to significantly enhanced cytotoxic effects in all of the tumor cell lines tested. In HeLa cells, this cytotoxicity was mainly caused by the induction of cell apoptosis. Further investigation revealed that HBP enhanced MAP30-induced apoptosis through the activation of the mitochondrial- and death receptor-mediated signaling pathways. In addition, the MAP30-HBP fusion protein caused more HeLa cells to become arrested in S phase compared to MAP30 alone. These results highlight the MAP30-HBP fusion protein as a promising drug candidate for cancer therapy and demonstrate HBP, a novel CPP derived from human HB-EGF, as a new potential vector for antitumor drug delivery. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  7. A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells.

    Directory of Open Access Journals (Sweden)

    Ki Jung Lim

    Full Text Available Cell-penetrating peptides (CPPs have proven very effective as intracellular delivery vehicles for various therapeutics. However, there are some concerns about non-specific penetration and cytotoxicity of CPPs for effective cancer treatments. Herein, based on the cell-penetrating motif of an anticancer peptide, buforin IIb, we designed several CPP derivatives with cancer cell specificity. Among the derivatives, a 17-amino acid peptide (BR2 was found to have cancer-specificity without toxicity to normal cells. After specifically targeting cancer cells through interaction with gangliosides, BR2 entered cells via lipid-mediated macropinocytosis. Moreover, BR2 showed higher membrane translocation efficiency than the well-known CPP Tat (49-57. The capability of BR2 as a cancer-specific drug carrier was demonstrated by fusion of BR2 to a single-chain variable fragment (scFv directed toward a mutated K-ras (G12V. BR2-fused scFv induced a higher degree of apoptosis than Tat-fused scFv in K-ras mutated HCT116 cells. These results suggest that the novel cell-penetrating peptide BR2 has great potential as a useful drug delivery carrier with cancer cell specificity.

  8. A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells.

    Science.gov (United States)

    Lim, Ki Jung; Sung, Bong Hyun; Shin, Ju Ri; Lee, Young Woong; Kim, Da Jung; Yang, Kyung Seok; Kim, Sun Chang

    2013-01-01

    Cell-penetrating peptides (CPPs) have proven very effective as intracellular delivery vehicles for various therapeutics. However, there are some concerns about non-specific penetration and cytotoxicity of CPPs for effective cancer treatments. Herein, based on the cell-penetrating motif of an anticancer peptide, buforin IIb, we designed several CPP derivatives with cancer cell specificity. Among the derivatives, a 17-amino acid peptide (BR2) was found to have cancer-specificity without toxicity to normal cells. After specifically targeting cancer cells through interaction with gangliosides, BR2 entered cells via lipid-mediated macropinocytosis. Moreover, BR2 showed higher membrane translocation efficiency than the well-known CPP Tat (49-57). The capability of BR2 as a cancer-specific drug carrier was demonstrated by fusion of BR2 to a single-chain variable fragment (scFv) directed toward a mutated K-ras (G12V). BR2-fused scFv induced a higher degree of apoptosis than Tat-fused scFv in K-ras mutated HCT116 cells. These results suggest that the novel cell-penetrating peptide BR2 has great potential as a useful drug delivery carrier with cancer cell specificity.

  9. Cell Penetrating Capacity and Internalization Mechanisms Used by the Synthetic Peptide CIGB-552 and Its Relationship with Tumor Cell Line Sensitivity.

    Science.gov (United States)

    Astrada, Soledad; Fernández Massó, Julio Raúl; Vallespí, Maribel G; Bollati-Fogolín, Mariela

    2018-03-30

    CIGB-552 is a twenty-amino-acid novel synthetic peptide that has proven to be effective in reducing tumor size and increasing lifespan in tumor-bearing mice. Such capability is conferred by its cell-penetrating peptide character, which allows it to enter cells and elicit a pro-apoptotic effect through its major mediator, COMMD1 protein. Cell-penetrating peptides are able to use different internalization mechanisms, such as endocytosis or direct transduction through the plasma membrane. Although CIGB-552 cytotoxicity has been evaluated in several non-tumor- and tumor-derived cell lines, no data regarding the relationship between cell line sensitivity, cell penetrating capacity, the internalization mechanisms involved, COMMD1 expression levels, or its subcellular localization has yet been produced. Here, we present the results obtained from a comparative analysis of CIGB-552 sensitivity, internalization capacity and the mechanisms involved in three human tumor-derived cell lines from different origins: mammary gland, colon and lung (MCF-7, HT-29 and H460, respectively). Furthermore, cell surface markers relevant for internalization processes such as phosphatidylserine, as well as CIGB-552 target COMMD1 expression/localization, were also evaluated. We found that both endocytosis and transduction are involved in CIGB-552 internalization in the three cell lines evaluated. However, CIGB-552 incorporation efficiency and contribution of each mechanism is cell-line dependent. Finally, sensitivity was directly correlated with high internalization capacity in those cell lines where endocytosis had a major contribution on CIGB-552 internalization.

  10. The feasibility of a targeted ultrasound contrast agent carrying genes and cell-penetrating peptides to hypoxic HUVEC

    International Nuclear Information System (INIS)

    Tian Ju; Wang Zhigang; Ren Jianli; Zhang Qingfeng; Liu Li

    2012-01-01

    Objective: To prepare an anti-P-selectin targeted ultrasound contrast agent carrying genes and cell-penetrating peptides (CPP) and to investigate its feasibility of delivery to hypoxic human umbilical vein endothelial cells (HUVEC). Methods: Anti-P-selectin targeted ultrasound contrast agent carrying a green fluorescent protein gene (pEGFP-N1) and CPP was prepared by mechanical vibration and carbodiimide techniques. The appearance, distribution, concentration and diameter of the ultrasound contrast agent were measured. The gene and CPP distribution on the agent was investigated using confocal laser scanning microscopy (CLSM). The efficiency of the ultrasound contrast agent to carry the gene and CPP was investigated by fluorospectrophotometry. HUVEC were cultured in vitro and hypoxic HUVEC were prepared using hydrogen peroxide (H 2 O 2 ). Hypoxic HUVEC were randomly assigned targeted ultrasound contrast agents and non-targeted ultrasound contrast agents for transfection. The transfection effect of green fluorescent protein in the two groups was observed using fluorescence microscopy and flow cytometry. T-test and linear correlation analysis were used for statistical analysis. Results: The average diameter of anti-P-selectin targeted ultrasound contrast agents carrying gene and CPP was (2.15 ±0.36) μm and the concentration was (1.58 ± 0.23) × 10 7 /ml.The results of CLSM showed that gene and CPP were distributed on the shell of the agent. The gene encapsulation efficiency was 28% (y=0.932x-0.09, r=0.993, P<0.05), and the CPP encapsulation efficiency was 25% (y=5.875x-0.81, r=0.987, P<0.05). EGFP expression was observed using fluorescence microscopy in targeted ultrasound contrast agents and non-targeted ultrasound contrast agents. The average transfection efficiencies of targeted ultrasound contrast agents and non-targeted ultrasound contrast agents were (18.74 ± 0.47) % and (15.34 ± 0.22) % after 24 h (t=10.923, P<0.001). Conclusions: The in vitro studies

  11. Comparative mode of action of novel hybrid peptide CS-1a and its rearranged amphipathic analogue CS-2a.

    Science.gov (United States)

    Joshi, Seema; Bisht, Gopal S; Rawat, Diwan S; Maiti, Souvik; Pasha, Santosh

    2012-10-01

    Cell selective, naturally occurring, host defence cationic peptides present a good template for the design of novel peptides with the aim of achieving a short length with improved antimicrobial potency and selectivity. A novel, short peptide CS-1a (14 residues) was derived using a sequence hybridization approach on sarcotoxin I (39 residues) and cecropin B (35 residues). The sequence of CS-1a was rearranged to enhance amphipathicity with the help of a Schiffer-Edmundson diagram to obtain CS-2a. Both peptides showed good antibacterial activity in the concentration range 4-16 μg·mL(-1) against susceptible as well as drug-resistant bacterial strains, including the clinically relevant pathogens Acenatobacter sp. and methicillin-resistant Staphylococcus aureus. The major thrust of these peptides is their nonhaemolytic activity against human red blood cells up to a high concentration of 512 μg·mL(-1). Compared to CS-1a, amphipathic peptide CS-2a showed a more pronounced α-helical conformation, along with a better membrane insertion depth in bacterial mimic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) small unilamellar vesicles. With equivalent lipid-binding affinity, the two peptides assumed different pathways of membrane disruption, as demonstrated by calcein leakage and the results of transmission electron microscopy on model bacterial mimic large unilamellar vesicles. Extending the work from model membranes to intact Escherichia coli cells, differences in membrane perturbation were visible in microscopic images of peptide-treated E. coli. The present study describes two novel short peptides with potent activity, cell selectivity and divergent modes of action that will aid in the future design of peptides with better therapeutic potential. © 2012 The Authors Journal compilation © 2012 FEBS.

  12. A novel strategy to improve antigen presentation for active immunotherapy in cancer. Fusion of the human papillomavirus type 16 E7 antigen to a cell penetrating peptide

    International Nuclear Information System (INIS)

    Granadillo, Milaid; Torrens, Isis; Guerra, Maribel

    2012-01-01

    Facilitating the delivery of exogenous antigens to antigen-presenting cells, ensuing processing and presentation via the major histocompatibility complex class I and induction of an effective immune response are fundamental for an effective therapeutic cancer vaccine. In this regard, we propose the use of cell-penetrating peptides fused to a tumor antigen. To demonstrate this concept we designed a fusion protein comprising a novel cell-penetrating and immunostimulatory peptide corresponding to residues 32 to 51 of the Limulus anti-lipopolysaccharide factor protein (LALF 32-51 ) linked to human papillomavirus 16 E7 antigen (LALF 32-51 -E7). In this work, we demonstrated that the immunization with LALF 32-51 -E7 using the TC-1 mouse model induces a potent and long-lasting anti-tumor response supported on an effective E7-specific CD8 +T -cell response. The finding that therapeutic immunization with LALF 32-51 or E7 alone, or an admixture of LALF32-51 and E7, does not induce significant tumor reduction indicates that covalent linkage between LALF 32-51 and E7 is required for the anti-tumor effect. These results support the use of this novel cell-penetrating peptide as an efficient means for delivering therapeutic targets into cellular compartments with the induction of a cytotoxic CD8 +T lymphocyte immune response. This approach is promissory for the treatment of tumors associated with the human papillomavirus 16, which is responsible for the 50% of cervical cancer cases worldwide and other malignancies. Furthermore, protein-based vaccines can circumvent the major histocompatibility complex specificity limitation associated with peptide vaccines providing a greater extent in their application

  13. Hydrophobic and electrostatic interactions between cell penetrating peptides and plasmid DNA are important for stable non-covalent complexation and intracellular delivery.

    Science.gov (United States)

    Upadhya, Archana; Sangave, Preeti C

    2016-10-01

    Cell penetrating peptides are useful tools for intracellular delivery of nucleic acids. Delivery of plasmid DNA, a large nucleic acid, poses a challenge for peptide mediated transport. The paper investigates and compares efficacy of five novel peptide designs for complexation of plasmid DNA and subsequent delivery into cells. The peptides were designed to contain reported DNA condensing agents and basic cell penetrating sequences, octa-arginine (R 8 ) and CHK 6 HC coupled to cell penetration accelerating peptides such as Bax inhibitory mutant peptide (KLPVM) and a peptide derived from the Kaposi fibroblast growth factor (kFGF) membrane translocating sequence. A tryptophan rich peptide, an analogue of Pep-3, flanked with CH 3 on either ends was also a part of the study. The peptides were analysed for plasmid DNA complexation, protection of peptide-plasmid DNA complexes against DNase I, serum components and competitive ligands by simple agarose gel electrophoresis techniques. Hemolysis of rat red blood corpuscles (RBCs) in the presence of the peptides was used as a measure of peptide cytotoxicity. Plasmid DNA delivery through the designed peptides was evaluated in two cell lines, human cervical cancer cell line (HeLa) and (NIH/3 T3) mouse embryonic fibroblasts via expression of the secreted alkaline phosphatase (SEAP) reporter gene. The importance of hydrophobic sequences in addition to cationic sequences in peptides for non-covalent plasmid DNA complexation and delivery has been illustrated. An alternative to the employment of fatty acid moieties for enhanced gene transfer has been proposed. Comparison of peptides for plasmid DNA complexation and delivery of peptide-plasmid DNA complexes to cells estimated by expression of a reporter gene, SEAP. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  14. DNA-histone complexes as ligands amplify cell penetration and nuclear targeting of anti-DNA antibodies via energy-independent mechanisms.

    Science.gov (United States)

    Zannikou, Markella; Bellou, Sofia; Eliades, Petros; Hatzioannou, Aikaterini; Mantzaris, Michael D; Carayanniotis, George; Avrameas, Stratis; Lymberi, Peggy

    2016-01-01

    We have generated three monoclonal cell-penetrating antibodies (CPAbs) from a non-immunized lupus-prone (NZB × NZW)F1 mouse that exhibited high anti-DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA-histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell-entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis-specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy-independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant. © 2015 John Wiley & Sons Ltd.

  15. In Vivo Imaging of the Stability and Sustained Cargo Release of an Injectable Amphipathic Peptide-Based Hydrogel.

    Science.gov (United States)

    Oyen, Edith; Martin, Charlotte; Caveliers, Vicky; Madder, Annemieke; Van Mele, Bruno; Hoogenboom, Richard; Hernot, Sophie; Ballet, Steven

    2017-03-13

    Hydrogels are promising materials for biomedical applications such as tissue engineering and controlled drug release. In the past two decades, the peptide hydrogel subclass has attracted an increasing level of interest from the scientific community because of its numerous advantages, such as biocompatibility, biodegradability, and, most importantly, injectability. Here, we report on a hydrogel consisting of the amphipathic hexapeptide H-FEFQFK-NH 2 , which has previously shown promising in vivo properties in terms of releasing morphine. In this study, the release of a small molecule, a peptide, and a protein cargo as representatives of the three major drug classes is directly visualized by in vivo fluorescence and nuclear imaging. In addition, the in vivo stability of the peptide hydrogel system is investigated through the use of a radiolabeled hydrogelator sequence. Although it is shown that the hydrogel remains present for several days, the largest decrease in volume takes place within the first 12 h of subcutaneous injection, which is also the time frame wherein the cargos are released. Compared to the situation in which the cargos are injected in solution, a prolonged release profile is observed up to 12 h, showing the potential of our hydrogel system as a scaffold for controlled drug delivery. Importantly, this study elucidates the release mechanism of the peptide hydrogel system that seems to be based on erosion of the hydrogel providing a generally applicable controlled release platform for small molecule, peptide, and protein drugs.

  16. An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1.

    Science.gov (United States)

    Herlo, Rasmus; Lund, Viktor K; Lycas, Matthew D; Jansen, Anna M; Khelashvili, George; Andersen, Rita C; Bhatia, Vikram; Pedersen, Thomas S; Albornoz, Pedro B C; Johner, Niklaus; Ammendrup-Johnsen, Ina; Christensen, Nikolaj R; Erlendsson, Simon; Stoklund, Mikkel; Larsen, Jannik B; Weinstein, Harel; Kjærulff, Ole; Stamou, Dimitrios; Gether, Ulrik; Madsen, Kenneth L

    2018-05-15

    BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N-terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin-producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation. This was accompanied by reduced hormone storage in the INS-1E cells. In Drosophila, disruption of the helix compromised growth regulation. By demonstrating size-dependent binding on insulin granules, our finding highlights the function of MCS for BAR domain proteins in a biological context distinct from their function, e.g., at the plasma membrane during endocytosis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.

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    Chai Ann Ng

    Full Text Available The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N-terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS domain (residues 26-135 as well as an amphipathic α-helix (residues 13-23 and an initial unstructured segment (residues 2-9. Deletion of residues 2-25, only the unstructured segment (residues 2-9 or replacement of the α-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal α-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.

  18. The N-terminal amphipathic helix of the topological specificity factor MinE is associated with shaping membrane curvature.

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    Yu-Ling Shih

    Full Text Available Pole-to-pole oscillations of the Min proteins in Escherichia coli are required for the proper placement of the division septum. Direct interaction of MinE with the cell membrane is critical for the dynamic behavior of the Min system. In vitro, this MinE-membrane interaction led to membrane deformation; however, the underlying mechanism remained unclear. Here we report that MinE-induced membrane deformation involves the formation of an amphipathic helix of MinE(2-9, which, together with the adjacent basic residues, function as membrane anchors. Biochemical evidence suggested that the membrane association induces formation of the helix, with the helical face, consisting of A2, L3, and F6, inserted into the membrane. Insertion of this helix into the cell membrane can influence local membrane curvature and lead to drastic changes in membrane topology. Accordingly, MinE showed characteristic features of protein-induced membrane tubulation and lipid clustering in in vitro reconstituted systems. In conclusion, MinE shares common protein signatures with a group of membrane trafficking proteins in eukaryotic cells. These MinE signatures appear to affect membrane curvature.

  19. The potent antimicrobial properties of cell penetrating peptide-conjugated silver nanoparticles with excellent selectivity for gram-positive bacteria over erythrocytes.

    Science.gov (United States)

    Liu, Lihong; Yang, Jun; Xie, Jianping; Luo, Zhentao; Jiang, Jiang; Yang, Yi Yan; Liu, Shaomin

    2013-05-07

    Silver nanoparticles are of great interest for use as antimicrobial agents. Studies aimed at producing potent nano-silver biocides have focused on manipulation of particle size, shape, composition and surface charge. Here, we report the cell penetrating peptide catalyzed formation of antimicrobial silver nanoparticles in N,N-dimethylformamide. The novel nano-composite demonstrated a distinctly enhanced biocidal effect toward bacteria (gram-positive Bacillus subtilis, gram-negative Escherichia coli) and pathogenic yeast (Candida albicans), as compared to triangular and extremely small silver nanoparticles. In addition, a satisfactory biocompatibility was verified by a haemolysis test. Our results provide a paradigm in developing strategies that can maximize the silver nanoparticle application potentials while minimizing the toxic effects.

  20. Liposome Model Systems to Study the Endosomal Escape of Cell-Penetrating Peptides: Transport across Phospholipid Membranes Induced by a Proton Gradient

    Directory of Open Access Journals (Sweden)

    Fatemeh Madani

    2011-01-01

    Full Text Available Detergent-mediated reconstitution of bacteriorhodopsin (BR into large unilamellar vesicles (LUVs was investigated, and the effects were carefully characterized for every step of the procedure. LUVs were prepared by the extrusion method, and their size and stability were examined by dynamic light scattering. BR was incorporated into the LUVs using the detergent-mediated reconstitution method and octyl glucoside (OG as detergent. The result of measuring pH outside the LUVs suggested that in the presence of light, BR pumps protons from the outside to the inside of the LUVs, creating acidic pH inside the vesicles. LUVs with 20% negatively charged headgroups were used to model endosomes with BR incorporated into the membrane. The fluorescein-labeled cell-penetrating peptide penetratin was entrapped inside these BR-containing LUVs. The light-induced proton pumping activity of BR has allowed us to observe the translocation of fluorescein-labeled penetratin across the vesicle membrane.

  1. Single-cell resolution imaging of retinal ganglion cell apoptosis in vivo using a cell-penetrating caspase-activatable peptide probe.

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    Xudong Qiu

    Full Text Available Peptide probes for imaging retinal ganglion cell (RGC apoptosis consist of a cell-penetrating peptide targeting moiety and a fluorophore-quencher pair flanking an effector caspase consensus sequence. Using ex vivo fluorescence imaging, we previously validated the capacity of these probes to identify apoptotic RGCs in cell culture and in an in vivo rat model of N-methyl- D-aspartate (NMDA-induced neurotoxicity. Herein, using TcapQ488, a new probe designed and synthesized for compatibility with clinically-relevant imaging instruments, and real time imaging of a live rat RGC degeneration model, we fully characterized time- and dose-dependent probe activation, signal-to-noise ratios, and probe safety profiles in vivo. Adult rats received intravitreal injections of four NMDA concentrations followed by varying TcapQ488 doses. Fluorescence fundus imaging was performed sequentially in vivo using a confocal scanning laser ophthalmoscope and individual RGCs displaying activated probe were counted and analyzed. Rats also underwent electroretinography following intravitreal injection of probe. In vivo fluorescence fundus imaging revealed distinct single-cell probe activation as an indicator of RGC apoptosis induced by intravitreal NMDA injection that corresponded to the identical cells observed in retinal flat mounts of the same eye. Peak activation of probe in vivo was detected 12 hours post probe injection. Detectable fluorescent RGCs increased with increasing NMDA concentration; sensitivity of detection generally increased with increasing TcapQ488 dose until saturating at 0.387 nmol. Electroretinography following intravitreal injections of TcapQ488 showed no significant difference compared with control injections. We optimized the signal-to-noise ratio of a caspase-activatable cell penetrating peptide probe for quantitative non-invasive detection of RGC apoptosis in vivo. Full characterization of probe performance in this setting creates an important in

  2. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis.

    Science.gov (United States)

    Chua, Ngee Kiat; Howe, Vicky; Jatana, Nidhi; Thukral, Lipi; Brown, Andrew J

    2017-12-08

    Cholesterol biosynthesis in the endoplasmic reticulum (ER) is tightly controlled by multiple mechanisms to regulate cellular cholesterol levels. Squalene monooxygenase (SM) is the second rate-limiting enzyme in cholesterol biosynthesis and is regulated both transcriptionally and post-translationally. SM undergoes cholesterol-dependent proteasomal degradation when cholesterol is in excess. The first 100 amino acids of SM (designated SM N100) are necessary for this degradative process and represent the shortest cholesterol-regulated degron identified to date. However, the fundamental intrinsic characteristics of this degron remain unknown. In this study, we performed a series of deletions, point mutations, and domain swaps to identify a 12-residue region (residues Gln-62-Leu-73), required for SM cholesterol-mediated turnover. Molecular dynamics and circular dichroism revealed an amphipathic helix within this 12-residue region. Moreover, 70% of the variation in cholesterol regulation was dependent on the hydrophobicity of this region. Of note, the earliest known Doa10 yeast degron, Deg1, also contains an amphipathic helix and exhibits 42% amino acid similarity with SM N100. Mutating SM residues Phe-35/Ser-37/Leu-65/Ile-69 into alanine, based on the key residues in Deg1, blunted SM cholesterol-mediated turnover. Taken together, our results support a model whereby the amphipathic helix in SM N100 attaches reversibly to the ER membrane depending on cholesterol levels; with excess, the helix is ejected and unravels, exposing a hydrophobic patch, which then serves as a degradation signal. Our findings shed new light on the regulation of a key cholesterol synthesis enzyme, highlighting the conservation of critical degron features from yeast to humans. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Amphipathic alpha-helices and putative cholesterol binding domains of the influenza virus matrix M1 protein are crucial for virion structure organisation.

    Science.gov (United States)

    Tsfasman, Tatyana; Kost, Vladimir; Markushin, Stanislav; Lotte, Vera; Koptiaeva, Irina; Bogacheva, Elena; Baratova, Ludmila; Radyukhin, Victor

    2015-12-02

    The influenza virus matrix M1 protein is an amphitropic membrane-associated protein, forming the matrix layer immediately beneath the virus raft membrane, thereby ensuring the proper structure of the influenza virion. The objective of this study was to elucidate M1 fine structural characteristics, which determine amphitropic properties and raft membrane activities of the protein, via 3D in silico modelling with subsequent mutational analysis. Computer simulations suggest the amphipathic nature of the M1 α-helices and the existence of putative cholesterol binding (CRAC) motifs on six amphipathic α-helices. Our finding explains for the first time many features of this protein, particularly the amphitropic properties and raft/cholesterol binding potential. To verify these results, we generated mutants of the A/WSN/33 strain via reverse genetics. The M1 mutations included F32Y in the CRAC of α-helix 2, W45Y and W45F in the CRAC of α-helix 3, Y100S in the CRAC of α-helix 6, M128A and M128S in the CRAC of α-helix 8 and a double L103I/L130I mutation in both a putative cholesterol consensus motif and the nuclear localisation signal. All mutations resulted in viruses with unusual filamentous morphology. Previous experimental data regarding the morphology of M1-gene mutant influenza viruses can now be explained in structural terms and are consistent with the pivotal role of the CRAC-domains and amphipathic α-helices in M1-lipid interactions. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

    Directory of Open Access Journals (Sweden)

    Xiang B

    2017-03-01

    Full Text Available Bai Xiang,1,* Xue-Li Jia,1,* Jin-Long Qi,2 Li-Ping Yang,1 Wei-Hong Sun,1 Xiao Yan,1 Shao-Kun Yang,1 De-Ying Cao,1 Qing Du,1 Xian-Rong Qi3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, 2Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 3School of Pharmaceutical Sciences, Peking University, Beijing, China *These authors contributed equally to this work Abstract: As a potent therapeutic agent, small interfering RNA (siRNA has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP, an acid-labile linker (hydrazone, and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4, the surface polycationic moieties of the CPP (polyarginine are “shielded” by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo

  5. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  6. Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery.

    Science.gov (United States)

    Wada, Shun-Ichi; Takesada, Anna; Nagamura, Yurie; Sogabe, Eri; Ohki, Rieko; Hayashi, Junsuke; Urata, Hidehito

    2017-12-15

    The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Design and mechanism of action of a novel bacteria-selective antimicrobial peptide from the cell-penetrating peptide Pep-1

    International Nuclear Information System (INIS)

    Zhu, W.L.; Lan Hongliang; Park, Il-Seon; Kim, Jae Il; Jin, H.Z.; Hahm, Kyung-Soo; Shin, S.Y.

    2006-01-01

    Here, we report the successful design of a novel bacteria-selective antimicrobial peptide, Pep-1-K (KKTWWKTWWTKWSQPKKKRKV). Pep-1-K was designed by replacing Glu-2, Glu-6, and Glu-11 in the cell-penetrating peptide Pep-1 with Lys. Pep-1-K showed strong antibacterial activity against reference strains (MIC = 1-2 μM) of Gram-positive and Gram-negative bacteria as well as against clinical isolates (MIC = 1-8 μM) of methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. In contrast, Pep-1-K did not cause hemolysis of human erythrocytes even at 200 μM. These results indicate that Pep-1-K may be a good candidate for antimicrobial drug development, especially as a topical agent against antibiotic-resistant microorganisms. Tryptophan fluorescence studies indicated that the lack of hemolytic activity of Pep-1-K correlated with its weak ability to penetrate zwitterionic phosphatidylcholine/cholesterol (10:1, w/w) vesicles, which mimic eukaryotic membranes. Furthermore, Pep-1-K caused little or no dye leakage from negatively charged phosphatidylethanolamine/phosphatidylglycerol (7:3, w/w) vesicles, which mimic bacterial membranes but had a potent ability to cause depolarization of the cytoplasmic membrane potential of intact S. aureus cells. These results suggested that Pep-1-K kills microorganisms by not the membrane-disrupting mode but the formation of small channels that permit transit of ions or protons but not molecules as large as calcein

  8. Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

    Science.gov (United States)

    Kamei, Noriyasu; Shingaki, Tomotaka; Kanayama, Yousuke; Tanaka, Misa; Zochi, Riyo; Hasegawa, Koki; Watanabe, Yasuyoshi; Takeda-Morishita, Mariko

    2016-03-07

    Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.

  9. Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells.

    Directory of Open Access Journals (Sweden)

    Betty R Liu

    Full Text Available Cell-penetrating peptides (CPPs have been shown to deliver cargos, including protein, DNA, RNA, and nanomaterials, in fully active forms into live cells. Most of the CPP sequences in use today are based on non-native proteins that may be immunogenic. Here we demonstrate that the L5a CPP (RRWQW from bovine lactoferricin (LFcin, stably and noncovalently complexed with plasmid DNA and prepared at an optimal nitrogen/phosphate ratio of 12, is able to efficiently enter into human lung cancer A549 cells. The L5a CPP delivered a plasmid containing the enhanced green fluorescent protein (EGFP coding sequence that was subsequently expressed in cells, as revealed by real-time PCR and fluorescent microscopy at the mRNA and protein levels, respectively. Treatment with calcium chloride increased the level of gene expression, without affecting CPP-mediated transfection efficiency. Zeta-potential analysis revealed that positively electrostatic interactions of CPP/DNA complexes correlated with CPP-mediated transport. The L5a and L5a/DNA complexes were not cytotoxic. This biomimetic LFcin L5a represents one of the shortest effective CPPs and could be a promising lead peptide with less immunogenic for DNA delivery in gene therapy.

  10. Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells.

    Science.gov (United States)

    Liu, Betty R; Huang, Yue-Wern; Aronstam, Robert S; Lee, Han-Jung

    2016-01-01

    Cell-penetrating peptides (CPPs) have been shown to deliver cargos, including protein, DNA, RNA, and nanomaterials, in fully active forms into live cells. Most of the CPP sequences in use today are based on non-native proteins that may be immunogenic. Here we demonstrate that the L5a CPP (RRWQW) from bovine lactoferricin (LFcin), stably and noncovalently complexed with plasmid DNA and prepared at an optimal nitrogen/phosphate ratio of 12, is able to efficiently enter into human lung cancer A549 cells. The L5a CPP delivered a plasmid containing the enhanced green fluorescent protein (EGFP) coding sequence that was subsequently expressed in cells, as revealed by real-time PCR and fluorescent microscopy at the mRNA and protein levels, respectively. Treatment with calcium chloride increased the level of gene expression, without affecting CPP-mediated transfection efficiency. Zeta-potential analysis revealed that positively electrostatic interactions of CPP/DNA complexes correlated with CPP-mediated transport. The L5a and L5a/DNA complexes were not cytotoxic. This biomimetic LFcin L5a represents one of the shortest effective CPPs and could be a promising lead peptide with less immunogenic for DNA delivery in gene therapy.

  11. Modulation of mitochondrial activity in HaCaT keratinocytes by the cell penetrating peptide Z-Gly-RGD(DPhe)-mitoparan.

    Science.gov (United States)

    Richardson, Adam; Muir, Lewis; Mousdell, Sasha; Sexton, Darren; Jones, Sarah; Howl, John; Ross, Kehinde

    2018-01-30

    Biologically active cell penetrating peptides (CPPs) are an emerging class of therapeutic agent. The wasp venom peptide mastoparan is an established CPP that modulates mitochondrial activity and triggers caspase-dependent apoptosis in cancer cells, as does the mastoparan analogue mitoparan (mitP). Mitochondrial depolarisation and activation of the caspase cascade also underpins the action of dithranol, a topical agent for treatment of psoriasis. The effects of a potent mitP analogue on mitochondrial activity were therefore examined to assess its potential as a novel approach for targeting mitochondria for the treatment of psoriasis. In HaCaT keratinocytes treated with the mitP analogue Z-Gly-RGD(DPhe)-mitP for 24 h, a dose-dependent loss of mitochondrial activity was observed using the methyl-thiazolyl-tetrazolium (MTT) assay. At 10 μmol L -1 , MTT activity was less than 30% that observed in untreated cells. Staining with the cationic dye JC-1 suggested that Z-Gly-RGD(DPhe)-mitP also dissipated the mitochondrial membrane potential, with a threefold increase in mitochondrial depolarisation levels. However, caspase activity appeared to be reduced by 24 h exposure to Z-Gly-RGD(DPhe)-mitP treatment. Furthermore, Z-Gly-RGD(DPhe)-mitP treatment had little effect on overall cell viability. Our findings suggest Z-Gly-RGD(DPhe)-mitP promotes the loss of mitochondrial activity but does not appear to evoke apoptosis in HaCaT keratinocytes.

  12. Synthesis, characterization and applications of carboxylated and polyethylene-glycolated bifunctionalized InP/ZnS quantum dots in cellular internalization mediated by cell-penetrating peptides.

    Science.gov (United States)

    Liu, Betty R; Winiarz, Jeffrey G; Moon, Jong-Sik; Lo, Shih-Yen; Huang, Yue-Wern; Aronstam, Robert S; Lee, Han-Jung

    2013-11-01

    Semiconductor nanoparticles, also known as quantum dots (QDs), are widely used in biomedical imaging studies and pharmaceutical research. Cell-penetrating peptides (CPPs) are a group of small peptides that are able to traverse cell membrane and deliver a variety of cargoes into living cells. CPPs deliver QDs into cells with minimal nonspecific absorption and toxic effect. In this study, water-soluble, monodisperse, carboxyl-functionalized indium phosphide (InP)/zinc sulfide (ZnS) QDs coated with polyethylene glycol lipids (designated QInP) were synthesized for the first time. The physicochemical properties (optical absorption, fluorescence and charging state) and cellular internalization of QInP and CPP/QInP complexes were characterized. CPPs noncovalently interact with QInP in vitro to form stable CPP/QInP complexes, which can then efficiently deliver QInP into human A549 cells. The introduction of 500nM of CPP/QInP complexes and QInP at concentrations of less than 1μM did not reduce cell viability. These results indicate that carboxylated and polyethylene-glycolylated (PEGylated) bifunctionalized QInP are biocompatible nanoparticles with potential for use in biomedical imaging studies and drug delivery applications. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. A+-Helix of Protein C Inhibitor (PCI) Is a Cell-penetrating Peptide That Mediates Cell Membrane Permeation of PCI*

    Science.gov (United States)

    Yang, Hanjiang; Wahlmüller, Felix Christof; Sarg, Bettina; Furtmüller, Margareta; Geiger, Margarethe

    2015-01-01

    Protein C inhibitor (PCI) is a serpin with broad protease reactivity. It binds glycosaminoglycans and certain phospholipids that can modulate its inhibitory activity. PCI can penetrate through cellular membranes via binding to phosphatidylethanolamine. The exact mechanism of PCI internalization and the intracellular role of the serpin are not well understood. Here we showed that testisin, a glycosylphosphatidylinositol-anchored serine protease, cleaved human PCI and mouse PCI (mPCI) at their reactive sites as well as at sites close to their N terminus. This cleavage was observed not only with testisin in solution but also with cell membrane-anchored testisin on U937 cells. The cleavage close to the N terminus released peptides rich in basic amino acids. Synthetic peptides corresponding to the released peptides of human PCI (His1–Arg11) and mPCI (Arg1–Ala18) functioned as cell-penetrating peptides. Because intact mPCI but not testisin-cleaved mPCI was internalized by Jurkat T cells, a truncated mPCI mimicking testisin-cleaved mPCI was created. The truncated mPCI lacking 18 amino acids at the N terminus was not taken up by Jurkat T cells. Therefore our model suggests that testisin or other proteases could regulate the internalization of PCI by removing its N terminus. This may represent one of the mechanisms regulating the intracellular functions of PCI. PMID:25488662

  14. Cell penetration to nanofibrous scaffolds

    Czech Academy of Sciences Publication Activity Database

    Rampichová, Michala; Buzgo, Matej; Chvojka, J.; Prosecká, Eva; Kofroňová, Olga; Amler, Evžen

    2014-01-01

    Roč. 8, č. 1 (2014), s. 36-41 ISSN 1933-6918 Grant - others:GA UK(CZ) 384311; GA UK(CZ) 626012; GA UK(CZ) 270513; GA UK(CZ) 330611; GA UK(CZ) 648112; GA MZd(CZ) NT12156; GA MŠk(CZ) project IPv6 Institutional support: RVO:68378041 ; RVO:61388971 Keywords : fibrous scaffold * mesenchymal stem cells * Forcespinning (R) Subject RIV: FP - Other Medical Disciplines Impact factor: 4.505, year: 2014

  15. Septal membrane localization by C-terminal amphipathic α-helices of MinD in Bacillus subtilis mutant cells lacking MinJ or DivIVA.

    Science.gov (United States)

    Ishikawa, Kazuki; Matsuoka, Satoshi; Hara, Hiroshi; Matsumoto, Kouji

    2017-10-18

    The Min system, which inhibits assembly of the cytokinetic protein FtsZ, is largely responsible for positioning the division site in rod-shaped bacteria. It has been reported that MinJ, which bridges DivIVA and MinD, is targeted to the cell poles by an interaction with DivIVA, and that MinJ in turn recruits MinCD to the cell poles. MinC, however, is located primarily at active division sites at mid-cell when expressed from its native promoter. Surprisingly, we found that Bacillus subtilis MinD is located at nascent septal membranes and at an asymmetric site on lateral membranes between nascent septal membranes in filamentous cells lacking MinJ or DivIVA. Bacillus subtilis MinD has two amphipathic α-helices rich in basic amino acid residues at its C-terminus; one of these, named MTS1 here, is the counterpart of the membrane targeting sequence (MTS) in Escherichia coli MinD while the other, named MTS-like sequence (MTSL), is the nearest helix to MTS1. These amphipathic helices were located independently at nascent septal membranes in cells lacking MinJ or DivIVA, whereas elimination of the helices from the wild type protein reduced its localization considerably. MinD variants with altered MTS1 and MTSL, in which basic amino acid residues were replaced with proline or acidic residues, were not located at nascent septal membranes, indicating that the binding to the nascent septal membranes requires basic residues and a helical structure. The septal localization of MTSL, but not of MTS1, was dependent on host cell MinD. These results suggest that MinD is targeted to nascent septal membranes via its C-terminal amphipathic α-helices in B. subtilis cells lacking MinJ or DivIVA. Moreover, the diffuse distribution of MinD lacking both MTSs suggests that only a small fraction of MinD depends on MinJ for its localization to nascent septal membranes.

  16. Blocking hepatic metastases of colon cancer cells using an shRNA against Rac1 delivered by activatable cell-penetrating peptide.

    Science.gov (United States)

    Bao, Ying; Guo, Huihui; Lu, Yongliang; Feng, Wenming; Sun, Xinrong; Tang, Chengwu; Wang, Xiang; Shen, Mo

    2016-11-22

    Hepatic metastasis is one of the critical progressions of colon cancer. Blocking this process is key to prolonging survival time in cancer patients. Studies on activatable cell-penetrating peptides (dtACPPs) have demonstrated their potential as gene carriers. It showed high tumor cell-targeting specificity and transfection efficiency and low cytotoxicity in the in vitro settings of drug delivery. However, using this system to silence target genes to inhibit metastasis in colorectal cancer cells has not been widely reported and requires further investigation. In this study, we observed that expression of Rac1, a key molecule for cytoskeletal reorganization, was higher in hepatic metastatic tumor tissue compared with prime colon cancer tissue and that patients with high Rac1-expressing colon cancer showed shorter survival time. Base on these findings, we created dtACPP-PEG-DGL (dtACPPD)/shRac1 nanoparticles and demonstrated that they downregulated Rac1 expression in colon cancer cells. Moreover, we observed inhibitory effects on migration, invasion and adhesion in HCT116 colorectal cancer cells in vitro, and our results showed that Rac1 regulated colon cancer cell matrix adhesion through the regulation of cytofilament dynamics. Moreover, mechanically, repression of Rac1 inhibiting cells migration and invasion by enhancing cell to cell adhesion and reducing cell to extracellular matrix adhesion. Furthermore, when atCDPPD/shRac1 nanoparticles were administered intravenously to a HCT116 xenograft model, significant tumor metastasis to the liver was inhibited. Our results suggest that atCDPP/shRac1 nanoparticles may enable the blockade of hepatic metastasis in colon cancer.

  17. Solid-Phase Synthesis of Difficult Purine-Rich PNAs through Selective Hmb Incorporation: Application to the Total Synthesis of Cell Penetrating Peptide-PNAs

    Directory of Open Access Journals (Sweden)

    Julien Tailhades

    2017-10-01

    Full Text Available Antisense oligonucleotide (ASO-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino and Spinraza (2′-O-methoxyethyl-phosphorothioate in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here, we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl and Dmb (2,4-dimethoxybenzyl to ameliorate difficult couplings and reduce “on-resin” aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.

  18. Solid-phase synthesis of difficult purine-rich PNAs through selective Hmb incorporation: Application to the total synthesis of cell penetrating peptide-PNAs

    Science.gov (United States)

    Tailhades, Julien; Takizawa, Hotake; Gait, Michael J.; Wellings, Don A.; Wade, John D.; Aoki, Yoshitsugu; Shabanpoor, Fazel

    2017-10-01

    Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2’-O-methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce “on-resin” aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.

  19. The cell-penetrating peptide domain from human heparin-binding epidermal growth factor-like growth factor (HB-EGF) has anti-inflammatory activity in vitro and in vivo

    International Nuclear Information System (INIS)

    Lee, Jue-Yeon; Seo, Yoo-Na; Park, Hyun-Jung; Park, Yoon-Jeong; Chung, Chong-Pyoung

    2012-01-01

    Highlights: ► HBP sequence identified from HB-EGF has cell penetration activity. ► HBP inhibits the NF-κB dependent inflammatory responses. ► HBP directly blocks phosphorylation and degradation of IκBα. ► HBP inhibits nuclear translocation of NF-κB p65 subunit. -- Abstract: A heparin-binding peptide (HBP) sequence from human heparin-binding epidermal growth factor-like growth factor (HB-EGF) was identified and was shown to exhibit cell penetration activity. This cell penetration induced an anti-inflammatory reaction in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. HBP penetrated the cell membrane during the 10 min treatment and reduced the LPS-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cytokines (TNF-α and IL-6) in a concentration-dependent manner. Additionally, HBP inhibited the LPS-induced upregulation of cytokines, including TNF-α and IL-6, and decreased the interstitial infiltration of polymorphonuclear leukocytes in a lung inflammation model. HBP inhibited NF-κB-dependent inflammatory responses by directly blocking the phosphorylation and degradation of IκBα and by subsequently inhibiting the nuclear translocation of the p65 subunit of NF-κB. Taken together, this novel HBP may be potentially useful candidate for anti-inflammatory treatments and can be combined with other drugs of interest to transport attached molecules into cells.

  20. Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity

    Directory of Open Access Journals (Sweden)

    Lee JY

    2015-08-01

    sites, such as the cytoplasm or nucleus, as hBD3-3 has the ability to be used as a carrier, and suggest a potential approach to effectively treat inflammatory diseases. Keywords: human beta-defensin 3, cell-penetrating peptide, anti-inflammatory activity, lipopolysaccharide, NF-κB canonical pathway

  1. Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block.

    Science.gov (United States)

    Tan, Zhe; Dhande, Yogesh K; Reineke, Theresa M

    2017-12-20

    delivery vehicles may be limited by their high cytotoxicity to certain cell types. Thus, the use of cell penetrating structures in polyplex formulations should be used with caution and carefully tailored toward individual cell/tissue types.

  2. Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

    Directory of Open Access Journals (Sweden)

    Park YJ

    2012-09-01

    Full Text Available Yoon Jung Choi,1,* Jue Yeon Lee,2,* Chong Pyoung Chung,2 Yoon Jeong Park,1,21Craniomaxillofacial Reconstructive Sciences, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea; 2Research Institute, Nano Intelligent Biomedical Engineering, Seoul, Republic of Korea*These authors contributed equally to this workBackground: Human dental pulp stem cells (DPSCs have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1 was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP, and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation.Results: LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21Cip1, induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide.Conclusion: Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.Keywords: superoxide

  3. A FRET-based probe for epidermal growth factor receptor bound non-covalently to a pair of synthetic amphipathic helixes

    International Nuclear Information System (INIS)

    Itoh, Reina E.; Kurokawa, Kazuo; Fujioka, Aki; Sharma, Alok; Mayer, Bruce J.; Matsuda, Michiyuki

    2005-01-01

    Epidermal growth factor (EGF) receptor plays a pivotal role in a variety of cellular functions, such as proliferation, differentiation, and migration. To monitor the EGF receptor (EGFR) activity in living cells, we developed a probe for EGFR activity based on the principle of fluorescence resonance energy transfer (FRET). Previously, we developed a probe designated as Picchu (Phosphorylation indicator of the CrkII chimeric unit), which detects the tyrosine phosphorylation of the CrkII adaptor protein. We used a pair of synthetic amphipathic helixes, WinZipA2 and WinZipB1, to bind Picchu non-covalently to the carboxyl-terminus of the EGFR. Using this modified probe named Picchu-Z, the activity of EGFR was followed in EGF-stimulated Cos7 cells. We found that a high level of tyrosine phosphorylation of Picchu-Z probe remained after endocytosis until the point when the EGFR was translocated to the perinuclear region. These findings are in agreement with the previously reported 'signaling endosome' model. Furthermore, by pulse stimulation with EGF and by acute ablation of EGFR activity with AG1478, it was suggested that the phosphorylation of Picchu-Z probe, and probably the phosphorylation of EGFR also, underwent a rapid equilibrium (τ 1/2 < 2 min) between the phosphorylated and dephosphorylated states in the presence of EGF

  4. Complex formation and vectorization of a phosphorothioate oligonucleotide with an amphipathic leucine- and lysine-rich peptide: study at molecular and cellular levels.

    Science.gov (United States)

    Boukhalfa-Heniche, Fatima-Zohra; Hernández, Belén; Gaillard, Stéphane; Coïc, Yves-Marie; Huynh-Dinh, Tam; Lecouvey, Marc; Seksek, Olivier; Ghomi, Mahmoud

    2004-04-15

    Optical spectroscopic techniques such as CD, Raman scattering, and fluorescence imaging allowed us to analyze the complex formation and vectorization of a single-stranded 20-mer phosphorothioate oligodeoxynucleotide with a 15-mer amphipathic peptide at molecular and cellular levels. Different solvent mixtures (methanol and water) and molecular ratios of peptide/oligodeoxynucleotide complexes were tested in order to overcome the problems related to solubility. Optimal conditions for both spectroscopic and cellular experiments were obtained with the molecular ratio peptide/oligodeoxynucleotide equal to 21:4, corresponding to a 7:5 ratio for their respective +/- charge ratio. At the molecular level, CD and Raman spectra were consistent with a alpha-helix conformation of the peptide in water or in a methanol-water mixture. The presence of methanol increased considerably the solubility of the peptide without altering its alpha-helix conformation, as evidenced by CD and Raman spectroscopies. UV absorption melting profile of the oligodeoxynucleotide gave rise to a flat melting profile, corresponding to its random structure in solution. Raman spectra of oligodeoxynucleotide/peptide complexes could only be studied in methanol/water mixture solutions. Drastic changes observed in Raman spectra have undoubtedly shown: (a) the perturbation occurred in the peptide secondary structure, and (b) possible interaction between the lysine residues of the peptide and the oligodeoxynucleotide. At the cellular level, the complex was prepared in a mixture of 10% methanol and 90% cell medium. Cellular uptake in optimal conditions for the oligodeoxynucleotide delivery with low cytotoxicity was controlled by fluorescence imaging allowing to specifically locate the compacted oligonucleotide labeled with fluorescein at its 5'-terminus with the peptide into human glioma cells after 1 h of incubation at 37 degrees C. Copyright 2004 Wiley Periodicals, Inc.

  5. An amphipathic alpha-helix controls multiple roles of brome mosaic virus protein 1a in RNA replication complex assembly and function.

    Directory of Open Access Journals (Sweden)

    Ling Liu

    2009-03-01

    Full Text Available Brome mosaic virus (BMV protein 1a has multiple key roles in viral RNA replication. 1a localizes to perinuclear endoplasmic reticulum (ER membranes as a peripheral membrane protein, induces ER membrane invaginations in which RNA replication complexes form, and recruits and stabilizes BMV 2a polymerase (2a(Pol and RNA replication templates at these sites to establish active replication complexes. During replication, 1a provides RNA capping, NTPase and possibly RNA helicase functions. Here we identify in BMV 1a an amphipathic alpha-helix, helix A, and use NMR analysis to define its structure and propensity to insert in hydrophobic membrane-mimicking micelles. We show that helix A is essential for efficient 1a-ER membrane association and normal perinuclear ER localization, and that deletion or mutation of helix A abolishes RNA replication. Strikingly, mutations in helix A give rise to two dramatically opposite 1a function phenotypes, implying that helix A acts as a molecular switch regulating the intricate balance between separable 1a functions. One class of helix A deletions and amino acid substitutions markedly inhibits 1a-membrane association and abolishes ER membrane invagination, viral RNA template recruitment, and replication, but doubles the 1a-mediated increase in 2a(Pol accumulation. The second class of helix A mutations not only maintains efficient 1a-membrane association but also amplifies the number of 1a-induced membrane invaginations 5- to 8-fold and enhances viral RNA template recruitment, while failing to stimulate 2a(Pol accumulation. The results provide new insights into the pathways of RNA replication complex assembly and show that helix A is critical for assembly and function of the viral RNA replication complex, including its central role in targeting replication components and controlling modes of 1a action.

  6. Regulator of differentiation 1 (ROD1) binds to the amphipathic C-terminal peptide of thrombospondin-4 and is involved in its mitogenic activity.

    Science.gov (United States)

    Sadvakassova, Gulzhakhan; Dobocan, Monica C; Difalco, Marcos R; Congote, Luis F

    2009-09-01

    The matrix protein thrombospondin-4 has an acidic amphipathic C-terminal peptide (C21) which stimulates erythroid cell proliferation. Here we show that C21 stimulates red cell formation in anemic mice in vivo. In vitro experiments indicated that the peptide-mediated increase of erythroid colony formation in cultures of human CD34+ hematopoietic progenitor cells was possible only under continuous presence of erythropoietin. In the absence of this cytokine, C21 stimulated exclusively myeloid colony formation. Therefore, the peptide is not a specific erythroid differentiation factor. In fact, it is mitogenic in non-erythroid cells, such as skin fibroblasts and kidney epithelial cells. In erythroleukemic TF-1 cells, it actually decreased the production of the erythroid differentiation marker glycophorin A. C21-affinity chromatography revealed regulator of differentiation 1 (ROD1) as a major C21-binding protein. ROD1 is the hematopoietic cell paralog of polypyrimidine tract binding proteins (PTBs), RNA splice regulators which regulate differentiation by repressing tissue-specific exons. ROD1 binding to C21 was strongly inhibited by synthetic RNAs in the order poly A > poly U > poly G = poly C and was weakly inhibited by a synthetic phosphorylated peptide mimicking the C-terminal domain of RNA polymerase II. Cellular overexpression or knockdown experiments of ROD1 suggest a role for this protein in the mitogenic activity of C21. Since the nuclear proteins ROD1 and PTBs regulate differentiation at a posttranscriptional level and there is a fast nuclear uptake of C21, we put forward the idea that the peptide is internalized, goes to the nucleus and maintains cells in a proliferative state by supporting ROD1-mediated inhibition of differentiation.

  7. A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

    Directory of Open Access Journals (Sweden)

    Barbari GR

    2017-05-01

    Full Text Available Ghullam Reza Barbari,1 Farid Abedin Dorkoosh,1 Mohsen Amini,2 Mohammad Sharifzadeh,3 Fateme Atyabi,1 Saeed Balalaie,4 Niyousha Rafiee Tehrani,5 Morteza Rafiee Tehrani1 1Department of Pharmaceutics, 2Department of Medicinal Chemistry, 3Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, 4Department of Chemistry, Khaje Nasiroddin University, 5Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Abstract: A simple and reproducible water-in-oil (W/O nanoemulsion technique for making ultrasmall (<15 nm, monodispersed and water-dispersible nanoparticles (NPs from chitosan (CS is reported. The nano-sized (50 nm water pools of the W/O nanoemulsion serve as “nano-containers and nano-reactors”. The entrapped polymer chains of CS inside these “nano-reactors” are covalently cross-linked with the chains of polyethylene glycol (PEG, leading to rigidification and formation of NPs. These NPs possess excessive swelling properties in aqueous medium and preserve integrity in all pH ranges due to chemical cross-linking with PEG. A potent and newly developed cell-penetrating peptide (CPP is further chemically conjugated to the surface of the NPs, leading to development of a novel peptide-conjugated derivative of CS with profound tight-junction opening properties. The CPP-conjugated NPs can easily be loaded with almost all kinds of proteins, peptides and nucleotides for oral delivery applications. Feasibility of this nanoparticulate system for oral delivery of a model peptide (insulin is investigated in Caco-2 cell line. The cell culture results for translocation of insulin across the cell monolayer are very promising (15%–19% increase, and animal studies are actively under progress and will be published separately. Keywords: ultrasmall, cell-penetrating peptide, chitosan, oral insulin, nanoemulsion, Caco-2 cell

  8. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Alberto Malerba

    2012-01-01

    Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

  9. Conformational changes in Sindbis virions resulting from exposure to low pH and interactions with cells suggest that cell penetration may occur at the cell surface in the absence of membrane fusion

    International Nuclear Information System (INIS)

    Paredes, Angel M.; Ferreira, Davis; Horton, Michelle; Saad, Ali; Tsuruta, Hiro; Johnston, Robert; Klimstra, William; Ryman, Kate; Hernandez, Raquel; Chiu Wah; Brown, Dennis T.

    2004-01-01

    Alphaviruses have the ability to induce cell-cell fusion after exposure to acid pH. This observation has served as an article of proof that these membrane-containing viruses infect cells by fusion of the virus membrane with a host cell membrane upon exposure to acid pH after incorporation into a cell endosome. We have investigated the requirements for the induction of virus-mediated, low pH-induced cell-cell fusion and cell-virus fusion. We have correlated the pH requirements for this process to structural changes they produce in the virus by electron cryo-microscopy. We found that exposure to acid pH was required to establish conditions for membrane fusion but that membrane fusion did not occur until return to neutral pH. Electron cryo-microscopy revealed dramatic changes in the structure of the virion as it was moved to acid pH and then returned to neutral pH. None of these treatments resulted in the disassembly of the virus protein icosahedral shell that is a requisite for the process of virus membrane-cell membrane fusion. The appearance of a prominent protruding structure upon exposure to acid pH and its disappearance upon return to neutral pH suggested that the production of a 'pore'-like structure at the fivefold axis may facilitate cell penetration as has been proposed for polio (J. Virol. 74 (2000) 1342) and human rhino virus (Mol. Cell 10 (2002) 317). This transient structural change also provided an explanation for how membrane fusion occurs after return to neutral pH. Examination of virus-cell complexes at neutral pH supported the contention that infection occurs at the cell surface at neutral pH by the production of a virus structure that breaches the plasma membrane bilayer. These data suggest an alternative route of infection for Sindbis virus that occurs by a process that does not involve membrane fusion and does not require disassembly of the virus protein shell

  10. In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

    Directory of Open Access Journals (Sweden)

    Ding Y

    2017-10-01

    Full Text Available Yuan Ding,1,* Wei Cui,2,* Dan Sun,1 Gui-Ling Wang,1 Yu Hei,1 Shuai Meng,1 Jian-Hua Chen,3 Ying Xie,1 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX-loaded novel cell-penetrating peptide (CPP-modified pH-sensitive liposomes (CPPL (referred to as CPPL(DOX with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01 and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%. Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX. Our findings provide important and detailed information regarding the distribution of CPPL(DOX in vivo and reveal their abilities of tumor penetration and potential for the treatment of

  11. Amenorrhea - primary

    Science.gov (United States)

    ... of periods - primary Images Primary amenorrhea Normal uterine anatomy (cut section) Absence of menstruation (amenorrhea) References Bulun SE. The physiology and pathology of the female reproductive axis. In: ...

  12. Primary explosives

    Energy Technology Data Exchange (ETDEWEB)

    Matyas, Robert; Pachman, Jiri [Pardubice Univ. (Czech Republic). Faculty of Chemical Technology

    2013-06-01

    The first chapter provides background such as the basics of initiation and differences between requirements on primary explosives used in detonators and igniters. The authors then clarify the influence of physical characteristics on explosive properties, focusing on those properties required for primary explosives. Furthermore, the issue of sensitivity is discussed. All the chapters on particular groups of primary explosives are structured in the same way, including introduction, physical and chemical properties, explosive properties, preparation and documented use.

  13. Primary fibromyalgia

    DEFF Research Database (Denmark)

    Jacobsen, S; Jensen, L T; Foldager, M

    1990-01-01

    Serum concentrations of procollagen type III aminoterminal peptide have previously been reported to be low in some patients with primary fibromyalgia and the aim of this study was to determine if such patients differ clinically from primary fibromyalgia patients with normal levels of procollagen...... type III aminoterminal peptide. Subjective symptoms, tender points and dynamic muscle strength in 45 women with primary fibromyalgia were related to serum concentrations of procollagen type III aminoterminal peptide. Patients with low serum concentrations of procollagen type III aminoterminal peptide...... concentrations of procollagen type III aminoterminal peptide of primary fibromyalgia patients are connected to the disease impact....

  14. Primary productivity

    Digital Repository Service at National Institute of Oceanography (India)

    Verlecar, X.N.; Parulekar, A.H.

    Photosynthetic production in the oceans in relation to light, nutrients and mixing processes is discussed. Primary productivity in the estuarine region is reported to be high in comparison to coastal and oceanic waters. Upwelling phenomenon...

  15. Primary Hyperparathyroidism

    Science.gov (United States)

    ... Neoplasia Type 1 Thyroid Disease & Pregnancy Primary Hyperparathyroidism Prolactinoma National Hormone and Pituitary Program (NHPP): Information for ... qualified health care provider nearby. Eating, Diet, and Nutrition Eating, diet, and nutrition have not been shown ...

  16. Primary Myelofibrosis

    Science.gov (United States)

    ... attack is higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left ...

  17. Nanoformulated cell-penetrating survivin mutant and its dual actions

    Directory of Open Access Journals (Sweden)

    Sriramoju B

    2014-07-01

    Full Text Available Bhasker Sriramoju, Rupinder K Kanwar, Jagat R Kanwar Nanomedicine Laboratory of Immunology and Molecular Biomedical Research (NLIMBR, School of Medicine, Faculty of Health, Deakin University, Geelong, Australia Abstract: In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells, and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome. Keywords: survivin mutant, neurological disorders, protein therapeutics, inhibitor of apoptosis protein family, poly(lactic-co-glycolic acid

  18. Cellular Reprogramming Using Protein and Cell-Penetrating Peptides

    Directory of Open Access Journals (Sweden)

    Bong Jong Seo

    2017-03-01

    Full Text Available Recently, stem cells have been suggested as invaluable tools for cell therapy because of their self-renewal and multilineage differentiation potential. Thus, scientists have developed a variety of methods to generate pluripotent stem cells, from nuclear transfer technology to direct reprogramming using defined factors, or induced pluripotent stem cells (iPSCs. Considering the ethical issues and efficiency, iPSCs are thought to be one of the most promising stem cells for cell therapy. Induced pluripotent stem cells can be generated by transduction with a virus, plasmid, RNA, or protein. Herein, we provide an overview of the current technology for iPSC generation and describe protein-based transduction technology in detail.

  19. [Hypertension: once primary, always primary?

    NARCIS (Netherlands)

    Braam, R.L.; Pieters, G.F.F.M.; Thien, Th.

    2002-01-01

    Three patients diagnosed with primary hypertension suddenly developed hard-to-treat blood pressure after several years of stable blood pressure. One patient, a man aged 48 years, had developed a renal artery stenosis, which had not been present five years earlier. The other two patients, a man aged

  20. Hyperthyroidism (primary)

    OpenAIRE

    Nygaard, Birte

    2010-01-01

    Hyperthyroidism is characterised by high levels of serum thyroxine and triiodothyronine, and low levels of thyroid-stimulating hormone (TSH). Thyrotoxicosis is the clinical effect of high levels of thyroid hormones, whether or not the thyroid gland is the primary source.The main causes of hyperthyroidism are Graves' disease, toxic multinodular goitre, and toxic adenoma.About 20 times more women than men have hyperthyroidism.

  1. Amphipathic dextran-doxorubicin prodrug micelles for solid tumor therapy.

    Science.gov (United States)

    Jin, Rong; Guo, Xuelian; Dong, Lingli; Xie, Enyuan; Cao, Aoneng

    2017-10-01

    A group of micelles self-assembled from deoxycholic acid-doxorubicin-conjugated dextran (denoted as Dex-DCA-DOX) prodrugs were designed and prepared for pH-triggered drug release and cancer chemotherapy. These prodrugs could be successfully produced by chemically coupling hydrophobic deoxycholic acid (DCA) to dextran hydrazine (denoted as Dex-NHNH 2 ) and hydrazone linker formation between doxorubicin (DOX) and Dex-NHNH 2 . These Dex-DCA-DOX prodrugs self-assembled to form micelles under physiological conditions with varied particle sizes depending on molecular weight of dextran, degree of substitution (DS) of DCA and DOX. After optimization, Dex10k-DCA9-DOX5.5 conjugate comprising dextran of 10kDa, DCA of DS 9 and DOX loading content of 5.5wt%, formed the micelles with the smallest size (110nm). These prodrug micelles could slowly liberate DOX under physiological conditions but efficiently released the drug at an acidified endosomal pH by the hydrolysis of acid-labile hydrazone linker. In vitro cytotoxicity experiment indicated that Dex10k-DCA9-DOX5.5 micelles exerted marked antitumor activity against MCF-7 and SKOV-3 cancer cells. Besides, intravenous administration of the micelles afforded growth inhibition of SKOV-3 tumor bearing in nude mice at a dosage of 2.5mg per kg with anti-cancer efficacy comparable to free DOX-chemotherapy but low systemic toxicity. This study highlights the feasibility of bio-safe and efficient dextran-based prodrug micelles designed for cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Primary Progressive Aphasia

    Science.gov (United States)

    ... which cause different symptoms. Semantic variant primary progressive aphasia Symptoms include these difficulties: Comprehending spoken or written ... word meanings Naming objects Logopenic variant primary progressive aphasia Symptoms include: Having difficulty retrieving words Frequently pausing ...

  3. Brain tumor - primary - adults

    Science.gov (United States)

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  4. Primary ovarian malignant melanoma

    Directory of Open Access Journals (Sweden)

    Kostov Miloš

    2010-01-01

    Full Text Available Background. Primary ovarian malignant melanoma is extremely rare. It usually appears in the wall of a dermoid cyst or is associated with another teratomatous component. Metastatic primary malignant melanoma to ovary from a primary melanoma elsewhere is well known and has been often reported especially in autopsy studies. Case report. We presented a case of primary ovarian malignant melanoma in a 45- year old woman, with no evidence of extraovarian primary melanoma nor teratomatous component. The tumor was unilateral, macroscopically on section presented as solid mass, dark brown to black color. Microscopically, tumor cells showed positive immunohistochemical reaction for HMB-45, melan-A and S-100 protein, and negative immunoreactivity for estrogen and progesteron receptors. Conclusion. Differentiate metastatic melanoma from rare primary ovarian malignant melanoma, in some of cases may be a histopathological diagnostic problem. Histopathological diagnosis of primary ovarian malignant melanoma should be confirmed by immunohistochemical analyses and detailed clinical search for an occult primary tumor.

  5. Investigating Primary Source Literacy

    Science.gov (United States)

    Archer, Joanne; Hanlon, Ann M.; Levine, Jennie A.

    2009-01-01

    Primary source research requires students to acquire specialized research skills. This paper presents results from a user study testing the effectiveness of a Web guide designed to convey the concepts behind "primary source literacy". The study also evaluated students' strengths and weaknesses when conducting primary source research. (Contains 3…

  6. Primary Hyperparathyroidism: An Overview

    Directory of Open Access Journals (Sweden)

    Jessica MacKenzie-Feder

    2011-01-01

    Full Text Available Primary hyperparathyroidism is a common condition that affects 0.3% of the general population. Primary and tertiary care specialists can encounter patients with primary hyperparathyroidism, and prompt recognition and treatment can greatly reduce morbidity and mortality from this disease. In this paper we will review the basic physiology of calcium homeostasis and then consider genetic associations as well as common etiologies and presentations of primary hyperparathyroidism. We will consider emerging trends in detection and measurement of parathyroid hormone as well as available imaging modalities for the parathyroid glands. Surgical indications and approach will be reviewed as well as medical management of primary hyperparathyroidism with bisphosphonates and calcimimetics.

  7. Normocalcemic Primary Hyperparathyroidism

    Science.gov (United States)

    Cusano, Natalie E.; Silverberg, Shonni J.; Bilezikian, John P.

    2013-01-01

    Primary hyperparathyroidism, a common endocrine disorder, is traditionally defined by hypercalcemia and elevated levels of parathyroid hormone (PTH). A newer presentation of primary hyperparathyroidism has been described over the past decade, in which PTH is elevated but serum calcium is consistently normal, in the absence of secondary causes of hyperparathyroidism, such as renal disease or vitamin D deficiency. Recognition of this phenotype of primary hyperparathyroidism, normocalcemic primary hyperparathyroidism, supports a biphasic chronological time course in some individuals in which PTH levels are first elevated but serum calcium is normal, followed by the development of frank hypercalcemia. This review focuses on the available literature regarding this newly described phenotype of primary hyperparathyroidism. PMID:23374739

  8. Multiple primary cancer

    International Nuclear Information System (INIS)

    Jung, Gyu Sik; Lee, Ouk; Kim, So Sun; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duck

    1989-01-01

    It is rare for one human being to be afflicted with more than one cancer. However with further advances in therapeutic regimens, histopathologic observation, diagnostic modalities, and increased curiosity, there are increasing number of case reports of multiple primary cancer. The present study evaluates 25 histologically confirmed cases of multiple primary cancer from 1974 to 1988 at Kosin Medical Center. The most frequent site of the first primary cancer in male was stomach and in female, uterine cervix. The first primary cancer in female occurred in endocrine-related organs (breast, uterus and thyroid) in 63.6 percent. Synchronous cancers are diagnosed simultaneously or within an interval of about six months and synchronous cancers were 16 out of 25 cases. Metachronous cancers are diagnosed at interval of more than six months. There were 9 metachronous cancers and average interval between the first and second primary cancer was 22.8 months. The incidence of multiple primary cancer was 0.11 percent. The average age was 51.9 years at the time of the first primary cancer (53.1 years in male and 50.3 years in female). CT scan was most helpful in early detection of multiple primary cancers facilitating biopsy and surgery. Multiple primary cancers are beyond the medical curiosity. Early diagnosis of the disease and careful follow-up study, based on an awareness of the possibility of second cancers, will substantially increase the survival of these patients

  9. Using Primary Source Documents.

    Science.gov (United States)

    Mintz, Steven

    2003-01-01

    Explores the use of primary sources when teaching about U.S. slavery. Includes primary sources from the Gilder Lehrman Documents Collection (New York Historical Society) to teach about the role of slaves in the Revolutionary War, such as a proclamation from Lord Dunmore offering freedom to slaves who joined his army. (CMK)

  10. Medics in Primary School

    Science.gov (United States)

    Press, Colin

    2003-01-01

    Some time ago a flyer on "Medics in Primary School" came the author's way. It described a programme for making placements in primary schools available to medical students. The benefits of the program to medical students and participating schools were highlighted, including opportunities to develop communication skills and demystify…

  11. Primary Sclerosing Cholangitis (PSC)

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Primary Sclerosing Cholangitis Back ...

  12. Primary cultures of astrocytes

    DEFF Research Database (Denmark)

    Lange, Sofie C; Bak, Lasse Kristoffer; Waagepetersen, Helle S

    2012-01-01

    During the past few decades of astrocyte research it has become increasingly clear that astrocytes have taken a central position in all central nervous system activities. Much of our new understanding of astrocytes has been derived from studies conducted with primary cultures of astrocytes...... subsequently found in vivo. Nevertheless, primary cultures of astrocytes are an in vitro model that does not fully mimic the complex events occurring in vivo. Here we present an overview of the numerous contributions generated by the use of primary astrocyte cultures to uncover the diverse functions...... of astrocytes. Many of these discoveries would not have been possible to achieve without the use of astrocyte cultures. Additionally, we address and discuss the concerns that have been raised regarding the use of primary cultures of astrocytes as an experimental model system....

  13. Primary Meningeal Rhabdomyosarcoma

    Science.gov (United States)

    Palta, Manisha; Riedel, Richard F.; Vredenburgh, James J.; Cummings, Thomas J.; Green, Scott; Chang, Zheng; Kirkpatrick, John P.

    2011-01-01

    Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy. PMID:21772793

  14. Primary Meningeal Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Manisha Palta

    2011-01-01

    Full Text Available Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13. Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC systemic therapy.

  15. Primary meningeal rhabdomyosarcoma.

    Science.gov (United States)

    Palta, Manisha; Riedel, Richard F; Vredenburgh, James J; Cummings, Thomas J; Green, Scott; Chang, Zheng; Kirkpatrick, John P

    2011-01-01

    Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy.

  16. Primary Nurse - Role Evolution

    Science.gov (United States)

    Mundinger, Mary O'Neil

    1973-01-01

    Primary nursing means that each patient has an individual nurse who is responsible for assessing his nursing needs and planning and evaluating his nursing care. The article describes the advantages and problems connected with this approach to patient care. (AG)

  17. Multiple Primary Tumors

    African Journals Online (AJOL)

    2017-12-05

    Dec 5, 2017 ... Multiple primary tumors occur in clinical practice causing diagnostic dilemma. It is not very .... was estrogen receptor negative, progesterone receptor negative, and ... cervical, ovarian, and urinary bladder cancers. Multiple.

  18. Primary infertility (image)

    Science.gov (United States)

    Primary infertility is a term used to describe a couple that has never been able to conceive a pregnancy ... to do so through unprotected intercourse. Causes of infertility include a wide range of physical as well ...

  19. Primary Intraorbital Ectopic Meningioma

    Science.gov (United States)

    Yokoyama, Tetsuo; Nishizawa, Shigeru; Sugiyama, Kenji; Yokota, Noki; Ohta, Seiji; Uemura, Kenichi; Hinokuma, Kaoru; Inenaga, Chikanori

    1999-01-01

    We report a case of intraorbital meningioma. Operative findings and histopathological examination revealed the tumoc to be meningothelial meningloma and to be located entirely outside the optic dura. This case demonstrates the occurrence of primary intraorbital ectopic meningioma, and the tumor was removed through a modified Dolenc approach. The primary intraorbital ectopic meningioma is discussed and the surgical approach to the orbital apex region is reviewed. ImagesFigure 1Figure 2Figure 4Figure 5 PMID:17171081

  20. Primary leiomyosarcoma of epididymis

    Directory of Open Access Journals (Sweden)

    Dillip Kumar Muduly

    2012-01-01

    Full Text Available Primary leiomyosarcomas rarely arise from epididymis. But they are the most common histopathological types of sarcoma arising from the epididymis. Primary epididymal leiomyosarcoma occurs usually in older patients. We report a young patient of 35 years presenting with leiomyosarcoma of left epididymis. He did not have any metastasis and underwent left high inguinal orchiectomy. He is on regular follow-up and disease free for last two years.

  1. Primary care ... where?

    Science.gov (United States)

    Adcock, G B

    1999-07-01

    Corporate-based nurse managed centers are not the national norm. More prevalent is the use of an occupational health or physician-directed medical model of care. The author describes how a 14-year-old primary care center at a North Carolina computer software company is just "business as usual" when viewed in the context of the company's philosophy, goals, and culture. Included are considerations for nurse practitioners interested in the successful transplantation of this primary care model to other settings.

  2. Other primary headaches

    Directory of Open Access Journals (Sweden)

    Anish Bahra

    2012-01-01

    Full Text Available The ′Other Primary Headaches′ include eight recognised benign headache disorders. Primary stabbing headache is a generally benign disorder which often co-exists with other primary headache disorders such as migraine and cluster headache. Primary cough headache is headache precipitated by valsalva; secondary cough has been reported particularly in association with posterior fossa pathology. Primary exertional headache can occur with sudden or gradual onset during, or immediately after, exercise. Similarly headache associated with sexual activity can occur with gradual evolution or sudden onset. Secondary headache is more likely with both exertional and sexual headache of sudden onset. Sudden onset headache, with maximum intensity reached within a minute, is termed thunderclap headache. A benign form of thunderclap headache exists. However, isolated primary and secondary thunderclap headache cannot be clinically differentiated. Therefore all headache of thunderclap onset should be investigated. The primary forms of the aforementioned paroxysmal headaches appear to be Indomethacin sensitive disorders. Hypnic headache is a rare disorder which is termed ′alarm clock headache′, exclusively waking patients from sleep. The disorder can be Indomethacin responsive, but can also respond to Lithium and caffeine. New daily persistent headache is a rare and often intractable headache which starts one day and persists daily thereafter for at least 3 months. The clinical syndrome more often has migrainous features or is otherwise has a chronic tension-type headache phenotype. Management is that of the clinical syndrome. Hemicrania continua straddles the disorders of migraine and the trigeminal autonomic cephalalgias and is not dealt with in this review.

  3. Primary Ectopic Ethmoidal Craniopharyngioma.

    Science.gov (United States)

    Preti, Andrea; Karligkiotis, Apostolos; Facco, Carla; Ottini, Giorgia; Volpi, Luca; Castelnuovo, Paolo

    2017-06-01

    Craniopharyngiomas are benign but aggressive epithelial tumors usually originating in the anterior lobe of the pituitary gland from squamous remnants of an incompletely involuted craniopharingeal duct developing from the Rathke pouch. To the authors' knowledge only 1 patient of a primary isolated ethmoidal craniopharyngioma has been reported in the literature.The authors report the case of a 17-year-old boy with a primary extracranial ethmoidal craniopharyngioma. An endoscopic endonasal approach was employed to resect the tumor. After 2 years of clinical and radiological follow-up no recurrence of disease was observed.Primary ethmoidal craniopharyngiomas are rare entities and biopsy is necessary for diagnosis. However, a preoperative assessment by means of nasal endoscopy, computed tomography scan, and enhanced magnetic resonance imaging is mandatory to better evaluate the extension and characteristics of the tumor. The endoscopic endonasal technique is a safe and effective approach for the treatment of these lesions.

  4. Primary renal synovial sarcoma

    Directory of Open Access Journals (Sweden)

    Girish D. Bakhshi

    2012-03-01

    Full Text Available Primary Renal Sarcoma is rare tumor comprising only 1% of all renal tumours. Synovial sarcomas are generally deep-seated tumors arising in the proximity of large joints of adolescents and young adults and account for 5-10% of all soft tissue tumours. Primary synovial sarcoma of kidney is rare and has poor prognosis. It can only be diagnosed by immunohistochemistry. It should be considered as a differential in sarcomatoid and spindle cell tumours. We present a case of 33-year-old female, who underwent left sided radical nephrectomy for renal tumour. Histopathology and genetic analysis diagnosed it to be primary renal synovial sarcoma. Patient underwent radiation therapy and 2 years follow up is uneventful. A brief case report with review of literature is presented.

  5. Primary headaches in children

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Pan

    2015-01-01

    Full Text Available Headache is a widespread clinical problem; the prevalence is high in all age groups, from which children and teenagers are not spared. It has been reported that, as many as 75% of school-age children may experience headache infrequently, among them 10% have recurrent headaches. [1],[2] The vast majority of headaches are primary and classified as migraine, tension-type headache (TTH, cluster headache, and other trigeminal autonomic cephalgias. The type of primary headaches could usually be diagnosed by a thorough and careful history taking, and physical examination. Once the diagnosis of migraine is established and appropriate reassurance provided, a balanced and individually tailored treatment plan can be instituted. The goal of treatment includes abortive or acute pain treatment, preventive long-term treatment, and biobehavioral therapy. Knowledge of precise impact of primary headaches on child′s quality of life helps to design a proper comprehensive treatment plan.

  6. Normocalcemic primary hyperparathyroidism

    Science.gov (United States)

    Bilezikian, John P.; Silverberg, Shonni J.

    2011-01-01

    SUMMARY Primary hyperparathyroidism is a common disorder of mineral metabolism characterized by incompletely regulated, excessive secretion of parathyroid hormone from one or more of the parathyroid glands. The historical view of this disease describes two distinct entities marked by two eras. When primary hyperparathyroidism was first discovered about 80 years ago, it was always symptomatic with kidney stones, bone disease and marked hypercalcemia. With the advent of the multichannel autoanalyzer about 40 years ago, the clinical phenotype changed to a disorder characterized by mild hypercalcemia and the absence of classical other features of the disease. We may now be entering a 3rd era in the history of this disease in which patients are being discovered with normal total and ionized serum calcium concentrations but with parathyroid hormone levels that are consistently elevated. In this article, we describe this new entity, normocalcemic primary hyperparathyroidism, a forme fruste of the disease. PMID:20485897

  7. [Primary care in Ireland].

    Science.gov (United States)

    Sánchez-Sagrado, T

    Spanish doctors are still leaving the country to look for quality work. Ireland is not a country with many Spanish professionals but it is interesting to know its particular Health care system. Ireland is one of the countries with a national health care system, although it has a mixture of private health care insurance schemes. People have a right to health care if they have been living in Ireland at least for a year. Access to the primary care health system depends on age and income: free of charge for Category 1 and co-payments for the rest. This division generates great inequalities among the population. Primary Care doctors are self-employed, and they work independently. However, since 2001 they have tended to work in multidisciplinary teams in order to strengthen the Primary Care practice. Salary is gained from a combination of public and private incomes which are not differentiated. The role of the General Practitioner consists in the treatment of acute and chronic diseases, minor surgery, child care, etc. There is no coordination between Primary and Secondary care. Access to specialised medicine is regulated by the price of consultation. Primary Care doctors are not gatekeepers. To be able to work here, doctors must have three years of training after medical school. After that, Continuing Medical Education is compulsory, and the college of general practitioners monitors it annually. The Irish health care system does not fit into the European model. Lack of a clear separation between public and private health care generates great inequalities. The non-existence of coordination between primary and specialised care leads to inefficiencies, which Ireland cannot allow itself after a decade of economic crisis. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Thoughts on primary care.

    Science.gov (United States)

    Raskin, Lynne

    2010-01-01

    The uptake of family health teams in Ontario has been tremendous. And the creation of group practices in primary care has taken root in other provinces as well. For many people, being involved with something new is exciting. At the same time, once they are committed, they discover the challenges that can be simultaneously exhilarating and frustrating. This issue of Healthcare Quarterly offers two articles that provide interesting reflections on what has been learned so far from the perspectives of both team leadership and the team members themselves within a transforming primary care system.

  9. Primary lymphoma of the brain

    Science.gov (United States)

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  10. Surgery of Primary Melanomas

    Directory of Open Access Journals (Sweden)

    Piotr Rutkowski

    2010-05-01

    Full Text Available Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

  11. Surgery of Primary Melanomas

    Energy Technology Data Exchange (ETDEWEB)

    Rutkowski, Piotr, E-mail: rutkowskip@coi.waw.pl; Zdzienicki, Marcin; Nowecki, Zbigniew I. [Soft Tissue/Bone Sarcoma and Melanoma Department, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw (Poland); Akkooi, Alexander C. J. van [Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

    2010-05-11

    Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

  12. Surgery of Primary Melanomas

    International Nuclear Information System (INIS)

    Rutkowski, Piotr; Zdzienicki, Marcin; Nowecki, Zbigniew I.; Akkooi, Alexander C. J. van

    2010-01-01

    Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas

  13. Primary intestinal lymphangiectasia.

    Science.gov (United States)

    Suresh, N; Ganesh, R; Sankar, Janani; Sathiyasekaran, Malathi

    2009-10-01

    Primary intestinal lymphangiectasia (PIL) is a rare disease of intestinal lymphatics presenting with hypoproteinemia, bilateral lower limb edema, ascites, and protein losing enteropathy. We report a series of 4 children from Chennai, India presenting with anasarca, recurrent diarrhea, hypoproteinemia and confirmatory features of PIL on endoscopy and histopathology.

  14. Healthcare is primary

    Directory of Open Access Journals (Sweden)

    Raman Kumar

    2015-01-01

    Full Text Available India is undergoing a rapid transformation in terms of governance, administrative reforms, newer policy develoment, and social movements. India is also considered one of the most vibrant economies in the world. The current discourse in public space is dominated by issues such as economic development, security, corruption free governance, gender equity, and women safety. Healthcare though remains a pressing need of population; seems to have taken a backseat. In the era of decreasing subsidies and cautious investment in social sectors, the 2 nd National Conference on Family Medicine and Primary Care 2015 (FMPC brought a focus on "healthcare" in India. The theme of this conference was "Healthcare is Primary." The conference participants discussed on the theme of why healthcare should be a national priority and why strong primary care should remain at the center of healthcare delivery system. The experts recommended that India needs to strengthen the "general health system" instead of focusing on disease based vertical programs. Public health system should have capacity and skill pool to be able to deliver person centered comprehensive health services to the community. Proactive implementation of policies towards human resource in health is the need of the hour. As the draft National Health Policy 2015 is being debated, "family medicine" (academic primary care, the unfinished agenda of National Health Policy 2002, remains a priority area of implementation.

  15. Multiple Primary Tumors

    African Journals Online (AJOL)

    2018-02-07

    Feb 7, 2018 ... breast and ascending colon. KEYWORDS: Carcinoid, colorectal cancer, metachronous, synchronous. Multiple Primary Tumors. MA Adeyanju, AA Ilori. Address for correspondence: Dr. MA Adeyanju,. Department of Surgery, Federal Medical Centre, Ebute Metta,. Lagos, Nigeria. E-mail: mbadeyanju@yahoo.

  16. Primary malignant intramedullary lymphoma

    International Nuclear Information System (INIS)

    Orrego P, E.; Heinicke Y, H.; Arbaiza A, D.; Yepez R, V.

    1999-01-01

    A case of primary malignant intramedullary lymphoma, localized in the dorsal part of the spinal cord is presented. The clinical symptoms were associated with motor and sensitive deficit. Clinical investigations excluded the presence of lymphoma in other locations in the central nervous system and the extra neural organs. Postoperative radiotherapy and chemotherapy improved relict neurological symptoms. (authors)

  17. Primary black holes

    International Nuclear Information System (INIS)

    Novikov, I.; Polnarev, A.

    1981-01-01

    Proves are searched for of the formation of the so-called primary black holes at the very origin of the universe. The black holes would weigh less than 10 13 kg. The formation of a primary black hole is conditional on strong fluctuations of the gravitational field corresponding roughly to a half of the fluctuation maximally permissible by the general relativity theory. Only big fluctuations of the gravitational field can overcome the forces of the hot gas pressure and compress the originally expanding matter into a black hole. Low-mass black holes have a temperature exceeding that of the black holes formed from stars. A quantum process of particle formation, the so-called evaporation takes place in the strong gravitational field of a black hole. The lower the mass of the black hole, the shorter the evaporation time. The analyses of processes taking place during the evaporation of low-mass primary black holes show that only a very small proportion of the total mass of the matter in the universe could turn into primary black holes. (M.D.)

  18. Familial primary hyperparathyroidism

    International Nuclear Information System (INIS)

    Iqbal, P.; Javed, R.

    2007-01-01

    A case of primary hyperparathyroidism in a 17 years old female is described. Patient presented with severe abdominal and pelvic pains associate with discomfort. Diagnostic testing revealed multiple upper and lower limb fractures and renal stones. Case was self limiting. Patient's condition resolved on parathyroidectomy for adenoma and partial thyroidectomy. Follow-up showed familial links. (author)

  19. Multiple Primary Cancer Monograph

    Science.gov (United States)

    To identify groups of cancer survivors that are at increased risk for multiple primary cancers, investigators led an effort to provide the first comprehensive population-based analysis of the risk of subsequent cancer in the U.S., resulting in a monograph.

  20. Primary cosmic ray flux

    Energy Technology Data Exchange (ETDEWEB)

    Stanev, Todor

    2001-05-01

    We discuss the primary cosmic ray flux from the point of view of particle interactions and production of atmospheric neutrinos. The overall normalization of the cosmic ray flux and its time variations and site dependence are major ingredients of the atmospheric neutrino predictions and the basis for the derivation of the neutrino oscillation parameters.

  1. in primary care

    African Journals Online (AJOL)

    Claire van Deventer

    Keywords: child HIV, doctor involvement, primary health care, quality improvement ... expertise increased, PHC facilities are now expected to be able to .... organised patient documentation were revisited. .... Review: what can we learn from quality ... South Pacific: Review of evidence and lessons from an innovative.

  2. [Primary and secondary encopresis].

    Science.gov (United States)

    Lang-Langer, Ellen

    2007-01-01

    While the difficulty of the child to part with its faeces in primary encopresis is linked to the incapability to experience the object as separated and independent from himself, secondary encopresis is a progressed psychical state of development. In this case we have to deal with regression caused by conflict. Two case-studies show clearly the differences.

  3. Spirometry in primary care

    Science.gov (United States)

    Coates, Allan L; Graham, Brian L; McFadden, Robin G; McParland, Colm; Moosa, Dilshad; Provencher, Steeve; Road, Jeremy

    2013-01-01

    Canadian Thoracic Society (CTS) clinical guidelines for asthma and chronic obstructive pulmonary disease (COPD) specify that spirometry should be used to diagnose these diseases. Given the burden of asthma and COPD, most people with these diseases will be diagnosed in the primary care setting. The present CTS position statement was developed to provide guidance on key factors affecting the quality of spirometry testing in the primary care setting. The present statement may also be used to inform and guide the accreditation process for spirometry in each province. Although many of the principles discussed are equally applicable to pulmonary function laboratories and interpretation of tests by respirologists, they are held to a higher standard and are outside the scope of the present statement. PMID:23457669

  4. Cancer of unknown primary

    DEFF Research Database (Denmark)

    Dyrvig, Anne-Kirstine; Yderstræde, Knud Bonnet; Gerke, Oke

    2017-01-01

    210 (38.7%) had a CUP diagnosis confirmed. Within the cohort, 347 patients (64.0%) had a registration in CR matching with the NPR registration. Exposure to diagnostic procedures included biopsy (n = 439, 81.0%) and image modalities (n = 532, 98.2%). Survival was poor with 67 (12.4%) individuals alive...... after 4 years.The validity of a CUP diagnosis in NPR was low when using data from CR as reference. More than half the suspected CUP patients had a previous cancer diagnosis with CUP being the most frequent. Patients were diagnosed in compliance with guidelines indicating high external validity, but less...... than 1 quarter had their primary identified and the 1-year survival was approximately 20%. Research is needed to develop efficacious methods for primary detection....

  5. Primary omental pregnancy

    International Nuclear Information System (INIS)

    Yildizhan, R.; Kurdoglu, M.; Kolusari, A.; Erten, R.

    2008-01-01

    Omental pregnancy is a rare form of ectopic pregnancy and can be seen primarily or secondary to a tubal pregnancy. A 25-yeal-old woman presented with abdominal distention with pain and anemia without vaginal bleeding. After a provisional diagnosis of ruptured ectopic pregnancy, laparotomy was performed. On surgical exploration, the bilateral tubes and ovaries were intact, however, an omental pregnancy was detected as the cause of hemoperitoneum. Partial omentectomy was performed. Although most cases are secondary, presented here is an additional case of primary omental pregnancy at 12 weeks according to Studdiford's criteria. Histological evidence of neovascularization into the supporting tissue confirmed our diagnosis. A primary omental pregnancy should always be considered as a possible explanation for severe hemoperitoneum in ectopic pregnancies presenting with acute abdomen and with intact adnexes on surgical exploration. (author)

  6. Basics of primary immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Claudia Hernández-Martínez

    2016-05-01

    Full Text Available Primary immunodeficiencies (PID are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis.

  7. [Primary care in France].

    Science.gov (United States)

    Sánchez-Sagrado, T

    2016-01-01

    The poor planning of health care professionals in Spain has led to an exodus of doctors leaving the country. France is one of the chosen countries for Spanish doctors to develop their professional career. The French health care system belongs to the Bismarck model. In this model, health care system is financed jointly by workers and employers through payroll deduction. The right to health care is linked to the job, and provision of services is done by sickness-funds controlled by the Government. Primary care in France is quite different from Spanish primary care. General practitioners are independent workers who have the right to set up a practice anywhere in France. This lack of regulation has generated a great problem of "medical desertification" with problems of health care access and inequalities in health. French doctors do not want to work in rural areas or outside cities because "they are not value for money". Medical salary is linked to professional activity. The role of doctors is to give punctual care. Team work team does not exist, and coordination between primary and secondary care is lacking. Access to diagnostic tests, hospitals and specialists is unlimited. Duplicity of services, adverse events and inefficiencies are the norm. Patients can freely choose their doctor, and they have a co-payment for visits and hospital care settings. Two years training is required to become a general practitioner. After that, continuing medical education is compulsory, but it is not regulated. Although the French medical Health System was named by the WHO in 2000 as the best health care system in the world, is it not that good. While primary care in Spain has room for improvement, there is a long way for France to be like Spain. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  8. [Primary care in Italy].

    Science.gov (United States)

    Sánchez-Sagrado, T

    Italy is not a country where Spanish doctors emigrate, as there is an over-supply of health care professionals. The Italian Servizio Sanitario Nazionale has some differences compared to the Spanish National Health System. The Servizio Sanitario Nazionale is financed by national and regional taxes and co-payments. There are taxes earmarked for health, and Primary Care receives 50% of the total funds. Italian citizens and residents in Italy have the right to free health cover. However, there are co-payments for laboratory and imaging tests, pharmaceuticals, specialist ambulatory services, and emergencies. Co-payments vary in the different regions. The provision of services is regional, and thus fragmentation and major inequities are the norm. Doctors in Primary Care are self-employed and from 2000 onwards, there are incentives to work in multidisciplinary teams. Salary is regulated by a national contract and it is the sum of per-capita payments and extra resources for specific activities. Responsibilities are similar to those of Spanish professionals. However, medical care is more personal. Relationships between Primary Care and specialised care depend on the doctors' relationships. Primary Care doctors are gatekeepers for specialised care, except for gynaecology, obstetrics and paediatrics. Specialised training is compulsory in order to work as general practitioner. The Italian Health Care System is a national health system like the Spanish one. However, health care professionals are self-employed, and there are co-payments. In spite of co-payments, Italians have one of the highest average life expectancy, and they support a universal and publicly funded health-care system. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Primary Tunnel Junction Thermometry

    International Nuclear Information System (INIS)

    Pekola, Jukka P.; Holmqvist, Tommy; Meschke, Matthias

    2008-01-01

    We describe the concept and experimental demonstration of primary thermometry based on a four-probe measurement of a single tunnel junction embedded within four arrays of junctions. We show that in this configuration random sample specific and environment-related errors can be avoided. This method relates temperature directly to Boltzmann constant, which will form the basis of the definition of temperature and realization of official temperature scales in the future

  10. Primary stabbing headache.

    Science.gov (United States)

    Pareja, Juan A; Sjaastad, Ottar

    2010-01-01

    Primary stabbing headache is characterized by transient, cephalic ultrashort stabs of pain. It is a frequent complaint with a prevalence of 35.2%, a female preponderance, and a mean age of onset of 28 years (Vågå study). Attacks are generally characterized by moderate to severe, jabbing or stabbing pain, lasting from a fraction of a second to 3s. Attack frequency is generally low, with one or a few attacks per day. The paroxysms generally occur spontaneously, during daytime. Most patients exhibit a sporadic pattern, with an erratic, unpredictable alternation between symptomatic and non-symptomatic periods. Paroxysms are almost invariably unilateral. Temporal and fronto-ocular areas are most frequently affected. Attacks tend to move from one area to another, in either the same or the opposite hemicranium. Jabs may be accompanied by a shock-like feeling and even by head movement - "jolts" -or vocalization. On rare occasions, conjunctival hemorrhage and monocular vision loss have been described as associated features. Primary stabbing headache may concur, synchronously or independently, with other primary headaches. In contrast to what is the case in adults, in childhood it is not usually associated with other headaches. Treatment is rarely necessary. Indomethacin, 75-150 mg daily, may seem to be of some avail. Celecoxib, nifedipine, melatonin, and gabapentin have been reported to be effective in isolated cases and small series of patients. The drug studies need corroboration. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. [Primary headache and depression].

    Science.gov (United States)

    Gesztelyi, Gyöngyi

    2004-11-28

    Primary headaches--mainly tension-type headache and migraine--affect a significant portion of the population. Depression is also highly prevalent. The co-existence of a primary headache and depression in the same patient therefore might be a coincidence due to the high prevalence of these conditions, but there might be a causal relationship between them, or headaches and depression might have a common background. This review of the literature summarizes the features of the relationship between primary headaches and depression. Depression is more prevalent in headache patients than in the headache-free population. Prospective epidemiological studies suggest a common genetic, biochemical or environmental background behind primary headaches and depression. This theory is supported by the role of the same neurotransmitter systems (mostly serotonin and dopamine) in headaches as well as in depression. Comorbid depression is associated with female gender, higher age, and higher frequency of headaches. Most depression inventories--questionnaires used to screen for the severity of depressive symptoms--contain transdiagnostic items, therefore their use in their original form is limited in organic diseases: due to the somatic items they might overestimate the severity of depression. When examining a headache patient special attention should be paid to the recognition of comorbid depression. The diagnosis of suspected mood disorder could be supported by using simple screening methods, such as the original or the abbreviated versions of standard depression inventories, but the final diagnosis of major depression needs psychiatric evaluation. Quality of life of the headache patient is affected not only by the characteristics of pain (frequency, duration, severity) but also by the disability caused by headache and the associating mood disorder. Recognizing coexisting mood disorder and disability helps to make the best treatment choice for the acute and preventive treatment of

  12. Cell-Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer

    Science.gov (United States)

    2015-10-01

    observations with DHT -stimulated luciferase activity assays, enzalutamide had no effect on the constitutive induction of luciferase activity by the AR...to expess firefly luciferase under the control of a synthetic ARE. Similar studies were also performed with intact LNCaP cells stimulated with DHT ...enzalutamide. B. Demonstration that 3E10-AR441 can inhibit non-genomic, AR-dependent signaling. These studies used LNCaP cells stimulated with DHT , with a

  13. Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B

    DEFF Research Database (Denmark)

    Ndeboko, Bénédicte; Lemamy, Guy Joseph; Nielsen, Peter E

    2015-01-01

    , such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck......-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics...

  14. Human DMBT1-Derived Cell-Penetrating Peptides for Intracellular siRNA Delivery

    DEFF Research Database (Denmark)

    Tuttolomondo, Martina; Casella, Cinzia; Hansen, Pernille Lund

    2017-01-01

    tumor 1) is a pattern recognition molecule that interacts with polyanions and recognizes and aggregates bacteria. Taking advantage of these properties, we investigated whether specific synthetic DMBT1-derived peptides could be used to formulate nanoparticles for siRNA administration. Using......-potential, circular dichroism, dynamic light scattering, and transmission electron microscopy revealed negatively charged nanoparticles with an average diameter of 10-800 nm, depending on the reaction conditions, and a spherical or rice-shaped morphology, depending on the peptide and β-helix conformation. We...

  15. Cell Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer

    Science.gov (United States)

    2016-12-01

    The pCMhAR plasmid was mutagenized to produce a Q680X variant, with a premature stop codon. We decided not to study the E231G mutation since current...compared two methods of producing 3E10-AR441 as a secreted protein in Pichia pastoris : a. the standard method of growing yeast in glycerol and then...3E10-AR441 bispecific antibody. L. Demonstration that scFv AR441 sequences prevent secretion of fusion proteins in yeast . We have used a yeast

  16. Enhanced cellular delivery of cell-penetrating peptide-peptide nucleic acid conjugates by photochemical internalization

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Nielsen, Peter E

    2011-01-01

    (antisense activity) is still limited by endocytotic entrapment. We have shown that this low bioavailability can be greatly improved by combining CPP-PNA conjugate administration with a photochemical internalization technique using photosensitizers such as aluminum phthalocyanine (AlPcS(2a...

  17. Intracellular O2 sensing probe based on cell-penetrating phosphorescent nanoparticles.

    Science.gov (United States)

    Fercher, Andreas; Borisov, Sergey M; Zhdanov, Alexander V; Klimant, Ingo; Papkovsky, Dmitri B

    2011-07-26

    A new intracellular O(2) (icO(2)) sensing probe is presented, which comprises a nanoparticle (NP) formulation of a cationic polymer Eudragit RL-100 and a hydrophobic phosphorescent dye Pt(II)-tetrakis(pentafluorophenyl)porphyrin (PtPFPP). Using the time-resolved fluorescence (TR-F) plate reader set-up, cell loading was investigated in detail, particularly the effects of probe concentration, loading time, serum content in the medium, cell type, density, etc. The use of a fluorescent analogue of the probe in conjunction with confocal microscopy and flow cytometry analysis, revealed that cellular uptake of the NPs is driven by nonspecific energy-dependent endocytosis and that the probe localizes inside the cell close to the nucleus. Probe calibration in biological environment was performed, which allowed conversion of measured phosphorescence lifetime signals into icO(2) concentration (μM). Its analytical performance in icO(2) sensing experiments was demonstrated by monitoring metabolic responses of mouse embryonic fibroblast cells under ambient and hypoxic macroenvironment. The NP probe was seen to generate stable and reproducible signals in different types of mammalian cells and robust responses to their metabolic stimulation, thus allowing accurate quantitative analysis. High brightness and photostability allow its use in screening experiments with cell populations on a commercial TR-F reader, and for single cell analysis on a fluorescent microscope.

  18. Localization of primary aldosteronism

    International Nuclear Information System (INIS)

    Pagny, J.Y.; Chatellier, G.; Raynaud, A.; Plouin, P.F.; Corvol, P.

    1988-01-01

    After diagnosis of primary aldosteronism on the basis of biochemical evidence, the detection of the tumour is of crucial importance in the management of the disease. The efficacy of CT-Scan, Iodo-Cholesterol Scintigraphy, digitalized phlebography, adrenal vein sampling for steroid measurements (AVS), and Nuclear Magnetic Resonance (NMR) in 160 hypertensive patients with primary aldosteronism was reviewed. Diagnosis of Conn's adenoma (n=96) or Adrenal Hyperplasia (n=40) was confirmed by surgery or at least two concordant tumour localization tests. Scintigraphy gave a correct diagnosis in 53% of the 51 exams, CT-Scan in 82% of the 85 exams, and phlebography in 79% of 61 exams. Plasma Aldosterone/ Cortisol ratio was 5 times higher on the side of adenoma in 55% of the 47 cases but this ratio was also present in 23% of 22 patients with adrenal hyperplasia. Each procedure exhibited few false positive and false negative cases. NMR performed in 15 patients with Conn's adenoma identified all the cases. But tumours displayed a signal close to the liver signal and identical to the normal adrenal. These results and the risk of invasive procedure (failure of catheterization of the right adrenal vein (n=6) and adrenal haematoma (n=2) lead to propose a schema of exploration of patients with primary aldosteronism. The CT-Scan could be performed at the first step once the biological diagnosis confirmed. Phlebography and AVS will be performed only if tumour was less than 1 cm at the CT-Scan despite important biological abnormalities. This schema requires to be validated by a prospective evaluation [fr

  19. Teacher of primary English

    CERN Multimedia

    2003-01-01

    Part-time teacher of primary English needed for September 2003 to teach English National Curriculum (KS2) and NLS to mother tongue or good second language English-speakers aged 7-10. 4 hours contact time per week, team planning, marking and meetings. Candidates should be English mother tongue qualified teachers, confident, flexible classroom practitioners and team players. For further details and how to apply see http://enpferney.org/staff_vacancies.htm English National Programme, Lycée International, Ferney-Voltaire (http://enpferney.org/)

  20. Primary isolated hepatic tuberculosis

    International Nuclear Information System (INIS)

    Sheikh, A.S.F.; Qureshi, I.H.; Saba, K.; Bukhari, M.H.

    2013-01-01

    Isolated hepatic tuberculosis without pulmonary or bowel involvement is a diagnostic challenge and can cause considerable morbidity. A young lady from Lahore presented with fever, pain in right hypochondria, nausea and weight loss. CT scan of abdomen showed multiple small hypodense non-enhancing lesions and a heterogeneous texture of liver. Biopsy confirmed the diagnosis of hepatic tuberculosis. It was concluded a case of isolated hepatic tuberculosis without evidence of other primary sites involvement. It is important to consider tuberculosis in the differential diagnosis when suspecting lymphoproliferative or metastatic diseases in a patient with vague symptoms and abnormal hepatic texture on CT. (author)

  1. PRIMARY CARIES: AN OVERVIEW

    Directory of Open Access Journals (Sweden)

    Gaurav Solanki

    2012-01-01

    Full Text Available Primary caries is an initial lesions produced by direct extension from an external surface. Dental caries is called as tooth decay or a cavity is a disease in which bacterial processes changes carbohydrate to acid which than dematerializes the hard tooth structure like enamel, dentin and cementum. Streptococcus mutans and Lactobacillus are the bacteria responsible for the dental caries by acid production. This article throws light on the dental caries disease, its sign and symptoms, treatment and prevention of it. A review of some patents on dental caries is also provided that summarizes the recent technical advancements taken place in this area.

  2. Primary cutaneous lymphoma

    International Nuclear Information System (INIS)

    Nguyen, M. Connie; Cleary, Sean F.; Hoppe, Richard T.

    1995-01-01

    Purpose: A retrospective review analyzed the survival and freedom from relapse of patients with stage IE or IIE primary cutaneous lymphoma (non mycosis fungoides) after treatments with radiation therapy alone (XRT), chemotherapy alone (RX) or combined modality therapy (CMT). Methods and Materials: Fifty two patients with stage IE-IIE cutaneous lymphoma treated at Stanford University Hospital were reviewed. The median age was 57, with a range of 26 to 94 and a male to female ratio of 1.21:1. Patients were staged according to the Ann Arbor System. Pathology was classified according to the Working Formulation. Treatment outcomes were compared using Kaplan-Meier survival curves with a Gehan p-value test. Results: The follow up range was 6 months to 22 years (median 7 years.) Twenty one percent of patients had low grade, 63% had intermediate grade and 15% had high grade lymphoma. The most common histologic subtype was diffuse large cell lymphoma Thirty two patients received radiation alone as initial treatment and sixteen patients received combined modality as initial treatment. Four patients received chemotherapy alone. The only significant prognostic factor for survival was the stage at diagnosis. Patients with stage IE disease had a longer actuarial survival (5-yr=79%, 10-yr=71%), as compared to those with stage IIE (5-yr=49%, 10-yr=33%), (p=0.029). The only significant prognostic factor for freedom from relapse was the initial treatment. Initial combined modality treatment lead to a longer freedom from relapse compared to patients treated with radiation alone (p=0.002), (median 5 years vs. 1.2 years). Despite this, the actuarial overall survival in the combined modality group and the radiation alone group are similar (median survival 7.7 and 8 years). The efficacy of either radiation or chemotherapy as salvage treatment after radiation failure was equivalent and both salvage treatments lead to equally long survival and freedom from second relapse. Conclusion

  3. Bellefonte primary containment structure

    International Nuclear Information System (INIS)

    Olyniec, J.H.

    1981-01-01

    Construction of the reactor building primary containment structure at the Bellefonte Nuclear Plant involved several specialized construction techniques. This two unit plant is one of the nine nuclear units at six different sites now under construction by the Tennessee Valley Authority (TVA). The post-Tensioned, cast-in-place interior steel lined containment structure is unique within TVA. Problems during construction were identified at weekly planning meetings, and options were discussed. Close coordination between craft supervisors and on-site engineering personnel drew together ''hands-on''experience and technical background. Details of the construction techniques, problems, and solutions are presented

  4. Primary Carnitine Deficiency

    DEFF Research Database (Denmark)

    Rasmussen, Jan; Hougaard, David M; Sandhu, Noreen

    2017-01-01

    Primary carnitine deficiency (PCD) causes low levels of carnitine in patients potentially leading to metabolic and cardiac symptoms. Newborn screening for PCD is now routine in many countries by measuring carnitine levels in infants. In this study we report Apgar scores, length and weight...... scores, length and weight compared to controls. Newborns with PCD and newborns born to mothers with PCD had significantly lower levels of free carnitine (fC0) than controls. Screening algorithms focusing only on fC0 had a high rate of detection of newborns with PCD. Sample collection 4-9 days after birth...

  5. Aspirin for Primary Prevention.

    Science.gov (United States)

    Richman, Ilana B; Owens, Douglas K

    2017-07-01

    Aspirin reduces the risk of nonfatal myocardial infarction and stroke, and the risk of colorectal cancer. Aspirin increases the risk of gastrointestinal and intracranial bleeding. The best available evidence supports initiating aspirin in select populations. In 2016, the US Preventive Services Task Force recommended initiating aspirin for the primary prevention of both cardiovascular disease and colorectal cancer among adults ages 50 to 59 who are at increased risk for cardiovascular disease. Adults 60 to 69 who are at increased cardiovascular disease risk may also benefit. There remains considerable uncertainty about whether younger and older patients may benefit. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Primary cutaneous lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, M Connie; Cleary, Sean F; Hoppe, Richard T

    1995-07-01

    Purpose: A retrospective review analyzed the survival and freedom from relapse of patients with stage IE or IIE primary cutaneous lymphoma (non mycosis fungoides) after treatments with radiation therapy alone (XRT), chemotherapy alone (RX) or combined modality therapy (CMT). Methods and Materials: Fifty two patients with stage IE-IIE cutaneous lymphoma treated at Stanford University Hospital were reviewed. The median age was 57, with a range of 26 to 94 and a male to female ratio of 1.21:1. Patients were staged according to the Ann Arbor System. Pathology was classified according to the Working Formulation. Treatment outcomes were compared using Kaplan-Meier survival curves with a Gehan p-value test. Results: The follow up range was 6 months to 22 years (median 7 years.) Twenty one percent of patients had low grade, 63% had intermediate grade and 15% had high grade lymphoma. The most common histologic subtype was diffuse large cell lymphoma Thirty two patients received radiation alone as initial treatment and sixteen patients received combined modality as initial treatment. Four patients received chemotherapy alone. The only significant prognostic factor for survival was the stage at diagnosis. Patients with stage IE disease had a longer actuarial survival (5-yr=79%, 10-yr=71%), as compared to those with stage IIE (5-yr=49%, 10-yr=33%), (p=0.029). The only significant prognostic factor for freedom from relapse was the initial treatment. Initial combined modality treatment lead to a longer freedom from relapse compared to patients treated with radiation alone (p=0.002), (median 5 years vs. 1.2 years). Despite this, the actuarial overall survival in the combined modality group and the radiation alone group are similar (median survival 7.7 and 8 years). The efficacy of either radiation or chemotherapy as salvage treatment after radiation failure was equivalent and both salvage treatments lead to equally long survival and freedom from second relapse. Conclusion

  7. PRIMARY SCHOOL TEACHER

    CERN Multimedia

    Madeleine Dittus

    2002-01-01

    For January 2003, the A.P.E.G. has an opening for a primary school teacher in the German national language program. The position requires one afternoon of teaching (13:30 till 16:30) every Tuesday at the Collège in Prévessin. The candidate should be a native speaker of German and have some knowledge of French. If you are interested, please send your CV, a copy of your diploma, and a short letter of motivation, until December 9th, to the following address. Madeleine Dittus Présidente A.P.E.G. 5, La vie Destraz 01630 St. Genis-Pouilly (France)

  8. Pattern of Primary Nocturnal Enuresis in Primary School Children ...

    African Journals Online (AJOL)

    Pattern of Primary Nocturnal Enuresis in Primary School Children (First Grade) in ... The control group consisting of 100 age-matched non-enuretic children ... was insignificantly associated with a positive family history, family size or birth rank.

  9. Primary iris leiomyoma.

    Science.gov (United States)

    Yeaney, Gabrielle A; Platt, Sean; Singh, Arun D

    Intraocular leiomyomas are uncommon and usually occur in the ciliary body. Primary leiomyoma of the iris is both rare and a difficult diagnosis to make, given melanocytic tumors are more common and may be amelanotic. The somewhat controversial diagnosis of iris leiomyoma requires further confirmation by immunohistochemistry and electron microscopy. Herein, we describe a 58-year-old man with a 2-mm round translucent pink lesion of the iris. The tumor was excised by sector iridectomy. Immunohistochemistry showed positivity for both smooth muscle actin and desmin and negativity for S-100, HMB45, SOX10, MelanA, CD31, CD34, and h-caldesmon. Epstein-Barr virus-associated smooth muscle tumor was excluded by chromogenic in situ hybridization-Epstein-Barr virus-encoded RNA. Ultrastructural analysis showed cytoplasmic myofilaments with focal fusiform densities and micropinocytotic vesicles. Our review of previous literature confirmed the unusual nature of this tumor. Primary iris leiomyoma should be considered in the differential of an amelanotic S-100-immunonegative iris tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Imaging in primary osteosarcomas

    International Nuclear Information System (INIS)

    Davies, A.M.

    1998-01-01

    Osteosarcoma is the most common primary malignant bone tumour with the exception of myeloma. The majority of osteosarcoma cases arise within bone and are called conventional osteosarcoma. Intraosseous variants include telangiectatic, small-cell, low-grade intraosseous and cortical osteosarcoma. Less than 10% of osteosarcomas arise on the surface of bone and are subdivided into periosteal, high-grade surface and parosteal varieties. The imaging features of these subtypes of osteosarcoma are described and the impact on diagnosis highlighted. Using material from over 750 osteosarcomas treated at the author's centre, this article reviews the role of imaging in the management of this condition. Detection still relies principally on the conventional radiograph with bone scintigraphy and MR imaging useful in occult tumours. Establishing the radiological diagnosis depends on careful analysis of the radiographs, with particular attention paid to the nature and extent of bone destruction, periosteal new bone formation and matrix mineralization. The prudent radiologist will be wary of those bone conditions, such as stress fractures and osteomyelitis, which are frequently mistaken for osteosarcoma. Appropriate surgical staging requires MR imaging of the primary tumour to show the bony and soft tissue extent of the lesion and to confirm/exclude skip metastases and local lymph-node involvement. Staging should also include bone scintigraphy to confirm/exclude multiple lesions and chest CT to confirm/exclude pulmonary metastases. Following definitive surgery, imaging is used in the follow-up to monitor potential local recurrence and the development of pulmonary or osseous metastases. (orig.) [de

  11. [Normocalcemic primary hyperparathyroidism].

    Science.gov (United States)

    Spivacow, Francisco R; Sapag Durán, Ana; Zanchetta, María B

    2014-01-01

    This report shows our conclusions on the clinical, biochemical and densitometry characteristics of 35 normocalcemic primary hyperparathyroidism (PHPT) patients. This condition is defined by a high level of intact parathyroid hormone (iPTHI) with persistently normal serum and ionized calcium in the absence of secondary hyperparathyroidism. Our selection consisted of 30 women (90%) and 5 men (10%). The control group of 55 hypercalcemic patients with primary hyperparathyroidism included 51 women (93%) and 4 men (7%). The average age at diagnosis of normocalcemic PHPT was 61.4 ± 11.7 years and 56.4 ± 11.3 years in hypercalcemic PHPT. Besides the expected differences in serum calcium, ionized calcium, phosphorus and 24 h urinary calcium, we found no significant changes in other biochemical variables, and no differences in densitometry evaluations such as the presence of osteopenia or osteoporosis and the number of fractures in the two types of PHPT. But there was a significant difference in the presence of renal lithiasis between normocalcemic PHPT (11.4%) and clasic PHPT (49.1%) p < 0.0005, to some extent associated to the presence of hypercalciuria in classic PHPT. Two of the 35 patients with normocalcemic PHPT became classic hypercalcemic PHPT over a 4 year follow-up period. Our findings support the hypothesis that the normocalcemic PHPT could be an early stage of the classic PHPT, both having similar clinical effects to metabolic renal and bone levels.

  12. Asymptomatic Primary Hyperparathyroidism

    Science.gov (United States)

    Silverberg, Shonni J.; Walker, Marcella D.; Bilezikian, John P.

    2014-01-01

    The clinical profile of primary hyperparathyroidism (PHPT) as it is seen in the United States and most Western countries has evolved significantly over the past half century. The introduction of the multichannel serum autoanalyzer in the 1970s led to the recognition of a cohort of individuals with asymptomatic hypercalcemia, in whom evaluation led to the diagnosis of PHPT. The term “asymptomatic primary hyperparathyroidism” was introduced to describe patients who lack obvious signs and symptoms referable to either excess calcium or parathyroid hormone. Although it was expected that asymptomatic patients would eventually develop classical symptoms of PHPT, observational data suggest that most patients do not evolve over time to become overtly symptomatic. In most parts of the world, the asymptomatic phenotype of PHPT has replaced classical PHPT. This report is a selective review of data on asymptomatic PHPT: its demographic features, presentation and natural history, as well as biochemical, skeletal, neuromuscular, psychological, and cardiovascular manifestations. In addition, we will summarize available information on treatment indications and options for those with asymptomatic disease. PMID:23374736

  13. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    Journal of Community Medicine and Primary Health Care. ... Ladoke Akintola University of Technology, PMB 4400, Osogbo, Osun State. ... weak management and poor adherence to the basic infrastructure e.g. primary, secondary and tertiary.

  14. Bezafibrate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Rudic, Jelena S; Poropat, Goran; Krstic, Miodrag N

    2012-01-01

    Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet....

  15. BR-5 primary circuit decontamination

    International Nuclear Information System (INIS)

    Efimov, I.A.; Nikulin, M.P.; Smirnov-Averin, A.P.; Tymosh, B.S.; Shereshkov, V.S.

    1976-01-01

    Results and methodology of steam-water and acid decontamination of the primary coolant circuit SBR-5 reactor in 1971 are discussed. Regeneration process in a cold trap of the primary coolant circuit is discussed

  16. Primary Prevention With Statins

    DEFF Research Database (Denmark)

    Mortensen, Martin B; Afzal, Shoaib; Nordestgaard, Børge G

    2015-01-01

    BACKGROUND: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility. OBJECTIVES: This study...... the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin......-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC...

  17. Primary care guidelines

    DEFF Research Database (Denmark)

    Ijäs, Jarja; Alanen, Seija; Kaila, Minna

    2009-01-01

    OBJECTIVE: To describe the adoption of the national Hypertension Guideline in primary care and to evaluate the consistency of the views of the health centre senior executives on the guideline's impact on clinical practices in the treatment of hypertension in their health centres. DESIGN: A cross...... Guideline. RESULTS: Data were available from 143 health centres in Finland (49%). The views of head physicians and senior nursing officers on the adoption of the Hypertension Guideline were not consistent. Head physicians more often than senior nursing officers (44% vs. 29%, p ...: Hypertension Guideline recommendations that require joint agreements between professionals are less often adopted than simple, precise recommendations. More emphasis on effective multidisciplinary collaboration is needed....

  18. Adrenal incidentalomas. Primary hyperaldosteronism

    International Nuclear Information System (INIS)

    Murat, A.; Dupas, B.; Zenatti, M.; Aupetit-Faisant, B.; Tenenbaum, F.; Tabarin, A.; Barrat, J.L.; Gosse, P.; Olivier-Puel, F.; Leprat, F.; Trouette, H.; Laurent, F.; Roger, P.

    1993-01-01

    Adrenal incidentalomas are masses incidentally discovered at X rays, ultrasound or MRI examination of the abdomen. In 100 CT scans, one can expect to find two incidentalomas on average. The article by Murat and Dupas is dealing with the strategy of biological, morphological and scintigraphic examinations to be performed in such patients, to assess whether the tumor is of a benign or a malignant nature. Zenatti et al propose a detailed exploration of the aldosterone pathways, since adrenal carcinoma may be responsible for a specific profile of the serum concentrations of mineralo-steroids, compatible with a blockade of the last step of the aldosterone synthesis. The exploration of primary hyperaldosteronism requires biological and imaging techniques. Tabarin et al summarize the main biological parameters and tests available for the diagnosis of this condition and delineate the indications of imaging techniques, associated to hormonal tests to distinguish between adenoma and bilateral adrenal hyperplasia. (author). 104 refs

  19. Primary Anorectal Melanoma

    Directory of Open Access Journals (Sweden)

    Maliha Khan

    2014-03-01

    Full Text Available Primary malignant melanoma of the anus and rectum is a rare and aggressive neoplasm that tends to invade locally and metastasize early in the course of the disease. It is often misdiagnosed as hemorrhoids or as one of the other benign anorectal conditions and is thus linked to an overall poor prognosis and a 5-year survival rate of less than 20%. Optimal treatment is still controversial, and current evidence does not show any preferential survival benefit from abdominoperineal resection over wide local excision. Chemotherapy or radiotherapy may be used for advanced disease. We report a 71-year-old female presenting with painful bowel movements and blood in stools. She was eventually found to have a mass arising from the anorectal junction with regional lymph node involvement. The patient underwent an abdominoperineal resection and is currently scheduled for chemotherapy.

  20. Primary conjunctival amyloidosis

    Directory of Open Access Journals (Sweden)

    Chandana Chakraborti

    2014-01-01

    Full Text Available A 19-year-old previously healthy male presented with a 4 year history of painless drooping of right upper eyelid.On eversion of the right upper eyelid, a yellowish pink mass was seen in the tarsal region. Rest of the ocular examination was normal in both the eyes. Initial biopsy showed chronic inflammation. Subsequently, the entire mass was excised and histopathological examination showed the presence of amyloid in the subconjunctival stroma. At 3 months follow-up, similar lesion was detected in the right lower, left upper, and lower lid, which were treated with cryotherapy, with partial resolution. Patient has been followed up for more than 2 years without any complaints. To our knowledge, this is the first case report of an isolated primary conjunctival amyloidosis with involvement of both the upper and lower palpebral conjunctiva of either eye. It was treated successfully by excision and cryotherapy.

  1. Prostaglandins and primary dysmenorrhea

    International Nuclear Information System (INIS)

    Seifert, B.; Liedtke, M.P.; Kempf, H.J.; Richter, H.; Alexander, H.; Herter, U.

    1978-01-01

    In 100 patients a total of 171 PG determinations in the menstrual blood was performed under standardized conditions. The primary PGE 1 and PGFsub(2α) were determined by RIA. The evaluation of the analysis of the sexual hormones resulted in a group with a biphasic cycle without dysmenorrhea and a group with a biphasic cycle with dysmenorrhea. Highly significant differences (p < 0.01) were found in the PGFsub(2α) concentration in menstrual blood between a group of healthy women and one of patients with dysmenorrhea. In dysmenorrhea the ratio of the PGs investigated is shifted in favor of PGFsub(2α). Indomethacin can decrease the PGFsub(2α) levels in dysmenorrhea up to 15% (p < 0.01). All treated patients reported that their conditions had improved. Five out of seven women were completely without any complaints. (author)

  2. PRIMARY SCHOOL TEACHER

    CERN Multimedia

    Madeleine Dittus

    2002-01-01

    For the beginning of the school year 2002/2003, the A.P.E.G. has an opening for a primary school teacher in the German national language program. The position requires one afternoon of teaching (13:30 till 16:30) every Tuesday at the Collège in Prévessin. The candidate should be a native speaker of German and have some knowledge of French. If you are interested, please send your CV, a copy of your diploma, and a short letter of motivation, until March 10th, to the following address. Madeleine Dittus - Présidente A.P.E.G. 5, La vie Destraz 01630 St. Genis-Pouilly - France

  3. Primary Fallopian Tube Carcinoma

    Directory of Open Access Journals (Sweden)

    Prasad K Shetty

    2011-01-01

    Full Text Available Primary Fallopian Tube Carcinoma (PFTC is rare and accounts for about 0.3% of all gynecologic cancers. Less than 1500 cases have been reported in the literature. It arises in postmenopausal women and typically presents with abdominal pelvic pain, vaginal bleeding and watery discharge. However, a correct diagnosis is rarely achieved preoperative, and in many cases, the diagnosis is made after incidental surgery for unrelated conditions commonly being ovarian carcinoma . Compared with ovarian carcinoma, PFTC more often presents at early stages, but it has a worse prognosis. PFTC is usually managed in the same manner as ovarian cancer. We report a case of Left PFTC that presented as Left ovarian mass, and we briefly review the literature.

  4. Primary aldosteronism. Clinical management

    International Nuclear Information System (INIS)

    Grant, C.S.; Carpenter, P.; van Heerden, J.A.; Hamberger, B.

    1984-01-01

    We retrospectively reviewed the clinical features, methods of diagnosis and localization, and results of treatment in 105 patients with primary aldosteronism seen between 1969 and 1981. Coincident with the use of computed tomography (CT), 131 I-6-beta-iodomethyl norcholesterol scans (NP-59), and postural response studies, the study group was temporally divided into pre-1976 and post-1976 groups, and subdivided into groups with aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia. Our results indicate that aldosterone postural response studies and CT differentiate and localize APA and IHA reliably. Adrenalectomy is a safe and effective treatment for APA, whereas medical treatment alone is preferable for IHA

  5. Primary Identity in Literature

    DEFF Research Database (Denmark)

    Graham, Brian Russell

    In our times, literary criticism, as well as larger political and cultural developments, is characterized by identity politics, meaning that our discourses are structured around the notion of different socially identifiable populations in society. In relation to literature, this results in our...... viewing the characters in literature in terms of these political identities. Literature is consequently discussed in relation to political causes. Literary criticism is animated by the same causes, and is viewed as having a direct intervention in society in relation to them. In this paper, I will discuss......, in relation to Frye’s works, the idea that the primary identities of characters in literature were and, to a considerable extent, continue to be those of family-member identities. As such, literature should not be appropriated to a political context too readily. Whereas viewing characters in terms of...

  6. [Primary care in Belgium].

    Science.gov (United States)

    Sánchez-Sagrado, T

    2017-09-01

    Belgium is an attractive country to work in, not just for doctors but for all Spanish workers, due to it having the headquarters of European Union. The health job allure is double; on the one hand, the opportunity to find a decent job, and on the other, because it is possible to develop their professional abilities with patients of the same nationality in a health system with a different way of working. The Belgium health care system is based on security social models. Health care is financed by the government, social security contributions, and voluntary private health insurance. Primary care in Belgium is very different to that in Spain. Citizens may freely choose their doctor (general practitioner or specialist) increasing the lack of coordination between primary and specialized care. This leads to serious patient safety problems and loss of efficiency within the system. Belgium is a European country with room to improve preventive coverage. General practitioners are self-employed professionals with free choice of setting, and their salary is linked to their professional activity. Ambulatory care is subjected to co-payment, and this fact leads to great inequities on access to care. The statistics say that there is universal coverage but, in 2010, 14% of the population did not seek medical contact due to economic problems. It takes 3 years to become a General Practitioner and continuing medical education is compulsory to be revalidated. In general, Belgian and Spaniards living and working in Belgium are happy with the functioning of the health care system. However, as doctors, we should be aware that it is a health care system in which access is constrained for some people, and preventive coverage could be improved. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Primary Teacher Education in Malaysia

    Science.gov (United States)

    Ching, Chin Phoi; Yee, Chin Peng

    2012-01-01

    In Malaysia the training of primary school teachers is solely carried out by teacher training institutes which offer the Bachelor of Teaching with Honors (Primary education) program and was first launched in 2007. This program prepares primary school teachers specializing in various subjects or major and is carried out in 27 teacher training…

  8. Bilateral supernumerary primary maxillary canines

    Directory of Open Access Journals (Sweden)

    Santanu Mukhopadhyay

    2018-01-01

    Full Text Available Supernumerary teeth are more common in the permanent than in primary dentition. In the primary dentition, the anomaly is most frequently observed in the maxillary lateral incisor region, followed by the maxillary midline where they are termed as mesiodens. Supernumerary teeth in the primary canine region are rare. This paper describes a rare case of nonsyndromic supernumerary primary maxillary canine distributed bilaterally in a 4-year-old boy. Both the supernumeraries resembled size and shape of normal primary canine. The right supplemental canine is high labially placed, whereas the left one is seen normally aligned in the dental arch distal to lateral incisor. One of the most significant sequelae of primary supernumerary teeth is their duplication in the permanent series. Radiographic examination of supernumerary primary canine did not indicate any such anomaly in the permanent dentition. The patient was kept under observation.

  9. Comparison between Primary Teacher Educators' and Primary School Teachers' Beliefs of Primary Geography Education Quality

    Science.gov (United States)

    Bent, Gert Jan; Bakx, Anouke; den Brok, Perry

    2016-01-01

    In this study teacher educators' beliefs concerning primary geography education have been investigated and compared with primary school teachers' beliefs. In this study 45 teacher educators and 489 primary school teachers completed a questionnaire, and nine teacher educators have been interviewed as well. It has been found that teacher educators…

  10. Primary hepatic pheochromocytoma

    International Nuclear Information System (INIS)

    Rimmelin, A.; Hartheiser, M.; Gangi, A.; Welsch, M.; Jeung, M.Y.; Jaeck, D.; Tongio, J.; Dietemann, J.L.

    1996-01-01

    Pheochromocytomas are uncommon tumors that represent a potentially curable cause of hypertension. They are usually located in the adrenal glands, but 10% arise from extra-adrenal sites, located along the paravertebral sympathetic chains. We report a case of primary hepatic pheochromocytoma responsible for a severe hypertension in a 24-year-old man. Echotomography showed a lightly heterogeneous mass located in the segment 8 of the liver. Iodine 131 -metaiodobenzylguanidine scintigraphy showed a large hepatic concentration of the tracer and no other localization. This tumor appeared highly vascularized on enhanced CT scan and on aortic angiography. Magnetic resonance imaging revealed a hepatic tumor with a high signal intensity on T2-weighted images and with a signal isointense to the liver on T1-weighted images. The hepatic venous sampling contained the highest catecholamine level, whereas the adrenal venous samping was normal. After surgical resection of the hepatic tumor, the tension level and catecholamines plasmatic level normalized. No recurrent symptoms appeared during a 3-year follow-up. (orig.)

  11. Primary intestinal lymphangiectasia: Minireview

    Science.gov (United States)

    Ingle, Sachin B; Hinge (Ingle), Chitra R

    2014-01-01

    Primary idiopathic intestinal lymphangiectasia is an unusual disease featured by the presence of dilated lymphatic channels which are located in the mucosa, submucosa or subserosa leading to protein loosing enteropathy.Most often affected were children and generally diagnosed before third year of life but may be rarely seen in adults too. Bilateral pitting oedema of lower limb is the main clinical manifestation mimicking the systemic disease and posing a real diagnostic dilemma to the clinicians to differentiate it from other common systemic diseases like Congestive cardiac failure, Nephrotic Syndrome, Protein Energy Malnutrition, etc. Diagnosis can be made on capsule endoscopy which can localise the lesion but unable to take biopsy samples. Thus, recently double-balloon enteroscopy and biopsy in combination can be used as an effective diagnostic tool to hit the correct diagnosis. Patients respond dramatically to diet constituting low long chain triglycerides and high protein content with supplements of medium chain triglyceride. So early diagnosis is important to prevent untoward complications related to disease or treatment for the sake of accurate pathological diagnosis. PMID:25325063

  12. Primary hyperoxaluria in infants

    Directory of Open Access Journals (Sweden)

    Manel Jellouli

    2016-01-01

    Full Text Available The infantile form of primary hyperoxaluria type-1 (PH-1 is characterized by a rapid progression to the end-stage renal disease (ESRD due to both increased oxalate load and reduced glomerular filtration rate. In the literature, data on this form are limited. The purpose of this study is to analyze retrospectively the clinical, biological, and radiological features of children who were diagnosed with PH-1 during the 1styear of life. We reviewed the records of all children with PH-1 diagnosed and followed-up at our department between January 1995 and December 2013. Among them, only infants younger than 12 months of age were retrospectively enrolled in the study. Fourteen infants with the median age of two months were enrolled in the study. At diagnosis, 11 patients had ESRD. All patients had nephrocalcinosis and two of them had calculi. The diagnosis was established in nine patients on the basis of the positive family history of PH-1, bilateral nephrocalcinosis, and quantitative crystalluria. In four patients, the diagnosis was made with molecular analysis of DNA. Kidney biopsy contributed to the diagnosis in one patient. During follow-up, two patients were pyridoxine sensitive and preserved renal function. Seven among 11 patients who had ESRD died, four patients are currently undergoing peritoneal dialysis. Children with infantile PH and ESRD are at high risk of early death. Peritoneal dialysis is not a treatment of choice. Combined liver-kidney transplantation is mandatory.

  13. Primary hyperparathyroidism: recent advances.

    Science.gov (United States)

    Walker, Marcella D; Bilezikian, John P

    2018-07-01

    The purpose of this review is to describe recent advances and changes in the evaluation and management of primary hyperparathyroidism (PHPT). Although it has long been recognized that asymptomatic PHPT is associated with bone loss, particularly at cortical skeletal sites when evaluated with dual-energy X-ray absorptiometry, new imaging techniques suggest that trabecular skeletal deterioration as well as clinically silent vertebral fractures and nephrolithiasis are common. Nonclassical targets of asymptomatic PHPT as well as the effect of vitamin D deficiency and treatment upon PHPT presentation have been the subject of recent intense investigation. Randomized clinical trials are now available regarding the effect of parathyroidectomy (PTX) upon both classical and nonclassical target organs. They have confirmed results from observational studies with regard to the skeletal benefits of PTX but have not consistently shown improvements in nonclassical symptoms. These findings have led to recommendations for more extensive renal and skeletal evaluation and broader criteria for PTX in PHPT. In addition to dual-energy X-ray absorptiometry, vertebral and renal imaging is recommended. When available, trabecular imaging techniques may be helpful. PTX criteria now include subclinical kidney stones, vertebral fractures and hypercalciuria, in addition to those based on age, serum calcium, bone densitometry and renal function.

  14. Primary sclerosing cholangitis

    Directory of Open Access Journals (Sweden)

    Marina G Silveira

    2008-01-01

    Full Text Available Primary sclerosing cholangitis (PSC is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver disease and reduced life expectancy. PSC primarily affects young and middle-aged men, often in association with underlying inflammatory bowel disease. The etiology of PSC includes immune-mediated components and elements of undefined nature. A cholestatic picture of liver biochemistries with elevations in serum alkaline phosphatase, nonspecific autoantibodies such as perinuclear antineutrophilic antibody, antinuclear antibodies and smooth muscle antibodies, and diffuse multifocal biliary strictures, resulting in a ‘beaded’ appearance on radiographic studies, are the hallmarks of the disease. No effective medical therapy is currently available, although clinical studies are in progress. Ursodeoxycholic acid at high doses (28 mg/kg/day to 30 mg/kg/day is the most promising agent but is unproven so far. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease, although recurrent disease can be observed in the transplanted liver. The multiple complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, peristomal varices, bacterial cholangitis, dominant biliary strictures, gallbladder stones and polyps, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of PSC.

  15. Primary sclerosing cholangitis

    Directory of Open Access Journals (Sweden)

    Chapman Roger

    2006-10-01

    Full Text Available Abstract Primary sclerosing cholangitis (PSC is a chronic cholestatic liver disease of unknown aetiology characterised by inflammation and fibrosis of the biliary tree. The mean age at diagnosis is 40 years and men are affected twice as often as women. There is a reported annual incidence of PSC of 0.9–1.31/100,000 and point prevalence of 8.5–13.6/100,000. The onset of PSC is usually insidious and many patients are asymptomatic at diagnosis or have mild symptoms only such as fatigue, abdominal discomfort and pruritus In late stages, splenomegaly and jaundice may be a feature. In most, the disease progresses to cirrhosis and liver failure. Cholangiocarcinoma develops in 8–30% of patients. PSC is thought to be immune mediated and is often associated with inflammatory bowel disease, especially ulcerative colitis. The disease is diagnosed on typical cholangiographic and histological findings and after exclusion of secondary sclerosing cholangitis. Median survival has been estimated to be 12 years from diagnosis in symptomatic patients. Patients who are asymptomatic at diagnosis, the majority of whom will develop progressive disease, have a survival rate greater than 70% at 16 years after diagnosis. Liver transplantation remains the only effective therapeutic option for patients with end-stage liver disease from PSC, although high dose ursodeoxycholic acid may have a beneficial effect.

  16. Consanguinity and primary immunodeficiencies.

    Science.gov (United States)

    Al-Herz, Waleed; Aldhekri, Hasan; Barbouche, Mohamed-Ridha; Rezaei, Nima

    2014-01-01

    Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders caused by defects in the immune system that predispose patients to infections, autoimmune diseases, lymphoproliferation and malignancies. Most PIDs are inherited in an autosomal recessive pattern; therefore, they are more common in areas with high rates of consanguineous marriage. Reports about PIDs from these areas have demonstrated a peculiar prevalence of more severe forms of diseases compared to other regions, and patients born to consanguineous parents have increased rates of morbidity and mortality compared to other patients. Individuals at high risk of having a child with a PID who wish to have a healthy child have limited options, these include prenatal diagnosis and pre-implantation genetic diagnosis. However, these options require a collaborative team of specialists and may not always be implemented due to geographic, religious, financial or social factors. The recent introduction of newborn-screening programs for a number of T and B lymphocyte deficiencies will facilitate early diagnosis and therapeutic interventions, which may include hematopoietic stem cell transplantation and intravenous immunoglobulin treatment. There is a need for the implementation of strategies to increase public awareness of the health risks associated with consanguineous marriage. It should be stressed that genetic counseling should be an important component of the care of patients with PIDs as well as their families. © 2014 S. Karger AG, Basel.

  17. Idiopathic (primary achalasia

    Directory of Open Access Journals (Sweden)

    Vaezi Michael F

    2007-09-01

    Full Text Available Abstract Idiopathic achalasia is a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal lower esophageal sphincter (LES relaxation in response to deglutition. It is a rare disease with an annual incidence of approximately 1/100,000 and a prevalence rate of 1/10,000. The disease can occur at any age, with a similar rate in men and women, but is usually diagnosed between 25 and 60 years. It is characterized predominantly by dysphagia to solids and liquids, bland regurgitation, and chest pain. Weight loss (usually between 5 to 10 kg is present in most but not in all patients. Heartburn occurs in 27%–42% of achalasia patients. Etiology is unknown. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. Association of achalasia with viral infections and auto-antibodies against myenteric plexus has been reported, but the causal relationship remains unclear. The diagnosis is based on history of the disease, radiography (barium esophagogram, and esophageal motility testing (esophageal manometry. Endoscopic examination is important to rule out malignancy as the cause of achalasia. Treatment is strictly palliative. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents aimed at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Although it cannot be permanently cured, excellent palliation is available in over 90% of patients.

  18. Idiopathic (primary) achalasia

    Science.gov (United States)

    Farrokhi, Farnoosh; Vaezi, Michael F

    2007-01-01

    Idiopathic achalasia is a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal lower esophageal sphincter (LES) relaxation in response to deglutition. It is a rare disease with an annual incidence of approximately 1/100,000 and a prevalence rate of 1/10,000. The disease can occur at any age, with a similar rate in men and women, but is usually diagnosed between 25 and 60 years. It is characterized predominantly by dysphagia to solids and liquids, bland regurgitation, and chest pain. Weight loss (usually between 5 to 10 kg) is present in most but not in all patients. Heartburn occurs in 27%–42% of achalasia patients. Etiology is unknown. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. Association of achalasia with viral infections and auto-antibodies against myenteric plexus has been reported, but the causal relationship remains unclear. The diagnosis is based on history of the disease, radiography (barium esophagogram), and esophageal motility testing (esophageal manometry). Endoscopic examination is important to rule out malignancy as the cause of achalasia. Treatment is strictly palliative. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents) aimed at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Although it cannot be permanently cured, excellent palliation is available in over 90% of patients. PMID:17894899

  19. Achieving Value in Primary Care: The Primary Care Value Model.

    Science.gov (United States)

    Rollow, William; Cucchiara, Peter

    2016-03-01

    The patient-centered medical home (PCMH) model provides a compelling vision for primary care transformation, but studies of its impact have used insufficiently patient-centered metrics with inconsistent results. We propose a framework for defining patient-centered value and a new model for value-based primary care transformation: the primary care value model (PCVM). We advocate for use of patient-centered value when measuring the impact of primary care transformation, recognition, and performance-based payment; for financial support and research and development to better define primary care value-creating activities and their implementation; and for use of the model to support primary care organizations in transformation. © 2016 Annals of Family Medicine, Inc.

  20. A Peptide-based Vector for Efficient Gene Transfer In Vitro and In Vivo

    Science.gov (United States)

    Lehto, Taavi; Simonson, Oscar E; Mäger, Imre; Ezzat, Kariem; Sork, Helena; Copolovici, Dana-Maria; Viola, Joana R; Zaghloul, Eman M; Lundin, Per; Moreno, Pedro MD; Mäe, Maarja; Oskolkov, Nikita; Suhorutšenko, Julia; Smith, CI Edvard; Andaloussi, Samir EL

    2011-01-01

    Finding suitable nonviral delivery vehicles for nucleic acid–based therapeutics is a landmark goal in gene therapy. Cell-penetrating peptides (CPPs) are one class of delivery vectors that has been exploited for this purpose. However, since CPPs use endocytosis to enter cells, a large fraction of peptides remain trapped in endosomes. We have previously reported that stearylation of amphipathic CPPs, such as transportan 10 (TP10), dramatically increases transfection of oligonucleotides in vitro partially by promoting endosomal escape. Therefore, we aimed to evaluate whether stearyl-TP10 could be used for the delivery of plasmids as well. Our results demonstrate that stearyl-TP10 forms stable nanoparticles with plasmids that efficiently enter different cell-types in a ubiquitous manner, including primary cells, resulting in significantly higher gene expression levels than when using stearyl-Arg9 or unmodified CPPs. In fact, the transfection efficacy of stearyl-TP10 almost reached the levels of Lipofectamine 2000 (LF2000), however, without any of the observed lipofection-associated toxicities. Most importantly, stearyl-TP10/plasmid nanoparticles are nonimmunogenic, mediate efficient gene delivery in vivo, when administrated intramuscularly (i.m.) or intradermally (i.d.) without any associated toxicity in mice. PMID:21343913

  1. Primary intracranial malignant lymphoma

    International Nuclear Information System (INIS)

    Matsumoto, Mikiro; Ohtsuka, Takatsugu; Kuroki, Takao; Shibata, Iekado; Terao, Hideo; Kudo, Motoshige

    1988-01-01

    Nine cases of primary intracranial malignant lymphoma, which accounts for 3.3 % of all intracranial tumors seen in the authors' institution, were studied in terms of diagnostic computed tomographic (CT) features, the tumors' histologic appearance, treatment, post-treatment blood immunologic and cerebrospinal fluid (CSF) characteristics, and outcome. The patients were seven males and two females aged 42 to 67 years. Their chief signs and symptoms on admission were intracranial hypertension, focal signs, and disturbance of consciousness. CT, which proved the most useful preoperative diagnostic technique, demonstrated multiple lesions in seven cases and, in all cases, regions of isodensity or slight high density that were enhanced by contrast medium. According to the patterns of enhancement, the tumors were classed as diffuse (three cases) or nodular (six cases). The former is considered typical of malignant lymphoma, whereas the latter type was sometimes indistinguishable from metastatic tumor and meningioma. At surgery, one patient underwent radical tumor excision, two partial removal, and six biopsy only. Histologic examination revealed one tumor to be of the diffuse small cell type, three of the medium cell type, and five of the large cell type (Lymphoma Study Group classification). Of seven tumors in which lymphocytes were examined by peroxidase-antiperoxidase staining, four were of the B cell type. Postoperatively, whole brain irradiation with 29 to 46 Gy was followed by local irradiation with 15 to 50 Gy. If the tumor persisted, one of three chemotherapies was administered. In one case, methotrexate was given intrathecally. Seven patients were divided into two groups: long remission (three) and recurrence (four). These two groups were compared in terms of serum immunoglobulin levels, T and B cell ratios, CSF characteristics, CT features, tumor cell type, and treatment. No clear differences were found. (author)

  2. Primary cosmic radiation

    International Nuclear Information System (INIS)

    Anderson, H.R.

    1972-01-01

    The term cosmic radiation means the charged particle flux that reaches the earth from outside its magnetosphere with energies above the solar wind energy of a few keV. There are two sources of flux. Sporadically the sun produces such particles, generally within the energy range 1--200 MeV, and these solar cosmic rays arrive at the earth for a period ranging from hours to days. There may be a small, rather constant flux from the sun also, but the bulk of the steady flux originates outside the earth's orbit. Although some have conjectured that part of this latter flux may be accelerated in the outer portions of the solar system where the outward flowing interplanetary medium meets the interstellar medium, it is generally thought that most or all of it arises in unique systems such as supernovae, and is distributed throughout the galaxy. These galactic particles range in energy from a few MeV to at least 10 13 MeV and consist primarily of protons with significant numbers of heavier nuclei, positrons and electrons. They are supposed to fill our galaxy, or at least the disc, more or less uniformly. However, the flux with energies below a few GeV that reaches earth's orbit is modulated by the interplanetary medium so that the number at earth varies inversely with solar activity and is always somewhat below the interstellar flux. A discussion is presented of primary galactic radiation at earth, its modulation by solar activity, and its interaction with the geomagnetic field. (U.S.)

  3. [Primary care in Portugal].

    Science.gov (United States)

    Sánchez-Sagrado, T

    2018-04-01

    The economic crisis and deterioration of the Portuguese National Health service has forced professionals to leave the country. The Portuguese National Health System was introduced in 1976, but it has been unable to provide citizens with the social and health advantages of an equality of access and free national health system. The Portuguese National Health System is financed by taxes. However, a 35% of its incomes are from private sources. The health minister decides the budget, and it is based on an historical financing plus a per capita system. Portuguese citizens and immigrants are entitled to free health care, but there is a co-payment for care, diagnostic, pharmacy, and emergency care. Health care provision is a mixture of public and private health care at a regional level. It leads to fragmentation of services and greater inequalities. Doctors are civil servants. Salary is regulated and it depends on seniority and on-call shifts. Primary care activities are similar to those of their Spanish counterparts. General practitioners have gatekeeper function, but the system is imperfect, and patients with private insurance get direct access to the specialist. Specialist training is similar to the training system in Spain. Continuing education is not regulated. The Portuguese Health System has been trying to become a national health system since 1979. Political instability, fragmentation of services, lack of clarity between public and private and co-payments are important constraints. Inequalities are an important problem to reconsider while discussing a national health system. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  4. African Primary Care Research: qualitative interviewing in primary care.

    Science.gov (United States)

    Reid, Steve; Mash, Bob

    2014-06-05

    This article is part of a series on African Primary Care Research and focuses on the topic of qualitative interviewing in primary care. In particular it looks at issues of study design, sample size, sampling and interviewing in relation to individual and focus group interviews.There is a particular focus on helping postgraduate students at a Masters level to write their research proposals.

  5. Primary epiploic appendagitis

    Directory of Open Access Journals (Sweden)

    Carlos Augusto Real Martinez

    2013-07-01

    Full Text Available Primary epiploic appendagitis (PEA is a seldom reported disease caused by spontaneous torsion of one or more epiploic appendices. The aim of this study is to describe two cases of PEA reviewing the main aspects of the diagnosis and treatment of disease. Case report: Case 1 Male patient, 55 years old, obese, with abdominal right iliac fossa (RIF pain for two days. Abdominal examination showed pain on palpation in the RIF with rebound tenderness. Abdominal computed tomography identified lobulated lesion in the cecum, measuring 4.5 cm in diameter, which was suggestive of PEA or early neoplasm of the colon wall. The lapa- roscopic assessment confirmed the diagnosis of PEA and the appendix was removed. The pa- tient had a satisfactory outcome, being discharged on the second postoperative day. Case 2 Female patient, obese, 47 years old, with abdominal pain for six days, with sudden RIF onset. She had pain at palpation with rebound tenderness. Acute diverticulitis was suspected and patient underwent abdominal CT that identified PEA in the sigmoid colon. After expectant management, the patient showed progressive improvement resuming her activities in seven days. PEA is a rarely recalled condition during the investigation of inflammatory acute abdo- men which can be easily recognized by modern imaging methods of assessment. Resumo: Apendagite epiplóica primária (AEP é uma enfermidade raramente descrita, ocasionada pela torção espontânea de um ou mais apêndices epiplóicos. O objetivo deste estudo é descrever dois casos de AEP revisando os principais aspectos do diagnóstico e tratamento da doença. Relato dos Casos: 1° Homem, 55 anos, obeso com dor abdominal em FID há dois dias. No exame do abdômen apresentava dor à palpação na FID e descompressão brusca presente. A tomografia computadorizada do abdômen identificou lesão expansiva no ceco, lobulada, medindo 4,5 cm de diâmetro, suspeitando-se de AEP ou neoplasia primitiva da parede c

  6. Primary ectopic frontotemporal extradural craniopharyngioma

    Directory of Open Access Journals (Sweden)

    Reza Pourkhalili

    2016-01-01

    Full Text Available We present a case of primary ectopic frontotemporal extradural craniopharyngioma. Primary ectopic craniopharyngiomas are very rare and have been reported involving the fourth ventricle, infrasellar region, lateral ventricle, temporal area, cerebellopontine angle, clivus, corpus callosum, and prepontine cistern. There was just 1 case of craniopharyngioma previously presented in the literature, with nearly same location as the presenting case.

  7. Methotrexate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Giljaca, Vanja; Poropat, Goran; Stimac, Davor

    2010-01-01

    Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since...... that last review version, follow-up data of the included trials have been published....

  8. Primary Science Interview: Science Sparks

    Science.gov (United States)

    Bianchi, Lynne

    2016-01-01

    In this "Primary Science" interview, Lynne Bianchi talks with Emma Vanstone about "Science Sparks," which is a website full of creative, fun, and exciting science activity ideas for children of primary-school age. "Science Sparks" started with the aim of inspiring more parents to do science at home with their…

  9. Cardiovascular Risk in Primary Hyperaldosteronism

    NARCIS (Netherlands)

    Prejbisz, A.; Warchol-Celinska, E.; Lenders, J.W.M.; Januszewicz, A.

    2015-01-01

    After the first cases of primary aldosteronism were described and characterized by Conn, a substantial body of experimental and clinical evidence about the long-term effects of excess aldosterone on the cardiovascular system was gathered over the last 5 decades. The prevalence of primary

  10. Primary care research in Denmark

    DEFF Research Database (Denmark)

    Vedsted, Peter; Kallestrup, Per

    2016-01-01

    International Perspectives on Primary Care Research examines how the evidence base from primary care research can strengthen health care services and delivery, tackle the growing burden of disease, improve quality and safety, and increase a person-centred focus to health care. Demonstrating...... the inter-professional nature of the discipline, the book also features a section on cross-nation organisations and primary care networks supporting research. National perspectives are offered from researchers in 20 countries that form part of the World Organization of Family Doctors, providing case...... histories from research-rich to resource-poor nations that illustrate the range of research development and capacity building. This book argues the importance of primary care research, especially to policy makers, decision makers and funders in informing best practice, training primary health care providers...

  11. The Coming Primary Care Revolution.

    Science.gov (United States)

    Ellner, Andrew L; Phillips, Russell S

    2017-04-01

    The United States has the most expensive, technologically advanced, and sub-specialized healthcare system in the world, yet it has worse population health status than any other high-income country. Rising healthcare costs, high rates of waste, the continued trend towards chronic non-communicable disease, and the growth of new market entrants that compete with primary care services have set the stage for fundamental change in all of healthcare, driven by a revolution in primary care. We believe that the coming primary care revolution ought to be guided by the following design principles: 1) Payment must adequately support primary care and reward value, including non-visit-based care. 2) Relationships will serve as the bedrock of value in primary care, and will increasingly be fostered by teams, improved clinical operations, and technology, with patients and non-physicians assuming an ever-increasing role in most aspects of healthcare. 3) Generalist physicians will increasingly focus on high-acuity and high-complexity presentations, and primary care teams will increasingly manage conditions that specialists managed in the past. 4) Primary care will refocus on whole-person care, and address health behaviors as well as vision, hearing, dental, and social services. Design based on these principles should lead to higher-value healthcare, but will require new approaches to workforce training.

  12. Primary amenorrhea: diagnosis and management.

    Science.gov (United States)

    Marsh, Courtney A; Grimstad, Frances W

    2014-10-01

    Puberty is a defining time of many adolescents' lives. It is a series of events that includes thelarche, pubarche, and menarche. Primary amenorrhea is the absence of menarche. There are numerous etiologies including outflow tract obstructions, gonadal dysgenesis, and anomalies of the hypothalamic axis. This review's aims are to define primary amenorrhea and describe the various causes, their workups, associated comorbidities, and treatment options. At the end, a generalist should be able to perform an assessment of an adolescent who presents with primary amenorrhea and, if warranted, begin initial treatment.

  13. Primary vertebral tumours in children

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K.; Beluffi, G.; Masel, J.; Diard, F.; Ferrari-Ciboldi, F.; Le Dosseur, P.; Labatut, J.

    1984-03-01

    20 cases of primary benign and malignant bone tumours in children were reported. The most common tumours were Ewing's sarcoma, aneurismal bone cyst, benign osteoblastoma and osteoid osteoma. Some rare primary bone tumours in children (osteochondroma, chondroblastoma 6F, primary lymphoma of bone and neurofibromatosis with unusual cervical spinal changes) were also reported. The authors believe that radiographic findings together with clinical history and clinical examination may yield a high percentage of accurate diagnoses. Although microscopy is essential in the final diagnosis, the microscopic report should be also accepted with caution.

  14. Primary Productivity (PP_Master)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set included primary production for each subregion in the study (Georges Bank, Gulf of Maine, Southern New England, Middle Atlantic Bight) . The data came...

  15. Problems of Primary Education Today

    Science.gov (United States)

    Dubova, M. V.

    2014-01-01

    Primary education in Russia has failed to adapt to the needs of post-Soviet society, and is still based on rote learning and memorization instead of learning through discovery and learning to use and apply what is learned.

  16. Primary sclerosing cholangitis and pregnancy

    Directory of Open Access Journals (Sweden)

    Casper Q. Kammeijer

    2011-08-01

    Full Text Available Primary sclerosing cholangitis is a progressive disease, and coincidentally in pregnancy it is rare. It is characterized by progressive inflammation and destruction of bile ducts finally resulting in liver failure. A rare case of primary sclerosing cholangitis in pregnancy is presented. The course of the pregnancy was marked by threatened preterm delivery and exacerbation of cholestasis. She was successfully treated with ursodeoxycholic acid (UDCA. Although, primary sclerosing cholangitis has both maternal and fetal effects on pregnancy, the overall outcome is favorable. Only few cases have been reported using high dose ursodeoxycholic acid for primary sclerosing cholangitis in pregnancy, it often improves pruritus but has no protection against stillbirth. Data on the safety to the fetus or neonate and long-term outcome are scarce.

  17. COMMUNITY HEALTH & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    adedamla

    Quarry industry has become a major means of livelihood in Ebonyi state, but insufficient data exists on their operations ... of Dust Mask among Crushers of Selected Quarry (Crushed ... Journal of Community Medicine and Primary Health Care.

  18. Primary intracerebral lymphoma: Case report

    Directory of Open Access Journals (Sweden)

    Olcay Eser

    2012-09-01

    Full Text Available We describe a case of primary central nervous lymphoma (PCNSL that may be confused with magnetic resonance imaging (MRI findings of high grade glioma. Primary central nervous lymphoma is a rare tumour and it account for 0.3-3% of intracranial tumours. A 61 year’s old woman was admitted to our clinic with a severe headache, vomiting, left hemiparesia and transient loss of consciousness. Primary central nervous lymphoma may show various biological and radiological characteristics. We herein emphasized being confused with MRI findings of PCNSL and high grade glioma. J Clin Exp Invest 2012; 3 (3: 409-411Key words: Primary central nervous lymphoma, high grade glioma, B-cell, diagnosis

  19. Structures in the primary spectrum

    International Nuclear Information System (INIS)

    Kempa, J.; Knurenko, S.P.; Malecki, R.

    2009-01-01

    Structures in the energy spectrum of primary cosmic rays at the 'knee' region and for energies higher than 1 EeV are obtained through studying extensive air showers (EAS). The main problem of the research is the fact that we work in the ranges of highly fluctuating parameters used to obtain the primary energy spectrum. In this paper the log-normal distribution for the error function has been used in convolution with the power spectrum to explain the Yakutsk experimental data. Similar results have been obtained for the gamma distribution as the error function. Using the power law primary spectrum in the energy region around 10 19 eV we will argue that the primary Yakutsk spectrum is overestimated. In the best case this overestimation is not less than 42%.

  20. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    ajiboro

    3Department of Community and Primary Health Care, College of Medicine, University of Lagos, Idiaraba, ... Some of the participants (45.3%) carry out physical exercises such as walking ..... hypertension, continuous effective management of.

  1. COMMUNITY HEALTH & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    2Primary Health Care Department, Ikpoba Okha Local Government Area, Benin City, ... selected from each of the ten wards in the LGA using multistage sampling technique. ..... Knowledge of HIV/AIDS Insurance Companies in Lagos State.

  2. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    Client Satisfaction with Antenatal Care Services in Primary Health Care. Centres in Sabon ... important information about how well clinicians and the population of women within child bearing. 8 ..... model. Health and Quality of Life outcomes.

  3. Primary optic nerve sheath meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Jeremic, Branislav [International Atomic Energy Agency, Vienna (Austria); Pitz, Susanne (eds.) [University Eye Hospital, Mainz (Germany)

    2008-07-01

    Optic nerve sheath meningioma (ONSM) is a rare tumour. Cases are usually separated into primary ONSM, which arises either intraorbitally or, less commonly, intracanalicularly, and secondary ONSM, which arises intracranially and subsequently invades the optic canal and orbit. This is the first book to cover all important aspects of the diagnosis and treatment of primary ONSM. After a general introduction, individual chapters discuss the clinical presentation, clinical examination and diagnosis, imaging, and histology. Treatment options are then addressed in detail, with special emphasis on external beam radiation therapy, and in particular stereotactic fractionated radiation therapy. The latter has recently produced consistently good results and is now considered the emerging treatment of choice for the vast majority of patients with primary ONSM. This well-illustrated book will prove invaluable to all practitioners who encounter primary ONSM in their clinical work. (orig.)

  4. Allegheny County Primary Care Access

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — The data on health care facilities includes the name and location of all the hospitals and primary care facilities in Allegheny County. The current listing of...

  5. & PRIMARY HEALTH CARE COMMUNITY MEDICINE

    African Journals Online (AJOL)

    Family planning is an important preventive measure against maternal and child ... users of the services, desire for more children, fear of side effects and partner's ... It is an essential component of primary development across the regions .

  6. Characteristics of Sissi primary beam

    International Nuclear Information System (INIS)

    Nghiem, P.; Payet, J.; Tkatchenko, A.

    1994-01-01

    This study concerns the definition of the Sissi primary beam characteristics. The calculations have been carried out in two steps : -a study of primary and secondary order with the help of BETA matrix code -a study of superior orders with the help of ZGOUBI code which is able to take into consideration the measured fields and in which the movement equations are integrated numerically. (O.L.). 9 figs., 3 tabs

  7. Insomnia (primary) in older people

    OpenAIRE

    Alessi, Cathy; Vitiello, Michael V

    2011-01-01

    Up to 40% of older adults have insomnia, with difficulty getting to sleep, early waking, or feeling unrefreshed on waking. The prevalence of insomnia increases with age. Other risk factors include medical and psychiatric illnesses, psychological factors, stress, daytime napping, and hyperarousal.Primary insomnia is a chronic and relapsing condition that may increase the risks of accidents.Primary insomnia is chronic insomnia without specific underlying medical, psychiatric, or other sleep ...

  8. Hyperuricemia in Childhood Primary Hypertension

    OpenAIRE

    Feig, Daniel I.; Johnson, Richard J.

    2003-01-01

    Experimental animal models suggest that uric acid might have a pathogenic role in the early development of primary hypertension. We hypothesized that serum uric acid is correlated with blood pressure in children with new-onset, untreated, primary hypertension. We evaluated 125 consecutive children referred to the Baylor Pediatric Renal Program for evaluation of hypertension. None of the subjects had previously been evaluated or treated for hypertension. The children ranged in age from 6 to 18...

  9. Glucocorticosteroids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Giljaca, Vanja; Poropat, Goran; Stimac, Davor

    2010-01-01

    Primary sclerosing cholangitis is a chronic cholestatic disease of intrahepatic and extrahepatic biliary ducts, characterised by chronic periductal inflammation and sclerosis of the ducts, which results in segmental stenoses of bile ducts, cholestasis, fibrosis, and ultimately, liver cirrhosis...... sclerosing cholangitis, like ursodeoxycholic acid, glucocorticosteroids, and immunomodulatory agents, but none has been successful in reversing the process of the disease. To date, liver transplantation is the only definite therapeutic solution for patients with advanced primary sclerosing cholangitis...

  10. Primary system boron dilution analysis

    International Nuclear Information System (INIS)

    Crump, R.J.; Naretto, C.J.; Borgen, R.A.; Rockhold, H.C.

    1978-01-01

    The results are presented for an analysis conducted to determine the potential paths through which nonborated water or water with insufficient boron concentration might enter the LOFT primary coolant piping system or reactor vessel to cause dilution of the borated primary coolant water. No attempt was made in the course of this analysis to identify possible design modifications nor to suggest changes in administrative procedures or controls

  11. Gender equality in primary immunisation

    Directory of Open Access Journals (Sweden)

    Deepak S Khismatrao

    2015-01-01

    Full Text Available Context: Immunization, a well-known and effective method of preventing childhood illnesses is basic service under primary health care. Most surveys in India measure primary immunization coverage and quality, but no "Gender Equality." Aims: Assess "Gender Equality" in primary immunization with reference to coverage, quality, and place of immunization. Settings and Design: Cross-sectional survey in a primary health center, Pune, Maharashtra using World Health Organization 30-cluster sampling method with 14 beneficiaries (7 girls and 7 boys to be selected from each cluster. Instead of 420 children, data collected for 345 children, as requisite numbers of children were not available in low population villages and also children whose mothers were not present during survey were excluded. Materials and Methods: Vaccination data collected from either records and/or history by mother. Children born on or between 13-09-2009 and 13-09-2010, were included. Statistical Analysis Used: SPSS 14.01 version with Chi-square as test of significance. Results: Of the study population, 171 (49.6% were females and 174 (50.4% males. A total of 64.1% children had immunization records with female proportion 69.0% and males 59.2%. Primary immunization coverage was 80.0%, with female proportion 82.5% and males 77.6%. One male child was completely unimmunized and remaining partially immunized, with unaware of schedule and illness of child being major reasons for partial immunization. There was no gender wise statistically significant difference observed in Primary Immunization with reference to coverage, quality, and place of immunization. Conclusions: Immunization coverage is nearing 85% benchmark with major contribution from Universal Immunization Program. Gender Equality observed in primary immunization. Preservation of immunization records by community and timely vaccinations are areas for improvement.

  12. Cardiovascular Risk in Primary Hyperaldosteronism.

    Science.gov (United States)

    Prejbisz, A; Warchoł-Celińska, E; Lenders, J W M; Januszewicz, A

    2015-12-01

    After the first cases of primary aldosteronism were described and characterized by Conn, a substantial body of experimental and clinical evidence about the long-term effects of excess aldosterone on the cardiovascular system was gathered over the last 5 decades. The prevalence of primary aldosteronism varies considerably between different studies among hypertensive patients, depending on patient selection, the used diagnostic methods, and the severity of hypertension. Prevalence rates vary from 4.6 to 16.6% in those studies in which confirmatory tests to diagnose primary aldosteronism were used. There is also growing evidence indicating that prolonged exposure to elevated aldosterone concentrations is associated with target organ damage in the heart, kidney, and arterial wall, and high cardiovascular risk in patients with primary aldosteronism. Therefore, the aim of treatment should not be confined to BP normalization and hypokalemia correction, but rather should focus on restoring the deleterious effects of excess aldosterone on the cardiovascular system. Current evidence convincingly demonstrates that both surgical and medical treatment strategies beneficially affect cardiovascular outcomes and mortality in the long term. Further studies can be expected to provide better insight into the relationship between cardiovascular risk and complications and the genetic background of primary aldosteronism. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Primary malignant small bowel tumor

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Kyung Seung; Suh, Ho Jong; Kim, So Sun; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duk [Kosin College, Pusan (Korea, Republic of)

    1990-07-15

    Small bowel tumors are rarely detected unless there is intestinal obstruction or bleeding. In the seven years 1982-1988, at Kosin Medical Center, 25 primary malignant small bowel tumors were studied radiographically with barium and / or computed tomography (CT). CT revealed gastrointestinal abnormalities in 20 patients. In ten, lesion were identified by upper G-I series, in 15 by small bowel series, and in addition, in 3 by colon enema. The most common malignant small bowel tumor was adenocarcinoma (N=15) and was next common lymphoma (N=7). On barium study, primary adenocarcinoma appeared as an irregular stricture (66.7%) and polypoid mass with intussusception was most prominent finding in lymphoma. Leiomyosarcoma appeared as an exophytic mass with excavation or ulceration. CT was found to be accurate in detecting wall thickening, complications and other associated findings. In conclusion, barium study was useful in the diagnosis of primary malignant small bowel tumor and CT was more accurate in detecting secondary findings.

  14. Primary malignant small bowel tumor

    International Nuclear Information System (INIS)

    Oh, Kyung Seung; Suh, Ho Jong; Kim, So Sun; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duk

    1990-01-01

    Small bowel tumors are rarely detected unless there is intestinal obstruction or bleeding. In the seven years 1982-1988, at Kosin Medical Center, 25 primary malignant small bowel tumors were studied radiographically with barium and / or computed tomography (CT). CT revealed gastrointestinal abnormalities in 20 patients. In ten, lesion were identified by upper G-I series, in 15 by small bowel series, and in addition, in 3 by colon enema. The most common malignant small bowel tumor was adenocarcinoma (N=15) and was next common lymphoma (N=7). On barium study, primary adenocarcinoma appeared as an irregular stricture (66.7%) and polypoid mass with intussusception was most prominent finding in lymphoma. Leiomyosarcoma appeared as an exophytic mass with excavation or ulceration. CT was found to be accurate in detecting wall thickening, complications and other associated findings. In conclusion, barium study was useful in the diagnosis of primary malignant small bowel tumor and CT was more accurate in detecting secondary findings

  15. Primary thyroid lymphoma: CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyo-Cheol; Han, Moon Hee E-mail: hanmh@radcom.snu.ac.kr; Kim, Keon Ha; Jae, Hwan Jun; Lee, Sang Hyun; Kim, Sam Soo; Kim, Kwang Hyun; Chang, Kee-Hyun

    2003-06-01

    Introduction: To evaluate the computed tomographic (CT) findings of primary thyroid lymphoma. Methods and material: The clinicopathological data and CT images of nine patients with primary thyroid lymphoma were retrospectively reviewed. The CT appearances were classified into three types: type 1, a solitary nodule surrounded by normal thyroid tissue; type 2, multiple nodules in the thyroid, and type 3, a homogeneously enlarged both thyroid glands with a reduced attenuation with or without peripheral thin hyperattenuating thyroid tissue. Results: All patients had a rapidly enlarging thyroid mass and coexistent Hashimoto's thyroiditis. One patient showed type 1 pattern, three type 2, and five type 3. Six patients had homogeneous tumor isoattenuating to surrounding muscles. The tumors had a strong tendency to compress normal remnant thyroid and the surrounding structure without invasion. Conclusion: Primary thyroid lymphoma should be included in the differential diagnosis when old female had a homogeneous thyroidal mass isoattenuating to muscles, which does not invade surrounding structures.

  16. Recurrent Primary Spinal Hydatid Cyst

    Directory of Open Access Journals (Sweden)

    Okan Turk

    2015-03-01

    Full Text Available Primary hydatid disease of spine is rare and spinal hydatitosis constitute only 1% of all hydatitosis. We report a case of recurrent primary intraspinal extradural hydatid cyst of the thoracic region causing progressive paraparesis. The patient was operated 16 years ago for primary spinal hydatid disease involvement and was instrumented dorsally for stabilization. The magnetic resonance imaging (MRI of thoracic spine showed a cystic lesion at T11-12 level and compressed spinal cord posterolaterally. Intraspinal cyst was excised through T11-12 laminectomy which made formerly. The early postoperative period showed a progressive improvement of his neurological deficit and he was discharged with antihelmintic treatment consisting of albendazole and amoxicillin-sulbactam combination. [Cukurova Med J 2015; 40(Suppl 1: 84-89

  17. Primary prevention of chronic obstructive pulmonary disease in primary care.

    Science.gov (United States)

    van der Molen, Thys; Schokker, Siebrig

    2009-12-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent disease, with cigarette smoking being the main risk factor. Prevention is crucial in the fight against COPD. Whereas primary prevention is targeted on whole populations, patient populations are the focus of primary care; therefore, prevention in this setting is mainly aimed at preventing further deterioration of the disease in patients who present with the first signs of disease (secondary prevention). Prevention of COPD in primary care requires detection of COPD at an early stage. An accurate definition of COPD is crucial in this identification process. The benefits of detecting new patients with COPD should be determined before recommending screening and case-finding programs in primary care. No evidence is available that screening by spirometry results in significant health gains. Effective treatment options in patients with mild disease are lacking. Smoking cessation is the cornerstone of COPD prevention. Because cigarette smoking is not only a major cause of COPD but is also a major cause of many other diseases, a decline in tobacco smoking would result in substantial health benefits.

  18. Summarizing primary and secondary effects

    DEFF Research Database (Denmark)

    Karlson, Kristian Bernt

    2013-01-01

    Current methods for decomposing class differentials in educational decisions into primary and secondary effects produce many parameters, rendering them ill-equipped for parsimonious comparisons across countries or birth cohorts. This paper develops a parametric method that provides an optimal...... summary of primary and secondary effects across discrete class origins. Under the testable assumption that the pattern of effects of class origins on academic ability is proportional to the pattern of effects of class origins on educational choice net of academic ability, the method returns a single...

  19. Primary orbital squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ana L. Campos Arbulú

    2017-02-01

    Full Text Available Primary orbital squamous cell carcinoma is a rare entity. There is little published literature. We report a case of primary squamous cell carcinoma of the orbital soft tissues. Surgical resection offered the best treatment for the patient. Complete resection of the lesion was achieved. The patient received adjuvant radiotherapy due to the proximity of the lesion to the surgical margins. Surgical treatment is feasible and should be considered as part of the surgeon's arsenal. However, therapeutic decisions must be made on a case-by-case basis

  20. Primary carcinoma of the duodenum

    International Nuclear Information System (INIS)

    Steidle, B.; Huetter, B.; Ziegler, F.

    1984-01-01

    Primary carcinoma of the duodenum represents about 0.35% of all gastrointestinal carcinomas and is thus a rare disease. The radiological diagnosis of a duodenal origin is made more difficult by the close proximity of the pancreas, biliary system, right kidney and transverse colon. Histologically, duodenal malignant tumours are usually adenocarcinomas. Between 1973 and 1983, eight patients with primary duodenal carcinomas were diagnosed at the University of Tuebingen. Average age of the patients was 67 years. There was no sex difference. Average survival was 3.3 years. (orig.) [de

  1. Primary Posterior Mediastinum Hydatid Cyst

    International Nuclear Information System (INIS)

    Ahmed, M.; Eid, A. F.; Sheikh, M. Y.; Yiannakou, N.

    2014-01-01

    Primary posterior mediastinal hydatid cyst is a serious health problem for the Mediterranean countries. We diagnosed a case of a 46-year-old female with a primary posterior mediastinum hydatid cyst on CT and MRI. It was provisionally identified as either a hydatid cyst or bronchogenic cyst or neuroenteric cyst. CT guided aspiration with 18 gauge needle confirmed as hydatid sand. This is very rare in this population but it should be kept in mind when one is looking at any cyst in the posterior mediastinum. (author)

  2. Shoulder arthropathy in primary hyperparathyroidism

    International Nuclear Information System (INIS)

    Nussbaum, A.J.; Doppman, J.L.

    1982-01-01

    An erosive arthropathy of the hands and wrists has been recognized in patients with primary and secondary hyperparathyroidism. Recently, intra-articular erosions of the humeral head were described in six patients who had been on chronic long-term hemodialysis with secondary hyperparathyroidism. We would like to present the finding of shoulder erosions in four patients with primary hyperparathyroidism and one patient with renal osteodystrophy and suggest that the humeral erosion can occur in both an intra-articular and peri-articular location. (orig.)

  3. Genetics Home Reference: primary spontaneous pneumothorax

    Science.gov (United States)

    ... Home Health Conditions Primary spontaneous pneumothorax Primary spontaneous pneumothorax Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Primary spontaneous pneumothorax is an abnormal accumulation of air in the ...

  4. Primary pachydermoperiostosis: a case report.

    Science.gov (United States)

    Thappa, D M; Sethuraman, G; Kumar, G R; Elangovan, S

    2000-02-01

    Pachydermoperiostosis (PDP), a rare genodermatosis, occurred in a 38-year-old Indian male. He presented with progressive thickening of the skin on the face and scalp of 15 years duration. Widening of his wrists and ankles and broadening of the fingers and toes had also developed since then. He was born of a consanguineous marriage and had no family history of a similar disorder. He had the typical findings of complete form of PDP including cutis verticis gyrata, coarse facial features, clubbing of the digits in the skin, and periostosis and cortical thickening at the distal ends of long bones of the extremities and small bones of the hands and feet. PDP has two different forms--primary and secondary. These two entities are differentiated by family history and presence or absence of a primary lesion, usually in the lungs. Clinically, in secondary PDP, the cutaneous findings (pachydermia, seborrhoea, oiliness) are less severe than primary PDP; osteoarthropathy is more severe and painful in secondary PDP, especially with congenital heart disease. The present case was suffering from primary PDP that had expressed itself in its complete form.

  5. Primary syphilis of the fingers

    OpenAIRE

    Starzycki, Z

    1983-01-01

    Six patients were seen with primary syphilitic chancres on their fingers between 1965 and 1980. Of these, two had bipolar chancres on their fingers and genitals resulting from sexual foreplay. Because syphilis is rarely suspected in such cases diagnostic errors are common.

  6. Primary acalvaria: a case report

    International Nuclear Information System (INIS)

    Rios, Livia Teresa Moreira; Martins, Marilia da Gloria; Simoes, Vanda Maria Ferreira; Nunes, Marynea do Vale; Marques, Patricia Franco; Godoy, Silvia Helena Cavalcante de Souza

    2010-01-01

    Acalvaria is a rare congenital malformation of unknown pathogenesis characterized by the absence of the flat bones of the cranial vault, dura mater and associated muscles, while the central nervous system is usually preserved. The most accepted physiopathogenic theory suggests the presence of a post neurulation defect with normal placement the embryonic ectoderm. The present report describes neonatal imaging findings of primary acalvaria. (author)

  7. The Primary Dental Care Workforce.

    Science.gov (United States)

    Neenan, M. Elaine; And Others

    1993-01-01

    A study describes the characteristics of the current primary dental care workforce (dentists, hygienists, assistants), its distribution, and its delivery system in private and public sectors. Graduate dental school enrollments, trends in patient visits, employment patterns, state dental activities, and workforce issues related to health care…

  8. Primary Teachers Opinion about Homework

    Science.gov (United States)

    Matei, Stefania; Ciasca, Liliana

    2015-01-01

    Homework assignments trigger various perceptions and attitudes in students, parents or teachers: some overestimate them, others reject them, some do it with pleasure and to others they cause tears. Literature indicates both benefits and disadvantages of homework. In Romania, at primary level, homework is a systematic practice. The explanation is…

  9. Hypertrichosis due to primary hypothyroidism.

    OpenAIRE

    Stern, S R; Kelnar, C J

    1985-01-01

    A 10 year old girl with hypertrichosis associated with primary hypothyroidism that resolved after 6 months' replacement treatment with thyroxine is reported. It is important to consider the diagnosis of hypothyroidism in children with abnormal hairiness or distribution of body hair.

  10. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    ajiboro

    2Department of Community Medicine & Primary Care, Faculty of Clinical Sciences, ... It may result from road traffic accident, near saving basic principles in emergency care that even drowning, electric ... (4.3%) at place of work, 8 (11.4%) at.

  11. COMMUNITY HEALTH & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    the_monk

    Journal of Community Medicine and Primary Health Care. 26 (1) 12-20 .... large proportions of the population work in the poor people use health care services far less than. 19 ... hypertension, cancers and road traffic accidents) below 1 dollar ...

  12. COMMUNITY HEALTH & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    the_monk

    VPDs, this represents 17% of global total. 1 ... Knowledge, Attitude and Practice of Childhood Immunization ... Department of Community Health & Primary Care, College of Medicine, University of Lagos, Idi-Araba, P.M.B. 12003, ... include access to services, parental (maternal) ... Calmette Guerin (BCG) vaccine Oral Polio.

  13. Primary Boys and Hegemonic Masculinities.

    Science.gov (United States)

    Skelton, Christine

    1997-01-01

    Explores the relationships between primary-aged boys, hegemonic masculinities, and sexualized/violent behaviors in the school setting. Shows that hegemonic masculinities vary from school to school and that boys draw upon, negotiate, and reject aspects of the hegemonic masculinity of the school in the process of constructing their masculine…

  14. Primary Prevention of Eating Disorders.

    Science.gov (United States)

    Shisslak, Catherine M.; And Others

    1987-01-01

    Summarizes current understanding of anorexia nervosa and bulimia (clinical symptoms and outcome, prevalence and risk factors), offering suggestions for the primary prevention of these disorders at the individual, family, and community levels, and emphasizing prevention in the schools. (Author/KS)

  15. The Relevance of Primary Education

    Science.gov (United States)

    Coe, John

    2018-01-01

    This article sketches a vision of how primary education needs to be re-shaped to let schools focus more sharply on the development of children as individuals. Rapid social change requires a fundamental re-thinking of formal education and assessment. High-stakes testing must end. Greater weight must be given to the application of knowledge and…

  16. Primary Schooling in West Bengal

    Science.gov (United States)

    Sen, Amartya

    2010-01-01

    With his Nobel Prize award money, Amartya Sen set up the Pratichi Trust which carries out research, advocacy and experimental projects in basic education, primary health care, and women's development in West Bengal and Bangladesh. Professor Sen himself took active interest in this work--helping set the agenda, looking at the evidence from…

  17. Patient evaluations of primary care.

    NARCIS (Netherlands)

    Schäfer, W.L.A.; Boerma, W.G.W.; Schellevis, F.G.; Groenewegen, P.P.

    2012-01-01

    Background: So far, studies about people’s appreciation of primary care services has shown that patient satisfaction seems to be lower in health care systems with regulated access to specialist services by gate keeping. Nevertheless, international comparative research about patients’ expectations

  18. Primary Sources and Inquiry Learning

    Science.gov (United States)

    Pappas, Marjorie L.

    2006-01-01

    In this article, the author discusses inquiry learning and primary sources. Inquiry learning puts students in the active role of investigators. Questioning, authentic and active learning, and interactivity are a few of the characteristics of inquiry learning that put the teacher and library media specialist in the role of coaches while students…

  19. Lead-free primary explosives

    Science.gov (United States)

    Huynh, My Hang V.

    2010-06-22

    Lead-free primary explosives of the formula (cat).sub.Y[M.sup.II(T).sub.X(H.sub.2O).sub.6-X].sub.Z, where T is 5-nitrotetrazolate, and syntheses thereof are described. Substantially stoichiometric equivalents of the reactants lead to high yields of pure compositions thereby avoiding dangerous purification steps.

  20. COMMUNITY HEALTH & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    adedamla

    Background: The well-being of women and children is one of the major determinants ... The Sample for the study were women recruited from 11 primary health care ... respondents educational level and knowledge of preconception care (X =24.76, ... single adult or married couple) are in an optimal state .... The major site for.

  1. Primary Science Education in China

    Science.gov (United States)

    Pook, Gayle

    2013-01-01

    Consider the extent to which primary science teaching has evolved since it became a core subject in England with the introduction of the National Curriculum in 1988, and the pace at which theory-driven classroom practice has advanced. It is no wonder that, given the recent economic restructuring and boom in technological development in China,…

  2. Civil Engineering in Primary Schools

    Science.gov (United States)

    Brown, Martin; Strong, Alan

    2010-01-01

    For many children of primary school age, an engineer is the man who comes to service the central heating system or who fixes the family car when it breaks down. Most have never met a "real" professional engineer, and have no idea of what is involved in the exciting world of engineering. Most assume that engineers are men. To try to…

  3. Assessing primary care data quality.

    Science.gov (United States)

    Lim, Yvonne Mei Fong; Yusof, Maryati; Sivasampu, Sheamini

    2018-04-16

    Purpose The purpose of this paper is to assess National Medical Care Survey data quality. Design/methodology/approach Data completeness and representativeness were computed for all observations while other data quality measures were assessed using a 10 per cent sample from the National Medical Care Survey database; i.e., 12,569 primary care records from 189 public and private practices were included in the analysis. Findings Data field completion ranged from 69 to 100 per cent. Error rates for data transfer from paper to web-based application varied between 0.5 and 6.1 per cent. Error rates arising from diagnosis and clinical process coding were higher than medication coding. Data fields that involved free text entry were more prone to errors than those involving selection from menus. The authors found that completeness, accuracy, coding reliability and representativeness were generally good, while data timeliness needs to be improved. Research limitations/implications Only data entered into a web-based application were examined. Data omissions and errors in the original questionnaires were not covered. Practical implications Results from this study provided informative and practicable approaches to improve primary health care data completeness and accuracy especially in developing nations where resources are limited. Originality/value Primary care data quality studies in developing nations are limited. Understanding errors and missing data enables researchers and health service administrators to prevent quality-related problems in primary care data.

  4. Primary processes during water radiolysis

    International Nuclear Information System (INIS)

    Pikaev, A.K.

    1980-01-01

    Briefly reviewed are investigations of primary process mechanism taking place during radiolysis of water and similar systems, executed by direct and indirect methods. A conclusion is made on the important role of the water structure during radiolysis of aqueous solutions of some substances. A necessity to take account of this factor during consideration of radiolysis theoretical models is pointed out

  5. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    ajiboro

    Result: Majority of the mothers (89.2%) had primary/secondary education and 69.4% were traders. Most ... regards immunization, 22.7% of the children were not fully immunized. A total of 69 ..... Nigeria: Perception and Attitudes of the. 17.

  6. Primary acalvaria: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Rios, Livia Teresa Moreira, E-mail: ltlrios@terra.com.b [Universidade Federal do Maranhao (UFMA), Sao Luis, MA (Brazil). Hospital Universitario. Unidade de Diagnostico por Imagem; Martins, Marilia da Gloria [Universidade Federal do Maranhao (UFMA), Sao Luis, MA (Brazil). Hospital Universitario. Servico de Ginecologia e Obstetricia; Simoes, Vanda Maria Ferreira; Nunes, Marynea do Vale; Marques, Patricia Franco; Godoy, Silvia Helena Cavalcante de Souza [Universidade Federal do Maranhao (UFMA), Sao Luis, MA (Brazil). Hospital Universitario. Servico de Neonatologia

    2010-07-15

    Acalvaria is a rare congenital malformation of unknown pathogenesis characterized by the absence of the flat bones of the cranial vault, dura mater and associated muscles, while the central nervous system is usually preserved. The most accepted physiopathogenic theory suggests the presence of a post neurulation defect with normal placement the embryonic ectoderm. The present report describes neonatal imaging findings of primary acalvaria. (author)

  7. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    ajiboro

    ... Experience in a primary health care facility in Rivers State, South-South Nigeria. ... health center increased by 3.09% (p-value > 0.05); the patients that had their babies in the facility were ... 100, 000 live births, based on historical studies and.

  8. Phytotherapy in primary health care

    Science.gov (United States)

    Antonio, Gisele Damian; Tesser, Charles Dalcanale; Moretti-Pires, Rodrigo Otavio

    2014-01-01

    OBJECTIVE To characterize the integration of phytotherapy in primary health care in Brazil. METHODS Journal articles and theses and dissertations were searched for in the following databases: SciELO, Lilacs, PubMed, Scopus, Web of Science and Theses Portal Capes, between January 1988 and March 2013. We analyzed 53 original studies on actions, programs, acceptance and use of phytotherapy and medicinal plants in the Brazilian Unified Health System. Bibliometric data, characteristics of the actions/programs, places and subjects involved and type and focus of the selected studies were analyzed. RESULTS Between 2003 and 2013, there was an increase in publications in different areas of knowledge, compared with the 1990-2002 period. The objectives and actions of programs involving the integration of phytotherapy into primary health care varied: including other treatment options, reduce costs, reviving traditional knowledge, preserving biodiversity, promoting social development and stimulating inter-sectorial actions. CONCLUSIONS Over the past 25 years, there was a small increase in scientific production on actions/programs developed in primary care. Including phytotherapy in primary care services encourages interaction between health care users and professionals. It also contributes to the socialization of scientific research and the development of a critical vision about the use of phytotherapy and plant medicine, not only on the part of professionals but also of the population. PMID:25119949

  9. Primary pigmented nodular adrenocortical disease

    Directory of Open Access Journals (Sweden)

    Marie T Manipadam

    2011-01-01

    Full Text Available Primary pigmented nodular adrenocortical disease (PPNAD is a rare cause of ACTH-independent Cushing′s syndrome and has characteristic gross and microscopic pathologic findings. We report a case of PPNAD in a 15-year-old boy, which was not associated with Carney′s complex. Bilateral adrenalectomy is the treatment of choice.

  10. Scenarios cancer in primary care.

    NARCIS (Netherlands)

    Velden, L.F.J. van der; Schellevis, F.G.

    2011-01-01

    Introduction: Previous studies predicted an increase in both the incidence and prevalence of cancer in the Netherlands. Other studies showed that cancer patients use primary care more frequently than non-cancer patients. Finally, during the “chronic phase” of the disease, task substitution from

  11. Second Languages in Primary Education.

    Science.gov (United States)

    Donoghue, Mildred R.; Kunkle, John F.

    A book on second languages in primary education, designed to assist both classroom teachers and language specialists, is presented. The following topics are addressed: (1) reasons for studying a second language; (2) reasons for children to learn a second language; (3) language choices; (4) qualifications of teachers; (5) FLES, bilingual education,…

  12. Primary Medical Care in Chile

    DEFF Research Database (Denmark)

    Scarpaci, Joseph L.

    Primary medical care in Chile: accessibility under military rule [Front Cover] [Front Matter] [Title Page] Contents Tables Figures Preface Chapter 1: Introduction Chapter 2: The Restructuring of Medical Care Financing in Chile Chapter 3: Inflation and Medical Care Accessibility Chapter 4: Help......-Seeking Behavior of the Urban Poor Chapter 5: Spatial Organization and Medical Care Accessibility Chapter 6: Conclusion...

  13. Primary Intradural Extraosseous Ewing's Sarcoma

    OpenAIRE

    Kim, Seok Won; Shin, Ho

    2009-01-01

    Ewing's sarcoma usually arises from skeletal bone, but rarely may have an extraskeletal origin. However, Ewing's sarcoma that originates around the spinal column, especially, the intradural extramedullary type is extremely rare. We report a rare case of primary intraspinal extraskeletal Ewing's sarcoma.

  14. Primary extracranial vertebral artery aneurysms.

    Science.gov (United States)

    Morasch, Mark D; Phade, Sachin V; Naughton, Peter; Garcia-Toca, Manuel; Escobar, Guillermo; Berguer, Ramon

    2013-05-01

    Extracranial vertebral artery aneurysms are uncommon and are usually associated with trauma or dissection. Primary cervical vertebral aneurysms are even rarer and are not well described. The presentation and natural history are unknown and operative management can be difficult. Accessing aneurysms at the skull base can be difficult and, because the frail arteries are often afflicted with connective tissue abnormalities, direct repair can be particularly challenging. We describe the presentation and surgical management of patients with primary extracranial vertebral artery aneurysms. In this study we performed a retrospective, multi-institutional review of patients with primary aneurysms within the extracranial vertebral artery. Between January 2000 and January 2011, 7 patients, aged 12-56 years, were noted to have 9 primary extracranial vertebral artery aneurysms. All had underlying connective tissue or another hereditary disorder, including Ehler-Danlos syndrome (n=3), Marfan's disease (n=2), neurofibromatosis (n=1), and an unspecified connective tissue abnormality (n=1). Eight of 9 aneurysms were managed operatively, including an attempted bypass that ultimately required vertebral ligation; the contralateral aneurysm on this patient has not been treated. Open interventions included vertebral bypass with vein, external carotid autograft, and vertebral transposition to the internal carotid artery. Special techniques were used for handling the anastomoses in patients with Ehler-Danlos syndrome. Although endovascular exclusion was not performed in isolation, 2 hybrid procedures were performed. There were no instances of perioperative stroke or death. Primary extracranial vertebral artery aneurysms are rare and occur in patients with hereditary disorders. Operative intervention is warranted in symptomatic patients. Exclusion and reconstruction may be performed with open and hybrid techniques with low morbidity and mortality. Copyright © 2013 Elsevier Inc. All rights

  15. Primary closure in colon trauma.

    Science.gov (United States)

    Salinas-Aragón, Luis Enrique; Guevara-Torres, Lorenzo; Vaca-Pérez, Enrique; Belmares-Taboada, Jaime Arístides; Ortiz-Castillo, Fátima de Guadalupe; Sánchez-Aguilar, Martín

    2009-01-01

    Primary repair of colon injuries is an accepted therapeutic option; however, controversy persists regarding its safety. Our objective was to report the evolution and presence of complications in patients with colon injury who underwent primary closure and to determine if the time interval (>6 h), degree of injury, contamination, anatomic site injured, PATI (Penetrating Abdominal Trauma Index) >25, and the presence of other injuries in colon trauma are associated with increased morbidity and mortality. This was a prospective, observational, longitudinal and descriptive study conducted at the Central Hospital "Dr. Ignacio Morones Prieto," San Luis Potosí, Mexico, from January 1, 2003 to December 31, 2007. We included patients with abdominal trauma with colon injury subjected to surgical treatment. chi(2) was used for basic statistical analysis. There were 481 patients with abdominal trauma who underwent surgery; 77(16.1%) had colon injury. Ninety percent (n = 69) were treated in the first 6 h; 91% (n = 70) were due to penetrating injuries, and gunshot wound accounted for 48% (n = 37). Transverse colon was the most frequently injured (38%) (n = 29). Grade I and II injuries accounted for 75.3% (n = 58). Procedures included primary repair (76.66 %) (n = 46); resection with anastomosis (8.3%) (n = 5); and colostomy (15%) (n = 9). Associated injuries were present in 76.6% (n = 59). There was some degree of contamination in 85.7% (n = 66); 82.8% (58) had PATI colon injury. Primary repair is a safe procedure for treatment of colon injuries. Patients with primary repair had lower morbidity (p <0.009). Surgery during the first 6 h (p <0.006) and in hemodynamically stable patients (p <0.014) had a lower risk of complications.

  16. Primary prevention of adolescent pregnancy.

    Science.gov (United States)

    Schinke, S P; Blythe, B J; Gilchrist, L D; Burt, G A

    1981-01-01

    Teenage pregnancy is associated with many health, emotional and socioeconomic problems including higher rates of anemia, labor complications, mortality, legal and social struggles and hhigher divorce rates. Professional social workers need strategies to help teenagers avoid early, unwanted pregnancy. This paper offers promising experential and research backing for a primary prevention group work strategy for all adolescents. Social and health programs overlook educational, cognitive anc interpersonal factors biasing youths' ability to comprehend and regulate contraception. Primary prevention to assist adolescents in thinking analytically about their sexual behavior must stress problem solving and decision-making as well as facts about human reproduction and birth control. To implement decisions, youths also need interpersonal communication skills. Small groups are ideal for delivering cognitive-behavioral primary prevention. This approach is based on the premise that youths become pregnant not because of a lack of relevant information, but because they lack cognitive and behavioral skills necessary to use information. Group work involving role-playing helps develop communication skills. Results from 2 field studies describe short-term and longitudinal benefits of the prevention strategy. Professionals can reach significant numbers of youth in this way. By treating sexual issues and the risk of pregnancy as normal in adolescence, social workers can introduce information and pertinent skills to all teenagers. No one is singled out as deviant and the group format enables young people to discuss taboo topics, discovering what the norms are and gradually learning how to deal with peers, family members, techers and others. Adolescents in primary prevention groups gained knowledge, cognitive skills and communication acumen. Improved attitudes toward family planning, increased regular contraception and less unsafe sex resulted from this cognitive-behavioral approach

  17. Introducing Cooperative Learning to Primary 1 and Primary 2 Pupils

    Science.gov (United States)

    Fong, Salim; Ho, Linda; Chew, Lay See; Wong, Kok Wah; Wee, Sheila; Jacobs, George M.

    2000-01-01

    It was scary at first. Just getting P1 and 2 students to follow basic instructions is hard enough; trying to get them to work together in groups seemed like asking for extra trouble. But, a dash or two of trouble adds a bit of spice to a veteran teacher's life; so the four of us teachers at Mayflower Primary School--a neighbourhood school in Ang…

  18. Synthesis, Self-Assembly, and Drug-Release Properties of New Amphipathic Liquid Crystal Polycarbonates

    Directory of Open Access Journals (Sweden)

    Yujiao Xie

    2018-03-01

    Full Text Available New amphiphilic liquid crystal (LC polycarbonate block copolymers containing side-chain cholesteryl units were synthesized. Their structure, thermal stability, and LC phase behavior were characterized with Fourier transform infrared (FT-IR spectrum, 1H NMR, gel permeation chromatographic (GPC, thermogravimetric analysis (TGA, differential scanning calorimetry (DSC, polarizing optical microscope (POM, and XRD methods. The results demonstrated that the LC copolymers showed a double molecular arrangement of a smectic A phase at room temperature. With the elevating of LC unit content in such LC copolymers, the corresponding properties including decomposition temperature (Td, glass temperature (Tg, and isotropic temperature (Ti increased. The LC copolymers showed pH-responsive self-assembly behavior under the weakly acidic condition, and with more side-chain LC units, the self-assembly process was faster, and the formed particle size was smaller. It indicated that the self-assembly driving force was derived from the orientational ability of LC. The particle size and morphologies of self-assembled microspheres loaded with doxorubicin (DOX, together with drug release tracking, were evaluated by dynamic light scattering (DLS, SEM, and UV–vis spectroscopy. The results showed that DOX could be quickly released in a weakly acidic environment due to the pH response of the self-assembled microspheres. This would offer a new strategy for drug delivery in clinic applications.

  19. Incorporation of Amphipathic Diblock Copolymer in Lipid Bilayer for Improving pH Responsiveness

    Directory of Open Access Journals (Sweden)

    Tian Xia

    2016-01-01

    Full Text Available Diblock copolymers (mPEG-b-PDPA, which were designed to possess pH-sensitivity as well as amphipathy, were used as an intelligent lock in the liposomal membrane. The so-called pH-sensitive liposomes were prepared by simple mixing of the synthesized mPEG-b-PDPA with phospholipids and cholesterol. Fluorescence polarization at pH 7.4 showed that the membrane stability of the hybrid liposome was significantly increased compared with the pure liposome. Therefore, in the neutral environment, the leakage of doxorubicin (DOX was inhibited. However, when pH decreased to 6.0, DOX release rate increased by 60% due to the escape of copolymer. The effects of the membrane composition and the PDPA segment length on bilayer membrane functions were investigated. These results revealed that the synthesized copolymers increased the difference in DOX cumulative release between pH 7.4 and 6.0, that is, improved the pH-controllability of the drug release from hybrid liposomes.

  20. Structure of the membrane anchor of pestivirus glycoprotein E(rns, a long tilted amphipathic helix.

    Directory of Open Access Journals (Sweden)

    Daniel Aberle

    2014-02-01

    Full Text Available E(rns is an essential virion glycoprotein with RNase activity that suppresses host cellular innate immune responses upon being partially secreted from the infected cells. Its unusual C-terminus plays multiple roles, as the amphiphilic helix acts as a membrane anchor, as a signal peptidase cleavage site, and as a retention/secretion signal. We analyzed the structure and membrane binding properties of this sequence to gain a better understanding of the underlying mechanisms. CD spectroscopy in different setups, as well as Monte Carlo and molecular dynamics simulations confirmed the helical folding and showed that the helix is accommodated in the amphiphilic region of the lipid bilayer with a slight tilt rather than lying parallel to the surface. This model was confirmed by NMR analyses that also identified a central stretch of 15 residues within the helix that is fully shielded from the aqueous layer, which is C-terminally followed by a putative hairpin structure. These findings explain the strong membrane binding of the protein and provide clues to establishing the E(rns membrane contact, processing and secretion.

  1. Structure of the Membrane Anchor of Pestivirus Glycoprotein Erns, a Long Tilted Amphipathic Helix

    Science.gov (United States)

    Aberle, Daniel; Muhle-Goll, Claudia; Bürck, Jochen; Wolf, Moritz; Reißer, Sabine; Luy, Burkhard; Wenzel, Wolfgang; Ulrich, Anne S.; Meyers, Gregor

    2014-01-01

    Erns is an essential virion glycoprotein with RNase activity that suppresses host cellular innate immune responses upon being partially secreted from the infected cells. Its unusual C-terminus plays multiple roles, as the amphiphilic helix acts as a membrane anchor, as a signal peptidase cleavage site, and as a retention/secretion signal. We analyzed the structure and membrane binding properties of this sequence to gain a better understanding of the underlying mechanisms. CD spectroscopy in different setups, as well as Monte Carlo and molecular dynamics simulations confirmed the helical folding and showed that the helix is accommodated in the amphiphilic region of the lipid bilayer with a slight tilt rather than lying parallel to the surface. This model was confirmed by NMR analyses that also identified a central stretch of 15 residues within the helix that is fully shielded from the aqueous layer, which is C-terminally followed by a putative hairpin structure. These findings explain the strong membrane binding of the protein and provide clues to establishing the Erns membrane contact, processing and secretion. PMID:24586172

  2. Structure of the membrane anchor of pestivirus glycoprotein E(rns), a long tilted amphipathic helix.

    Science.gov (United States)

    Aberle, Daniel; Muhle-Goll, Claudia; Bürck, Jochen; Wolf, Moritz; Reißer, Sabine; Luy, Burkhard; Wenzel, Wolfgang; Ulrich, Anne S; Meyers, Gregor

    2014-02-01

    E(rns) is an essential virion glycoprotein with RNase activity that suppresses host cellular innate immune responses upon being partially secreted from the infected cells. Its unusual C-terminus plays multiple roles, as the amphiphilic helix acts as a membrane anchor, as a signal peptidase cleavage site, and as a retention/secretion signal. We analyzed the structure and membrane binding properties of this sequence to gain a better understanding of the underlying mechanisms. CD spectroscopy in different setups, as well as Monte Carlo and molecular dynamics simulations confirmed the helical folding and showed that the helix is accommodated in the amphiphilic region of the lipid bilayer with a slight tilt rather than lying parallel to the surface. This model was confirmed by NMR analyses that also identified a central stretch of 15 residues within the helix that is fully shielded from the aqueous layer, which is C-terminally followed by a putative hairpin structure. These findings explain the strong membrane binding of the protein and provide clues to establishing the E(rns) membrane contact, processing and secretion.

  3. Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands

    DEFF Research Database (Denmark)

    Pedersen, Katrine E; Einholm, Anja P; Christensen, Anni

    2003-01-01

    Negatively charged organochemical inactivators of the anti-proteolytic activity of plasminogen activator inhibitor-1 (PAI-1) convert it to inactive polymers. As investigated by native gel electrophoresis, the size of the PAI-1 polymers ranged from dimers to multimers of more than 20 units. As com...

  4. [Addison's disease : Primary adrenal insufficiency].

    Science.gov (United States)

    Pulzer, A; Burger-Stritt, S; Hahner, S

    2016-05-01

    Adrenal insufficiency, a rare disorder which is characterized by the inadequate production or absence of adrenal hormones, may be classified as primary adrenal insufficiency in case of direct affection of the adrenal glands or secondary adrenal insufficiency, which is mostly due to pituitary or hypothalamic disease. Primary adrenal insufficiency affects 11 of 100,000 individuals. Clinical symptoms are mainly nonspecific and include fatigue, weight loss, and hypotension. The diagnostic test of choice is dynamic testing with synthetic ACTH. Patients suffering from chronic adrenal insufficiency require lifelong hormone supplementation. Education in dose adaption during physical and mental stress or emergency situations is essential to prevent life-threatening adrenal crises. Patients with adrenal insufficiency should carry an emergency card and emergency kit with them.

  5. Primary ovarian insufficiency: an update

    Directory of Open Access Journals (Sweden)

    Cox L

    2014-02-01

    Full Text Available Leticia Cox, James H LiuUH Case Medical Center, MacDonald Women's Hospital, Department of Obstetrics and Gynecology, Case Western Reserve University School of Medicine, Department of Reproductive Biology, Cleveland, OH, USAAbstract: Primary ovarian insufficiency is a condition that represents impaired ovarian function on a continuum with intermittent ovulation. This condition commonly leads to premature menopause, defined as cessation of ovulation prior to the age of 40 years. Because there are potential immediate and long-term consequences of hypoestrogenism, a timely diagnosis is invaluable. This comprehensive review will discuss identifiable causes for primary ovarian insufficiency, including genetic disorders and metabolic abnormalities, as well as review current strategies for diagnosis, evaluation, and management of women with this condition.Keywords: premature ovarian failure, premature menopause, ovarian dysfunction

  6. Turner syndrome with primary hyperparathyroidism

    Directory of Open Access Journals (Sweden)

    Jungmee Park

    2013-06-01

    Full Text Available Turner syndrome has multiple comorbidities such as osteoporosis, obesity, diabetes, hypothyroidism, and hypertension. As they are treatable conditions in Turner syndrome, early recognition and proper treatment should be needed. We report on a 23-year-old woman with Turner syndrome who presented with severe osteoporosis and hypercalcemia. Laboratory tests showed elevated levels of serum calcium and parathyroid hormone. Dual-energy X-ray absorptiometry showed severe osteopo-rosis (z score, -3.5. Ultrasound and 99mTc scintigraphy of parathyroid glands showed an adenoma in the right inferior gland. She was diagnosed with primary hyperparathyroidism due to an adenoma of the parathyroid gland. After excision of the adenoma, the patient's serum calcium and parathyroid hormone levels returned to normal. Although only a few cases of Turners syndrome with primary hyperparathyroidism have been reported, hyperparathyroidism should be considered in cases of Turner syndrome with severe osteoporosis and hypercalcemia.

  7. Decontamination of primary cooling system

    International Nuclear Information System (INIS)

    Morikawa, Yoshitake.

    1985-01-01

    Purpose: To effectively eliminate radioactivity accumulated in pipeways, equipments, etc in primary coolant circuits of BWR type power plants by utilizing ion displacement reactions. Method: The reactor pressure vessel is connected with a feedwater pipeway, steam pipeway and a recycling pipeway. The recycling pipeway is disposed with a recycling pump. A recycling by-pass line is branched from the recycling pipeway and disposed with a recycling system heat exchanger and chemical injection point. Water is filled in the primary coolant and heated 280 0 C. Then, while maintaining water at that temperature, non-radioactive cobalt ions are injected and circulated within the system, by which radioactivity accumulated in pipeways, equipments or the likes can effectively be removed. (Horiuchi, T.)

  8. The Etiology of Primary Hyperhidrosis

    DEFF Research Database (Denmark)

    Hashmonai, Moshe; Cameron, Alan E.P.; Connery, Cliff P.

    2017-01-01

    of patients with hyperhidrosis has been reported. Conclusions: Despite these accumulated data, the etiology of primary hyperhidrosis remains obscure. Nevertheless, three main lines for future research seem to be delineated: genetics, histological observations, and enzymatic studies.......Purpose: Primary hyperhidrosis is a pathological disorder of unknown etiology, affecting 0.6-5% of the population, and causing severe functional and social handicaps. As the etiology is unknown, it is not possible to treat the root cause. Recently some differences between affected and non......-affected people have been reported. The aim of this review is to summarize these new etiological data. Methods: Search of the literature was performed in the PubMed/Medline Database and pertinent articles were retrieved and reviewed. Additional publications were obtained from the references of these articles...

  9. Cinema Sessions in Primary Care

    Directory of Open Access Journals (Sweden)

    Francisco Ignacio MORETA-VELAYOS

    2016-04-01

    Full Text Available For a long time films have been used in teaching and at various levels of professional training  and more specifically in the medical area. In this case, through the description of a project developed in a Primary Care Health Center, we intend to justify the use of movies as a tool that could ease, the sometimes difficult task of continued education among Primary Care professionals. We propose different aspects of everyday practice in which cinema can be potentially useful, as well as the way to include it in the Plan of Continued Education of the Centre and its accreditation.Films and issues discussed in each session, and the project evaluation, are detailed.

  10. Primary shield displacement and bowing

    International Nuclear Information System (INIS)

    Scott, K.V.

    1978-01-01

    The reactor primary shield is constructed of high density concrete and surrounds the reactor core. The inlet, outlet and side primary shields were constructed in-place using 2.54 cm (1 in) thick steel plates as the forms. The plates remained as an integral part of the shields. The elongation of the pressure tubes due to thermal expansion and pressurization is not moving through the inlet nozzle hardware as designed but is accommodated by outward displacement and bowing of the inlet and outlet shields. Excessive distortion of the shields may result in gas seal failures, intolerable helium gas leaks, increased argon-41 emissions, and shield cooling tube failures. The shield surveillance and testing results are presented

  11. Encephalitis in primary HIV infection

    DEFF Research Database (Denmark)

    Helleberg, M; Kirk, O

    2013-01-01

    We report a case of primary HIV encephalitis, which initially presented as acute psychosis. Magnetic resonance imaging of the brain was suggestive of vasculitis and multiple infarctions, whereas a brain biopsy after six weeks of symptoms showed HIV encephalitis with microglial nodules, but no signs...... of vasculitis. We review previous reported cases and radiological findings in HIV encephalitis and discuss the role of antiretroviral therapy and steroids in its management....

  12. Primary biliary cirrhosis: natural history.

    Science.gov (United States)

    Tornay, A S

    1980-03-01

    All patients seen with primary biliary cirrhosis during this decade were reviewed. Sixty per cent were diagnosed during the earliest asymptomatic stage of this illness and only 20% progressed symptomatically during a mean follow-up period of 52 months. Those patients presenting with persistent jaundice followed a classic downhill course. These data establish the previously predicted trend toward earlier diagnosis and raise questions about the concept of universal progression of this disease and its time course.

  13. Primary cerebral lymphoma: radiological findings

    International Nuclear Information System (INIS)

    Ruiz, J.C.; Grandse, D.; Equidazu, J.; Elizagaray, E.; Grande, J.; Carrandi, J.

    1990-01-01

    We present four cases of primary cerebral lymphoma in non-immunodepressed adult patients. All cases were dsemonstrated with pathological study. CAT study showed solitary or multiple isodense lesions, which incorporated avidly and homoneneously the contrast. Arteriography performed in three patients and magnetic resonance, performed in one did not help for diagnosis. We also review the radiological findings obtained with different imaging methods, and suggest the criteria which could be useful for early diagnosis (Author)

  14. Primary bone tumours in infants

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K.; Beluffi, G.; Cohen, D.H.; Padovani, J.; Tamaela, L.; Azouz, M.; Bale, P.; Martin, H.C.; Nayanar, V.V.; Arico, M.

    1985-09-01

    Ten cases of primary bone tumours in infants (1 osteosarcoma, 3 Ewing's sarcoma, 1 chondroblastoma and 5 angiomastosis) are reported. All cases of angiomatosis showed characteristic radiographic findings. In all the other tumours the X-ray appearances were different from those usually seen in older children and adolescents. In the auhtors' opinion the precise diagnosis of malignant bone tumours in infancy is very difficult as no characteristic X-ray features are present in this age period.

  15. Clinical presentation of primary hypothyroidism

    International Nuclear Information System (INIS)

    Ahmed, B.; Hussain, T.; Memon, A. R.; Solangi, G. A.

    2001-01-01

    Objective: To determine the clinical preparation of primary hypothyroidism at the time of diagnosis. Design: It was an observational and prospective study. Place and Duration of Study: Civil Hospital, Karachi from 1st January 1997 to 31st December 1997. Subjects and Methods: Forty-eight consecutive cases of primary hypothyroidism were included. A detailed history with special emphasis on symptoms and signs was conducted and the findings observed were noted in previously made proforma. Results: Primary hypothyroidism was found to be 5 times more common in female patients, with male to female ratio 1:5, majority of cases (33.33%) were between 41 to 50 years of age. The common symptoms at the time of presentation were tiredness (95.8%), weakness (91.6%), weight gain (85.4%), hoarseness of voice (83.3%), cold intolerance (77.0%) and constipation (75.0%) in patients. Physical signs observed were delayed relaxation of ankle jerk (93.7%), periorbital edema (83.3%), thick tongue (62.5%), goiter (50.0%), dry and coarse skin (47.9%) in patients. Serum, TSH, T4 and T3 were performed in all cases through immunoradiometric technique. Serum TSH was markedly elevated, with normal to reduced T4 and T3 levels in all cases. Conclusion: Primary hypothyroidism was found more common in female than male of the age group 41-50 years. Weakness, tiredness, hoarseness of voice and constipation were the common symptoms noted. The diagnosis is almost certain on clinical grounds if the patient happens to have delayed relaxation of ankle jerks and periorbital puffiness. (author)

  16. Primary hypothyroidism masquerading pituitary macroadenoma

    Directory of Open Access Journals (Sweden)

    Agrawal Amit

    2014-03-01

    Full Text Available Diffuse and reactive pituitary gland enlargement secondary to primary hypothyroidism is an uncommon occurrence and that can masquerade many pituitary disorders. In present article, we report a case of 19 year female severe hypothyroidism presenting with diffuse enlargement of pituitary gland and hyperprolactinemia and review the clinical importance of this entity. Knowledge of this entity is very important to avoid unnecessary surgery and irreversible complications in this sub-group of patients.

  17. Primary hypothyroidism masquerading pituitary macroadenoma

    OpenAIRE

    Agrawal Amit; Reddy Amareesh P.; Malleswara Rao G.; Reddy V. Umamaheswara

    2014-01-01

    Diffuse and reactive pituitary gland enlargement secondary to primary hypothyroidism is an uncommon occurrence and that can masquerade many pituitary disorders. In present article, we report a case of 19 year female severe hypothyroidism presenting with diffuse enlargement of pituitary gland and hyperprolactinemia and review the clinical importance of this entity. Knowledge of this entity is very important to avoid unnecessary surgery and irreversible complications in this sub-group of patients.

  18. Renal manifestations of primary hyperparathyroidism

    OpenAIRE

    Lila, Anurag Ranjan; Sarathi, Vijaya; Jagtap, Varsha; Bandgar, Tushar; Menon, Padma S.; Shah, Nalini Samir

    2012-01-01

    Primary hyperparathyroidism (PHPT) is associated with nephrolithiasis and nephrocalcinosis. Hypercalciuria is one of the multiple factors that is implicated in the complex pathophysiology of stone formation. The presence of a renal stone (symptomatic or asymptomatic) categorizes PHPT as symptomatic and is an indication for parathyroid adenomectomy. Progression of nephrocalcinosis is largely reversible after successful surgery, but the residual risk persists. PHPT is also associated with decli...

  19. Managing obesity in primary care.

    Science.gov (United States)

    Goldie, Christine; Brown, Jenny

    Obesity is a complex problem and often difficult to tackle in primary care. A year-long pilot of a practice nurse-led scheme that used a holistic approach towards self-care in obesity management was set up to reduce the cardiovascular risk of patients who were obese and improve their quality of life. This person-centred approach may offer an important tool in the management of these patients in the GP surgery.

  20. Primary prevention of colorectal cancer.

    Science.gov (United States)

    Chan, Andrew T; Giovannucci, Edward L

    2010-06-01

    Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.

  1. Multiple primary cancers: An enigma

    Directory of Open Access Journals (Sweden)

    Amitabh Jena

    2016-01-01

    Full Text Available Background: Incidence of multiple primary cancers though uncommon, is being frequently reported now-a-days owing to better diagnostic techniques, the prolonged life span and the increased incidence of long-term survival of cancer patients. Materials and Methods: This is a retrospective study. Cases of multiple malignancies diagnosed histopathologically were retrieved from the archives of department of surgical oncology. Clinical data were obtained from the medical records. They were categorized as synchronous malignancies if the interval between them was less or equal to 6 months and metachronous, if the interval was more than 6 months. Results: A total of 13 cases were encountered in the 5 year study period. Out of them two were in the metachronous category and the rest were synchronous as the 2nd malignancy was detected mostly during clinical evaluation of the patients for the primary malignancy. There was female predominance with age range being 43-68 years. Majority of the cases were in the 7th decade. The most common organ involved was breast, followed by cervix. Apart from bilateral breast malignancies, there were combinations like breast with uterine endometrial carcinoma, cervical carcinoma and even papillary thyroid carcinoma. Conclusion: Detection of multiple primary malignancies is becoming increasingly common in day-to-day practice. Greater awareness of this is required among both cancer patients and their treating clinicians.

  2. Radiotherapy in primary cerebral lymphoma

    International Nuclear Information System (INIS)

    Legros, L.; Benezery, K.; Lagrange, J.L.

    1999-01-01

    Primary cerebral lymphoma is a rare disease with an unfavorable prognosis. Whole brain radiotherapy has been the standard treatment, but neither the optimal radiation fields nor optimal dose level of the regimen are as yet firmly establisheD. From this review of the literature, it seems that the whole brain must be treated, and a boost to the area of the primary site must be discussed. With regard to dose, the radiation dose-response relationship is not clearly proven. Yet, a minimum dose of 40 Gy is necessary, and the maximum dose is set at 50 Gy because of late neurological sequelae. Because of the poor prognosis of this disease and the risk of late sequelae, other avenues have been explored. Chemotherapy has been studied, seem to have a survival advantage and combinations of radiotherapy and chemotherapy, especially with high-dose methotrexate. Because primary cerebral lymphoma is an uncommon disease, randomized clinical trials that compare radiotherapy alone to chemotherapy plus radiotherapy may not be feasible. Finally, even if chemotherapy seems to have a survival advantage, the regimen of chemotherapy is still a matter of debate. (authors)

  3. Lymphocytes B and primary immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Gabriela López-Herrera

    2016-03-01

    Full Text Available Primary antibody deficiencies represent the most frequent genetic diseases of the immune system and the first to be recognized along immunology history. The antibodies were recognized as part of the humoral immune system long ago, and after immunoglobulin discovery, the first antibody immunodeficiency were recognized and named as “agammaglobulinemia”, followed by the common variable immunodeficiency and the hyper-IgM syndrome. The following discoveries in immunology history made possible the understanding of these pathologies, for example: the discoveries of B cells, pre-B cells, the signaling pathway directed by the antigen receptor and many other cellular and molecular mechanisms. Primary antibody deficiencies have been studied for a long time and the discoveries of new syndromes have been helpful in the understanding of immunological mechanisms that take place in our organism. Then, this manuscript pretends to review the relevant findings in the history of immunology, focused on the B cells and the connection with the description of representative clinical entities of primary antibody deficiencies. The aim of this manuscript is to show to the reader that the generation of scientific knowledge has a direct application in the understanding of the molecular mechanisms that are affected in these diseases.

  4. Common primary headaches in pregnancy

    Directory of Open Access Journals (Sweden)

    Anuradha Mitra

    2015-01-01

    Full Text Available Headache is a very common problem in pregnancy. Evaluation of a complaint of headache requires categorizing it as primary or secondary. Migrainous headaches are known to be influenced by fluctuation of estrogen levels with high levels improving it and low levels deteriorating the symptoms. Tension-type Headaches (TTHs are the most common and usually less severe types of headache with female to male ratio 3:1. Women known to have primary headache before conception who present with a headache that is different from their usual headache, or women not known to have primary headache before conception who present with new-onset of headache during pregnancy need neurologic assessments for potential secondary cause for their headache. In addition to proper history and physical examination, both non-contrast computed tomography (CT and Magnetic Resonance Imaging (MRI are considered safe to be performed in pregnant women when indicated. Treatment of abortive and prophylactic therapy should include non-pharmacologic tools, judicious use of drugs which are safe for mother and fetus.

  5. Technological Innovation in Primary Education

    Directory of Open Access Journals (Sweden)

    Luisana Sleny López Alvarado

    2018-05-01

    Full Text Available The purpose of this essay is to reflect on technological innovation in Primary Education. In this idea, information processing was used to support the analysis of the theoretical approaches related to the relevance of education that is based on a significant pedagogical practice capable of developing the capacities and interests, so that they can appropriate the global and local content in the vision of access to information, considering social opportunities. The restructuring to which education has been subjected has been influenced by advances in science, technology and the demands of a complex, dynamic and uncertain society in the processes of educational innovation, which involves the introduction of something new in education. the educational system, modifying its teaching-learning structures through the incorporation of Information and Communication Technologies (ICT in the curricular design of primary education in its intention to train for incursion into science and technology from use of a wide range of didactic resources that lead to pedagogical innovation. It was concluded that technological innovation in the educational praxis of primary education, requires in addition to the vocation of service, to study the new didactic paradigms to display their reflective capacity and assume the commitment to acquire digital literacy to assume the requirements of a knowledge society which is increasingly globalized.

  6. The primary protection system software

    International Nuclear Information System (INIS)

    Tooley, P.A.

    1992-01-01

    This paper continues the detailed description of the Primary Protection System for Sizewell-B by providing an overview of design and implementation of the software, including the features of the design process which ensure that quality is delivered by the contractor. The Nuclear Electric software assessment activities are also described. The argument for the excellence of the software is made on the basis of a quality product delivered by the equipment supplier's design process, and the confirmation of this provided by the Nuclear Electric assessment process, which is as searching and complete an examination as is reasonably practicable to achieve. (author)

  7. Extra osseous primary Ewing's sarcoma.

    Science.gov (United States)

    Ali, Syed Asad; Muhammad, Agha Taj; Soomro, Abdul Ghani; Siddiqui, Akmal Jamal

    2010-01-01

    The case of 20 years old boy with an extra osseous Ewing's sarcoma is described. He was initially diagnosed as a case of infiltrative malignant tumour of left suprarenal gland on the basis of preoperative workup but postoperative biopsy of surgically excised specimen confirmed Extra-osseous Ewing's Sarcoma (EES) suprarenal gland with no evidence of malignancy on skeletal scintiscan, bone marrow aspirate and histopathology Suprarenal location of primary EES is unknown and probably has not been reported in literature. We report a unique case of EES.

  8. Diuretics in primary hypertension - Reloaded.

    Science.gov (United States)

    Mishra, Sundeep

    Diuretics have long been cherished as drugs of choice for uncomplicated primary hypertension. Robust mortality and morbidity data is available for diuretics to back this strategy. Off-late the interest for diuretics has waned off perhaps due to availability of more effective drugs but more likely due to perceived lack of tolerance and side-effect profile of high-dose of diuretics required for mortality benefit. Low-dose diuretics particularly thiazide diuretics are safer but lack the mortality benefit shown by high-dose. However, indapamide and low dose chlorthalidone have fewer side-effects but continue to provide mortality benefit. Copyright © 2016. Published by Elsevier B.V.

  9. Traumatic primary brain stem haemorrhage

    International Nuclear Information System (INIS)

    Andrioli, G.C.; Zuccarello, M.; Trincia, G.; Fiore, D.L.; De Caro, R.

    1983-01-01

    We report 36 cases of post-traumatic 'primary brain stem haemorrhage' visualized by the CT scan and confirmed at autopsy. Clinical experience shows that many technical factors influence the inability to visualize brain stem haemorrhages. Experimental injection of fresh blood into the pons and midbrain of cadavers shows that lesions as small as 0.25 ml in volume may be visualized. The volume and the anatomical configuration of traumatic lesions of the brain stem extended over a rostro-caudal direction, and their proximity to bony structures at the base of the skull are obstacles to the visualization of brain stem haemorrhages. (Author)

  10. [Mental disorders in primary care].

    Science.gov (United States)

    Herzig, Lilli; Mühlemann, Nicole; Bischoff, Thomas

    2010-05-19

    Mental disorders (depression, anxiety and somatization) are frequent in Primary care and are often associated to physical complaints and to psychosocial stressors. Mental disorders have in this way a specific presentation and in addition patients may present different associations of them. Sometimes it is difficult to recognize them, but it is important to do so and to take rapidly care of these patients. Specific screening questions exist and have been used in a research of the Institute of General Medicine and the Department of Ambulatory Care and Community Medicine (PMU), University of Lausanne, Switzerland.

  11. Primary Anorectal Melanoma: An Update

    Directory of Open Access Journals (Sweden)

    P Carcoforo, M.T Raiji, G.M Palini, M Pedriali, U Maestroni, G Soliani, A Detroia, M.V Zanzi, A.L Manna, J.G Crompton, R.C Langan, A Stojadinovic, I Avital

    2012-01-01

    Full Text Available The anorectum is a rare anatomic location for primary melanoma. Mucosal melanoma is a distinct biological and clinical entity from the more common cutaneous melanoma. It portrays worse prognosis than cutaneous melanoma, with distant metastases being the overwhelming cause of morbidity and mortality. Surgery is the treatment of choice, but significant controversy exists over the extent of surgical resection. We present an update on the state of the art of anorectal mucosal melanoma. To illustrate the multimodality approach to anorectal melanoma, we present a typical patient.

  12. Interference with RUNX1/ETO Leukemogenic Function by Cell-Penetrating Peptides Targeting the NHR2 Oligomerization Domain

    Directory of Open Access Journals (Sweden)

    Yvonne Bartel

    2013-01-01

    Full Text Available The leukemia-associated fusion protein RUNX1/ETO is generated by the chromosomal translocation t(8;21 which appears in about 12% of all de novo acute myeloid leukemias (AMLs. Essential for the oncogenic potential of RUNX1/ETO is the oligomerization of the chimeric fusion protein through the nervy homology region 2 (NHR2 within ETO. In previous studies, we have shown that the intracellular expression of peptides containing the NHR2 domain inhibits RUNX1/ETO oligomerization, thereby preventing cell proliferation and inducing differentiation of RUNX1/ETO transformed cells. Here, we show that introduction of a recombinant TAT-NHR2 fusion polypeptide into the RUNX1/ETO growth-dependent myeloid cell line Kasumi-1 results in decreased cell proliferation and increased numbers of apoptotic cells. This effect was highly specific and mediated by binding the TAT-NHR2 peptide to ETO sequences, as TAT-polypeptides containing the oligomerization domain of BCR did not affect cell proliferation or apoptosis in Kasumi-1 cells. Thus, the selective interference with NHR2-mediated oligomerization by peptides represents a challenging but promising strategy for the inhibition of the leukemogenic potential of RUNX1/ETO in t(8;21-positive leukemia.

  13. Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides.

    Science.gov (United States)

    Dixon, James E; Osman, Gizem; Morris, Gavin E; Markides, Hareklea; Rotherham, Michael; Bayoussef, Zahia; El Haj, Alicia J; Denning, Chris; Shakesheff, Kevin M

    2016-01-19

    Protein transduction domains (PTDs) are powerful nongenetic tools that allow intracellular delivery of conjugated cargoes to modify cell behavior. Their use in biomedicine has been hampered by inefficient delivery to nuclear and cytoplasmic targets. Here we overcame this deficiency by developing a series of novel fusion proteins that couple a membrane-docking peptide to heparan sulfate glycosaminoglycans (GAGs) with a PTD. We showed that this GET (GAG-binding enhanced transduction) system could deliver enzymes (Cre, neomycin phosphotransferase), transcription factors (NANOG, MYOD), antibodies, native proteins (cytochrome C), magnetic nanoparticles (MNPs), and nucleic acids [plasmid (p)DNA, modified (mod)RNA, and small inhibitory RNA] at efficiencies of up to two orders of magnitude higher than previously reported in cell types considered hard to transduce, such as mouse embryonic stem cells (mESCs), human ESCs (hESCs), and induced pluripotent stem cells (hiPSCs). This technology represents an efficient strategy for controlling cell labeling and directing cell fate or behavior that has broad applicability for basic research, disease modeling, and clinical application.

  14. Membrane adsorption and binding, cellular uptake and cytotoxicity of cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone

    DEFF Research Database (Denmark)

    Jing, Xiaona; Yang, Mingjun; Kasimova, Marina Robertovna

    2012-01-01

    to evaluate the effect of α-chirality in the β-peptoid residues and the presence of guanidinium groups in the α-amino acid residues on membrane interaction. The molecular properties of the peptidomimetics in solution (surface and intramolecular hydrogen bonding, aqueous diffusion rate and molecular size) were...... studied along with their adsorption to lipid bilayers, cellular uptake, and toxicity. The surface hydrogen bonding ability of the peptidomimetics reflected their adsorbed amounts onto lipid bilayers as well as with their cellular uptake, indicating the importance of hydrogen bonding for their membrane...

  15. Conjugation of a cell-penetrating peptide to parathyroid hormone affects its structure, potency, and transepithelial permeation

    DEFF Research Database (Denmark)

    Kristensen, Mie; de Groot, Anne Marit; Berthelsen, Jens

    2015-01-01

    hormone, i.e. PTH(1-34), and to evaluate the effect with regards to secondary structure, potency in Saos-2 cells, immunogenicity, safety as well as the transepithelial permeation across monolayers by using the Caco-2 cell culture model. Further, co-administration of CPP and PTH(1-34) as an alternative...

  16. Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.

    Science.gov (United States)

    Goicochea, Nancy L; Garnovskaya, Maria; Blanton, Mary G; Chan, Grace; Weisbart, Richard; Lilly, Michael B

    2017-12-01

    Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Improved cellular uptake of antisense Peptide nucleic acids by conjugation to a cell-penetrating Peptide and a lipid domain

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Nielsen, Peter E

    2011-01-01

    based on a splicing correction of a mutated luciferase gene in HeLa pLuc705 cells by targeting antisense oligonucleotides to a cryptic splice site. Further improvement in the delivery of CatLip-PNA conjugates is achieved by using auxiliary agents/treatments (e.g., chloroquine, calcium ions......Unaided cellular uptake of RNA interference agents such as antisense oligonucleotides and siRNA is extremely poor, and in vivo bioavailability is also limited. Thus, effective delivery strategies for such potential drugs are in high demand. Recently, a novel approach using a class of short cationic....... We have found, however, that this low -bioavailability can be significantly improved by chemical conjugation to a lipid domain ("Lip," such as a fatty acid), thereby creating "CatLip"-conjugates. The cellular uptake of these conjugates is conveniently evaluated using a sensitive cellular assay system...

  18. Oncology in primary health care

    International Nuclear Information System (INIS)

    Mendoza del Pino, Mario Valentín

    2009-01-01

    The book O ncology in the primary health care , constitutes an important contribution to the prevention and treatment of cancer, from a very comprehensive assessment. It's a disease that is the second leading cause of death in our country, to much pain and suffering is for the patient and their family. The book has a very useful for basic health equipment approach, since it emphasizes that cancer can be prevented if achieved in the population changes in lifestyle. The book is valued not correct food as responsible for one third of all cancers. Currently important research being developed in relation to psiconeuroinmuno-Endocrinology, who is studying the association between psychological factors and the development of cancer valuing that kept stress and depression reduces the antitumor activity of the immune system; that made programs with encouraging results where the treatment of cancer has joined elements of psychotherapy, immunotherapy and the use of the biotherapy. The focus of the book fills an important place in the primary health care and is an indispensable guide for professionals at this level of care (author)

  19. The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage

    DEFF Research Database (Denmark)

    Christiansen, Stig Hill; Zhang, Xianwei; Juul-Madsen, Kristian

    2017-01-01

    in innate immunity. It shares the positive charge and amphipathic character of GA, and, as shown here, also the ability to kill human leukocyte. The cytotoxicity of both compounds depends on sialic acid in the cell membrane. The killing was associated with the generation of CD45 + debris, derived from cell...... membrane deformation. Nanoparticle tracking analysis confirmed the formation of such debris, even at low GA concentrations. Electric cell-substrate impedance sensing measurements also recorded stable alterations in T lymphocytes following such treatment. LL-37 forms oligomers through weak hydrophobic...

  20. Stages of Adult Primary Liver Cancer

    Science.gov (United States)

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Adult Primary Liver Cancer Treatment (PDQ®)–Patient Version Treatment ... are different types of treatment for patients with adult primary liver cancer. Different types of treatments are ...

  1. The skin in primary immunodeficiency disorders

    NARCIS (Netherlands)

    Sillevis Smitt, J. Henk; Wulffraat, Nico M.; Kuijpers, Taco W.

    2005-01-01

    Primary immunodeficiency disorders comprise serious and rare diseases, predominantly in children. The skin may be involved in a primary immunodeficiency and the cutaneous alterations such as infections, eczematous dermatitis, erythroderma, autoimmune dermatoses and vasculitis may be the basis for

  2. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Gluud, C

    2003-01-01

    Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear.......Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear....

  3. Genetics Home Reference: primary ciliary dyskinesia

    Science.gov (United States)

    ... primary ciliary dyskinesia also have year-round nasal congestion and a chronic cough. Chronic respiratory tract infections ... likely due to abnormal cilia in the fallopian tubes. Another feature of primary ciliary dyskinesia is recurrent ...

  4. Multiple neoplasms, single primaries, and patient survival

    International Nuclear Information System (INIS)

    Amer, Magid H

    2014-01-01

    Multiple primary neoplasms in surviving cancer patients are relatively common, with an increasing incidence. Their impact on survival has not been clearly defined. This was a retrospective review of clinical data for all consecutive patients with histologically confirmed cancer, with emphasis on single versus multiple primary neoplasms. Second primaries discovered at the workup of the index (first) primary were termed simultaneous, if discovered within 6 months of the index primary were called synchronous, and if discovered after 6 months were termed metachronous. Between 2005 and 2012, of 1,873 cancer patients, 322 developed second malignancies; these included two primaries (n=284), and three or more primaries (n=38). Forty-seven patients had synchronous primaries and 275 had metachronous primaries. Patients with multiple primaries were predominantly of Caucasian ancestry (91.0%), with a tendency to develop thrombosis (20.2%), had a strong family history of similar cancer (22.3%), and usually presented with earlier stage 0 through stage II disease (78.9%). When compared with 1,551 patients with a single primary, these figures were 8.9%, 15.6%, 18.3%, and 50.9%, respectively (P≤0.001). Five-year survival rates were higher for metachronous cancers (95%) than for synchronous primaries (59%) and single primaries (59%). The worst survival rate was for simultaneous concomitant multiple primaries, being a median of 1.9 years. The best survival was for patients with three or more primaries (median 10.9 years) and was similar to the expected survival for the age-matched and sex-matched general population (P=0.06991). Patients with multiple primaries are usually of Caucasian ancestry, have less aggressive malignancies, present at earlier stages, frequently have a strong family history of similar cancer, and their cancers tend to have indolent clinical behavior with longer survival rates, possibly related to genetic predisposition

  5. Depressive Disorders in Primary Health Care

    OpenAIRE

    Vuorilehto, Maria

    2008-01-01

    The Vantaa Primary Care Depression Study (PC-VDS) is a naturalistic and prospective cohort study concerning primary care patients with depressive disorders. It forms a collaborative research project between the Department of Mental and Alcohol Research of the National Public Health Institute, and the Primary Health Care Organization of the City of Vantaa. The aim is to obtain a comprehensive view on clinically significant depression in primary care, and to compare depressive patients in prima...

  6. Primary Leiomyosarcoma of the Kidney

    Directory of Open Access Journals (Sweden)

    Kusuma Venkatesh

    2010-01-01

    Full Text Available Primary leiomyosarcoma of the kidney is a rare tumor with an aggressive behaviour. A 55-year-old woman presented with a left sided abdominal mass in our outpatient department. Radiologic investigations revealed the mass to be renal in origin with colonic adhesions for which radical nephrectomy and hemicolectomy were done. The tumor completely appeared to replace the left kidney and had a whorled character focally on cut section. Microscopically, spindle cells having malignant features with cigar shaped nuclei were seen. The smooth muscle origin of the cells was confirmed by immunohistochemical positivity for smooth muscle actin. Sarcomatoid variant of the renal cell carcinoma was ruled out as the tumor was negative for cytokeratin. Tumors with spindle cell morphology in the kidney should not always be taken for a sarcomatoid variant of renal cell carcinoma and should be investigated thoroughly.

  7. Imaging in primary progressive aphasia

    International Nuclear Information System (INIS)

    Abe, K.; Ukita, H.; Yanagihara, T.

    1997-01-01

    Primary progressive aphasia (PPA) presents with aphasia, with or without other minor cognitive dysfunction. We report five patients with PPA to show the correlation between their clinical signs and imaging findings. The patients can be divided into those with nonfluent (group 1) and those with fluent (group 2) aphasia. The characteristic speech impairment was bradylalia in group 1 and word amnesia in group 2. Impairment of comprehension was common but mild in both groups. On MRI, patients in group 1 showed predominantly left frontal and perisylvian atrophy with reduced uptake in the same region on single photon emission computed tomography (SPECT) using technetium-99m hexamethyl propyleneamine oxime ( 99m Tc HMPAO). Patients in group 2 showed left temporal atrophy involving the superior, middle and inferior temporal gyri, hippocampus and parahippocampal gyrus on MRI and reduced uptake in the same region on SPECT. These findings correlated well with the functional anatomy of speech impairment. (orig.). With 4 figs., 1 tab

  8. Imaging in primary progressive aphasia

    Energy Technology Data Exchange (ETDEWEB)

    Abe, K. [Department of Neurology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565 (Japan); Ukita, H. [Rehabilitation Service, Osaka University Hospital, Osaka (Japan); Yanagihara, T. [Department of Neurology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565 (Japan)

    1997-08-01

    Primary progressive aphasia (PPA) presents with aphasia, with or without other minor cognitive dysfunction. We report five patients with PPA to show the correlation between their clinical signs and imaging findings. The patients can be divided into those with nonfluent (group 1) and those with fluent (group 2) aphasia. The characteristic speech impairment was bradylalia in group 1 and word amnesia in group 2. Impairment of comprehension was common but mild in both groups. On MRI, patients in group 1 showed predominantly left frontal and perisylvian atrophy with reduced uptake in the same region on single photon emission computed tomography (SPECT) using technetium-99m hexamethyl propyleneamine oxime ({sup 99m}Tc HMPAO). Patients in group 2 showed left temporal atrophy involving the superior, middle and inferior temporal gyri, hippocampus and parahippocampal gyrus on MRI and reduced uptake in the same region on SPECT. These findings correlated well with the functional anatomy of speech impairment. (orig.). With 4 figs., 1 tab.

  9. Primary hypoparathyroidism in a dog

    Directory of Open Access Journals (Sweden)

    Mateus do Amaral Freitas

    2014-02-01

    Full Text Available The hypoparathyroidism is a rare endocrinopathy reported in dogs, caused by a deficiency in the synthesis of parathyroid hormone (PTH. The lack of PTH causes hypocalcemia and hyperphosphatemia, resulting in a series of neurological and neuromuscular disorders. Unlike most endocrinopathies, hypoparathyroidism is a disease in which the exogenous hormone replacement is not being viable, becoming the treatment a challenge. The present report aims to describe a case of primary hypoparathyroidism in a Schnauzer dog with seizures and neuromuscular disorders, and successful treatment employed, this being the first case, according to the literature, of hypoparathyroidism diagnosed in Brazil. The hypoparathyroidism should be considered as a differential diagnosis in cases of seizure. A complete neurological evaluation and determination of serum ionized calcium and parathyroid hormone are essential for the diagnosis of this disease. Early diagnosis may improve the quality of life of affected animals, since after the initiation of therapy, there is complete remission of clinical signs.

  10. Primary Hepatic Lymphoma Mimicking Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Foroogh Forghani1,

    2017-07-01

    Full Text Available Primary hepatic lymphoma (PHL presenting with obstructive jaundice is rare and can mimic a preoperative diagnosis of cholangiocarcinoma. We should consider PHL in patients with radiological hepatic disease with normal serum alpha-fetoprotein and carcinoembryonic antigen levels, and elevated lactate dehydrogenase. We present the case of a 67-year-old male with no significant medical history presented with abdominal pain, jaundice, fever, and abnormal liver function tests. Abdominal sonography and computed tomography scan suggested a diagnosis of obstructive jaundice and cholangitis due to cholangiocarcinoma (Klatskin tumor. A subsequent liver biopsy diagnosed PHL, and the patient was treated with combination chemotherapy, including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP. PHL should be considered in patients presenting with biliary obstruction.

  11. Primary Prevention of Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Danny J. Eapen, MD

    2016-09-01

    Full Text Available Cardiovascular disease (CVD is the leading cause of death worldwide. This article focuses on current guidelines for the primary prevention of CVD and addresses management of key risk factors. Dietary modification, weight loss, exercise, and tobacco use cessation are specific areas where focused efforts can successfully reduce CVD risk on both an individual and a societal level. Specific areas requiring management include dyslipidemia, hypertension, physical activity, diabetes, aspirin use, and alcohol intake. These preventive efforts have major public health implications. As the global population continues to grow, health care expenditures will also rise, with the potential to eventually overwhelm the health care system. Therefore it is imperative to apply our collective efforts on CVD prevention to improve the cardiovascular health of individuals, communities, and nations.

  12. A case of primary hypersomnia

    Directory of Open Access Journals (Sweden)

    John Dinesh

    2007-01-01

    Full Text Available Primary hypersomnia (PH is a disorder of presumed central nervous system etiology that is associated with a normal or prolonged major sleep episode and excessive sleepiness consisting of prolonged (one or two hour episodes of non-rapid eye movement sleep. It has a similar presentation to narcolepsy, but is not generally associated with cataplexy or sleep-onset rapid eye movement. Although PH is a chronic disorder, fluctuations and spontaneous remissions are known to occur. Treatment with stimulants is beneficial in most patients. We present the case of a 32-year-old Caucasian woman with the classical features of PH. Her condition has progressed over the years and she sleeps for days on end or until aroused. She has been treated with multiple stimulants, with limited success. This case highlights the clinical presentation, diagnostic criteria and treatment modalities of this rare condition.

  13. Europeanizing Danish Primary School Students

    DEFF Research Database (Denmark)

    Ratner, Helene Gad

    , the primary school’s annual national test was changed to better align with PISA’s scale of assessment. With the new test, PISA becomes more than a means for comparison between different (EU) countries as the ‘Danish’ data links up to PISA data. The paper explores how ‘Europeanised’ national test data......EU uses the OECD’s Programme for International Student Assessment (PISA) to assemble and govern the different member states’ student populations (Nóvoa and Lord, 2002; Grek, 2009). This paper explores how ‘Europe-building’ occurs through PISA-affected Danish governmental data practices. In 2015...... inwards, tracking a temporal movement within each individual. This resonates a shift in EU policy from ‘education’ to ‘learning’ (Ozga et al, 2011). The conception of the population has also changed. A big data analysis concluded that students’ national test results can predict their PISA performance...

  14. Cutaneous manifestations of primary immunodeficiency

    Directory of Open Access Journals (Sweden)

    Safa Abdelhakim

    2017-01-01

    Full Text Available Primary immunodeficiency diseases (PIDs are a group of rare, chronic disorders with deficient or malfunctioning immune system. It commonly affects the hematopoietic system, with skin the second most affected organ. Skin involvement is observed in half of pediatric PID cases and often precedes the final diagnosis. Skin infections and eczemas are the two most common manifestations in PID.[1] Skin manifestations associated with PIDs can be of infectious and noninfectious causes. Common noninfectious causes are eczema, erythroderma, cutaneous granulomas, dysplasia, vasculitis, and telangiectasia. It is important to be aware of skin manifestations in pediatric patients as early detection of PID may aid in the management of serious immunologic conditions and prevent associated morbidity and mortality.

  15. Primary unilateral cleft lip repair.

    Science.gov (United States)

    Adenwalla, H S; Narayanan, P V

    2009-10-01

    The unilateral cleft lip is a complex deformity. Surgical correction has evolved from a straight repair through triangular and quadrilateral repairs to the Rotation Advancement Technique of Millard. The latter is the technique followed at our centre for all unilateral cleft lip patients. We operate on these at five to six months of age, do not use pre-surgical orthodontics, and follow a protocol to produce a notch-free vermillion. This is easy to follow even for trainees. We also perform closed alar dissection and extensive primary septoplasty in all these patients. This has improved the overall result and has no long-term deleterious effect on the growth of the nose or of the maxilla. Other refinements have been used for prevention of a high-riding nostril, and correction of the vestibular web.

  16. Primary unilateral cleft lip repair

    Directory of Open Access Journals (Sweden)

    Adenwalla H

    2009-10-01

    Full Text Available The unilateral cleft lip is a complex deformity. Surgical correction has evolved from a straight repair through triangular and quadrilateral repairs to the Rotation Advancement Technique of Millard. The latter is the technique followed at our centre for all unilateral cleft lip patients. We operate on these at five to six months of age, do not use pre-surgical orthodontics, and follow a protocol to produce a notch-free vermillion. This is easy to follow even for trainees. We also perform closed alar dissection and extensive primary septoplasty in all these patients. This has improved the overall result and has no long-term deleterious effect on the growth of the nose or of the maxilla. Other refinements have been used for prevention of a high-riding nostril, and correction of the vestibular web.

  17. Bilateral persistent hyperplastic primary vitreous

    Directory of Open Access Journals (Sweden)

    Jain Tarun

    2009-01-01

    Full Text Available A case of bilateral persistent hyperplastic primary vitreous (PHPV in a 3-month-old male infant, who had bilateral leukokoria, is presented. The child was referred for imaging with a clinical suspicion of retinoblastoma. Gray-scale ultrasound evaluation revealed an echogenic band in the posterior segment of both globes, extending from the posterior surface of the lens capsule to the optic disc. Doppler examination revealed the presence of arterial flow in the band in both globes. Associated echogenic hemorrhage was also seen, which was confirmed by computed tomography. Most cases of PHPV are sporadic and unilateral, and bilateral PHPV is rare. The imaging features in this case suggest the diagnosis of bilateral PHPV and differentiate it from retinoblastoma. This entity, although infrequent, should be considered in the differential diagnosis while evaluating bilateral leukokoria.

  18. Primary neural leprosy: systematic review

    Directory of Open Access Journals (Sweden)

    Jose Antonio Garbino

    2013-06-01

    Full Text Available The authors proposed a systematic review on the current concepts of primary neural leprosy by consulting the following online databases: MEDLINE, Lilacs/SciELO, and Embase. Selected studies were classified based on the degree of recommendation and levels of scientific evidence according to the “Oxford Centre for Evidence-based Medicine”. The following aspects were reviewed: cutaneous clinical and laboratorial investigations, i.e. skin clinical exam, smears, and biopsy, and Mitsuda's reaction; neurological investigation (anamnesis, electromyography and nerve biopsy; serological investigation and molecular testing, i.e. serological testing for the detection of the phenolic glycolipid 1 (PGL-I and the polymerase chain reaction (PCR; and treatment (classification criteria for the definition of specific treatment, steroid treatment, and cure criteria.

  19. Primary encopresis: evaluation and treatment.

    Science.gov (United States)

    O'Brien, S; Ross, L V; Christophersen, E R

    1986-01-01

    Cathartic and behavioral treatment procedures for eliminating diurnal and nocturnal primary encopresis were investigated using a multiple-baseline design across four children. The dependent and independent variables measured were appropriate bowel movements, soiling accidents, independent toiletings, and cathartic use. Over 177 reliability observations (home visits) were conducted. For two of the children, treatment with cathartics and child-time remedied their soiling accidents and increased their independent toiletings in 8 to 11 weeks. While the cathartics and child-time increased the rate of appropriate bowel movements, they did not eliminate the soiling accidents with the other two children. Independent toiletings for these two children were achieved after 32 to 39 weeks of treatment when punishment procedures (positive practice, time-out, and hourly toilet sits) were incorporated and the suppositories were faded systematically. PMID:3733585

  20. Renal manifestations of primary hyperparathyroidism

    Directory of Open Access Journals (Sweden)

    Anurag Ranjan Lila

    2012-01-01

    Full Text Available Primary hyperparathyroidism (PHPT is associated with nephrolithiasis and nephrocalcinosis. Hypercalciuria is one of the multiple factors that is implicated in the complex pathophysiology of stone formation. The presence of a renal stone (symptomatic or asymptomatic categorizes PHPT as symptomatic and is an indication for parathyroid adenomectomy. Progression of nephrocalcinosis is largely reversible after successful surgery, but the residual risk persists. PHPT is also associated with declining renal function. In case of asymptomatic mild PHPT, annual renal functional assessment is advised. Guidelines suggest that an estimated glomerular filtration rate (eGFR < 60 ml / minute / 1.73 m 2 is an indication for parathyroid adenomectomy. This article discusses how to monitor and manage renal stones and other related renal parameters in case of PHPT.

  1. Optimizing the Primary Prevention of Type-2 Diabetes in Primary Health Care

    Science.gov (United States)

    2017-08-18

    Interprofessional Relations; Primary Health Care/Organization & Administration; Diabetes Mellitus, Type 2/Prevention & Control; Primary Prevention/Methods; Risk Reduction Behavior; Randomized Controlled Trial; Life Style

  2. Childhood Leukemia and Primary Prevention

    Science.gov (United States)

    Whitehead, Todd P.; Metayer, Catherine; Wiemels, Joseph L.; Singer, Amanda W.; Miller, Mark D.

    2016-01-01

    Leukemia is the most common pediatric cancer, affecting 3,800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia – usually before age five – and the presence at birth of “pre-leukemic” genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature – in the United States and internationally – that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the pre-conception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors – including pooled analyses from around the world and systematic reviews – is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children’s health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgement until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co

  3. Primary care performance in Dominica

    Directory of Open Access Journals (Sweden)

    James Macinko

    2015-02-01

    Full Text Available Objective. To document the structure and functions of primary care (PC in the country of Dominica using the Primary Care Assessment Tools (PCAT, a set of questionnaires that evaluate PC functions. Methods. This cross-sectional study combined data from two surveys. The systems PCAT (S-PCAT survey gathered national-level data from key informants about health system characteristics and PC performance. The provider version (P-PCAT survey collected data on PC performance from health providers (nurses and physicians at all PC facilities in the country. Provider-level data were aggregated to obtain national and district-level results for PC domains scored from 0.00 (worst to 1.00 (best. Results. From the systems perspective, results showed several knowledge gaps in PC policy, financing, and structure. Key informants gave “Good” (adequate ratings for “first-contact” care (0.74, continuity of care (0.77, comprehensive care (0.70, and coordinated care (0.78; middling scores for family-centered care and community-oriented care (0.65; and low scores for access to care (0.57. PC providers assessed access to care (which included “first-contact” care, in the P-PCAT surveys (0.84, continuity of care (0.86, information systems (0.84, family-centered care (0.92, and community-oriented care (0.85 as “Very Good”; comprehensive care as “Good” (0.79; and coordinated care as “Reasonable” (0.68. Overall, the scores for the country's health districts were good, although the ratings varied by specific PC domain. Conclusions. The assessments described here were carried out with relatively little expense and have provided important inputs into strategic planning, strategies for improving PC, and identification of priority areas for further investigation. This two-staged approach could be adapted and used in other countries.

  4. Conceptualising primary labour relationship quality

    Directory of Open Access Journals (Sweden)

    Lukas I. Ehlers

    2017-05-01

    Full Text Available Background: A typology of desirable social conditions in supervisory relationships suggested that such conditions may also be desirable in other forms of labour relationships. A literature review confirmed that trust, compliance, fairness and good faith can be confidently regarded as universally desirable social conditions in all forms of individual or collective labour relationships between employers and employees. Aim: The purpose of this study was to determine if primary labour relationship quality (PLQ can be confidently conceptualised as a social construct that strongly relates to the perceived levels of compliance, fairness and good faith in supervisory or primary labour relationships. Setting: A combination of random and convenience sampling approaches was implemented to collect PLQ related data from 454 voluntary respondents, who were subordinate employees in the Tshwane region. Methods: A quantitative research methodology was adopted. This included conceptual definition of the PLQ construct, objective measurement of PLQ levels of voluntary respondents in an adequately sized sample, factor analysis and testing for relationships and differences in means between variables. Results: Data analysis results confirmed that it can be confidently concluded that the conceptual definition of PLQ was valid, and that positive PLQ perceptions of subordinate employees were significantly related to at least two other forms of desirable organisational outcomes. Conclusion: PLQ perceptions can be confidently defined as a distinct subjective quality estimate that is assimilated from unique expectations and perceptions of the levels of compliance, fairness, good faith and trust that a supervisor displays in a labour relationship with an immediate subordinate.

  5. Primary School Teachers' Knowledge, Attitude and Perceived ...

    African Journals Online (AJOL)

    This study endeavored to investigate primary school teachers' knowledge, attitudes, and perceived practices of continuous assessment (CA). Ninety-five primary school teachers from three primary schools in West Gojjam, Ethiopia, were randomly selected for the study. Questionnaire, interviews and content analyses were ...

  6. Screening and Identification in Pediatric Primary Care

    Science.gov (United States)

    Simonian, Susan J.

    2006-01-01

    This article reviews issues related to behavioral screening in pediatric primary care settings. Structural-organizational issues affecting the use of pediatric primary care screening are discussed. This study also reviewed selected screening instruments that have utility for use in the primary care setting. Clinical and research issues related to…

  7. Primary care workforce development in Europe.

    NARCIS (Netherlands)

    Groenewegen, P.; Heinemann, S.; Gress, S.; Schäfer, W.

    2014-01-01

    Background: There is a large variation in the organization of primary care in Europe. In some health care systems, primary care is the gatekeeper to more specialized care, whilst in others patients have the choice between a wide range of providers. Primary care has increasingly become teamwork.

  8. PRIMARY MALIGNANT MELANOMA OF ARYEPIGLOTTIC FOLD

    African Journals Online (AJOL)

    2015-12-01

    Dec 1, 2015 ... commonly in larynx, tongue, and tonsil.2 Primary mel- anoma of the larynx and trachea are very rare among the group of non-cutaneous melanomas. In primary melanoma of the larynx, the least common site is the subglottic mucosa.3 Here we present a case of primary malignant melanoma of aryepiglottic ...

  9. 45 CFR 96.47 - Primary care.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Primary care. 96.47 Section 96.47 Public Welfare... and Tribal Organizations § 96.47 Primary care. Applications for direct funding of Indian tribes and tribal organizations under the primary care block grant must comply with 42 CFR Part 51c (Grants for...

  10. the relationship between primary school teachers extrinsic

    African Journals Online (AJOL)

    PROF EKWUEME

    Primary School Teachers Motivation Questionnaire (PSTMQ) and objective test items in English Language, Mathematics and Primary Science to measure students' performance. ... Mathematics and Primary Science. ... teachers as those who mediate pupils learning and act as facilitators ..... Students' perception of teacher- ...

  11. Reactor primary pumps dynamic balancing test

    International Nuclear Information System (INIS)

    Lu Qunxian

    2002-01-01

    Reactor primary Pump is the important equipment in the primary circuit, its working quality would directly influence the safety and operation of nuclear power plant. The author describes that the primary pump vibration status, vibration fault diagnosis and dynamic balancing process on site have been performed since commercial operation of DA YA BAY Nuclear Power plant

  12. 30 CFR 817.151 - Primary roads.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Primary roads. 817.151 Section 817.151 Mineral... roads. Primary roads shall meet the requirements of § 817.150 and the additional requirements of this section. (a) Certification. The construction or reconstruction of primary roads shall be certified in a...

  13. 30 CFR 816.151 - Primary roads.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Primary roads. 816.151 Section 816.151 Mineral... roads. Primary roads shall meet the requirements of section 816.150 and the additional requirements of this section. (a) Certification. The construction or reconstruction of primary roads shall be certified...

  14. Multiple primary cancers: Simultaneously occurring prostate cancer ...

    African Journals Online (AJOL)

    We also reviewed the existing literatures for possible biologic links between prostatic carcinoma and other primary tumors. ... The primary tumors co-existing with prostate cancer were colonic adenocarcinoma, rectal adenocarcinoma, urinary bladder transitional cell carcinoma, primary liver cell carcinoma, and thyroid ...

  15. Sensitivity to friction for primary explosives.

    Science.gov (United States)

    Matyáš, Robert; Šelešovský, Jakub; Musil, Tomáš

    2012-04-30

    The sensitivity to friction for a selection of primary explosives has been studied using a small BAM friction apparatus. The probit analysis was used for the construction of a sensitivity curve for each primary explosive tested. Two groups of primary explosives were chosen for measurement (a) the most commonly used industrially produced primary explosives (e.g. lead azide, tetrazene, dinol, lead styphnate) and (b) the most produced improvised primary explosives (e.g. triacetone triperoxide, hexamethylenetriperoxide diamine, mercury fulminate, acetylides of heavy metals). A knowledge of friction sensitivity is very important for determining manipulation safety for primary explosives. All the primary explosives tested were carefully characterised (synthesis procedure, shape and size of crystals). The sensitivity curves obtained represent a unique set of data, which cannot be found anywhere else in the available literature. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. [Primary intestinal lymphangiectasia (Waldmann's disease)].

    Science.gov (United States)

    Vignes, S; Bellanger, J

    2017-08-31

    Primary intestinal lymphangiectasia (PIL), Waldmann's disease, is a rare disorder of unknown etiology characterized by dilated intestinal lacteals leading to lymph leakage into the small-bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. The main symptom is bilateral lower limb edema. Edema may be moderate to severe including pleural effusion, pericarditis or ascites. Protein-losing enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance and diagnosis by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of biopsies. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Several B-cell lymphomas of the gastrointestinal tract or with extra-intestinal localizations were reported in PIL patients. A long-term strictly low-fat diet associated with medium-chain triglyceride and liposoluble vitamin supplementation is the cornerstone of PIL medical management. Octreotide, a somatostatin analog, have been proposed with an inconsistent efficacy in association with diet. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. A prolonged clinical and biological follow-up is recommended. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  17. Primary Prevention of Food Allergy.

    Science.gov (United States)

    Greenhawt, Matthew J; Fleischer, David M

    2017-04-01

    Food allergy is estimated to affect approximately 8% of children in the USA. This is a disease without any known treatment or cure and, for some, a disease that can be quite severe, even life-threatening. While recent advances in potential treatment have made remarkable strides, with two food-targeted immunotherapy products now in phase III trials, perhaps the biggest gains in the field have come in the advent of potential preventative strategies to avoid the development of food allergy in high-risk individuals. There have been multiple, randomized, controlled trials (RCTs) performed in the past 5 years that have demonstrated significant risk reduction from early allergen introduction. These include two trials for early peanut introduction and five trials for early egg introduction in the first year of life. The results indicate that primary prevention of food allergy through early allergen introduction may represent a strategy that could potentially avert tens of thousands of children from becoming food allergic. In support of the data for peanut, the National Institute of Allergy and Infectious Diseases recently sponsored an addendum to the 2010 food allergy guidelines, specifically recommending peanut be introduced in both high- and standard-risk infants to reduce the risk of developing peanut allergy. To date, no formal recommendations have been made for egg, however. This review will focus on the latest evidence supporting early introduction as a strategy to prevent food allergy, as well as on practical aspects for its successful implementation.

  18. Rare primary headaches: clinical insights.

    Science.gov (United States)

    Casucci, G; d'Onofrio, F; Torelli, P

    2004-10-01

    So-called "rare" headaches, whose prevalence rate is lower than 1% or is not known at all and have been reported in only a few dozen cases to date, constitute a very heterogeneous group. Those that are best characterised from the clinical point of view can be classified into forms with prominent autonomic features and forms with sparse or no autonomic features. Among the former are trigeminal autonomic cephalalgias (TACs) and hemicrania continua, while the latter comprise classical trigeminal neuralgia, hypnic headache, primary thunderclap headache, and exploding head syndrome. The major clinical discriminating factor for the differential diagnosis of TACs is the relationship between duration and frequency of attacks: the forms in which pain is shorter lived are those with the higher frequency of daily attacks. Other aspects to be considered are the time pattern of symptoms, intensity and timing of attacks, the patient's behaviour during the attacks, the presence of any triggering factors and of the refractory period after an induced attack, and response to therapy, especially with indomethacin. Often these are little known clinical entities, which are not easily detected in clinical practice. For some of them, e. g., thunderclap headache, it is always necessary to perform instrumental tests to exclude the presence of underlying organic diseases.

  19. [Teenager counselling in primary care].

    Science.gov (United States)

    Millán, Teresa; Morera, Iván; Vargas, Nelson A

    2007-04-01

    Teenager counseling to recognize risks and reinforce strengths is carried out in a primary care outpatient clinic since 2003. To describe the epidemiology and causes for consultation in this teenage counseling program. Retrospective review of the records of 116 teenagers (median age 13 years, 67% females) that received teenager counseling. Seventy percent of women and 50% of men came from nuclear families. More than two thirds were primogenital. Most adolescents were accompanied by their mother, that were the main adult raw model. Fifty percent had dysfunctional families. All were attending school regularly and 21% of women and 29% of men had repeated a school level. Sixty eight percent of women and 62% of men declared to have a life project. Twenty percent were worried about their physical appearance. Seventy seven percent of women and 62% of men considered themselves as happy. Thirty six percent of women and 14% of men smoked. The figures for alcohol consumption were 21% and 14%, respectively. The causes for consultation were obesity, overweight, unspecific symptoms, behavioral problems, bad school achievement, communication problems or pregnancy. Reasons for counseling were family dysfunction, low self esteem, bad school achievement and information about sexuality. The information obtained could help to improve the interdisciplinary work and to coordinate counseling with the family and schools.

  20. ITER primary cryopump test facility

    International Nuclear Information System (INIS)

    Petersohn, N.; Mack, A.; Boissin, J.C.; Murdoc, D.

    1998-01-01

    A cryopump as ITER primary vacuum pump is being developed at FZK under the European fusion technology programme. The ITER vacuum system comprises of 16 cryopumps operating in a cyclic mode which fulfills the vacuum requirements in all ITER operation modes. Prior to the construction of a prototype cryopump, the concept is tested on a reduced scale model pump. To test the model pump, the TIMO facility is being built at FZK in which the model pump operation under ITER environmental conditions, except for tritium exposure, neutron irradiation and magnetic fields, can be simulated. The TIMO facility mainly consists of a test vessel for ITER divertor duct simulation, a 600 W refrigerator system supplying helium in the 5 K stage and a 30 kW helium supply system for the 80 K stage. The model pump test programme will be performed with regard to the pumping performance and cryogenic operation of the pump. The results of the model pump testing will lead to the design of the full scale ITER cryopump. (orig.)

  1. Bone disease in primary hyperparathyroidism

    Science.gov (United States)

    Bandeira, Francisco; Cusano, Natalie E.; Silva, Barbara C.; Cassibba, Sara; Almeida, Clarissa Beatriz; Machado, Vanessa Caroline Costa; Bilezikian, John P.

    2015-01-01

    Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT. PMID:25166047

  2. Ocular changes in primary hypothyroidism.

    Science.gov (United States)

    Ozturk, Banu T; Kerimoglu, Hurkan; Dikbas, Oguz; Pekel, Hamiyet; Gonen, Mustafa S

    2009-12-29

    To determine the ocular changes related to hypothyrodism in newly diagnosed patients without orbitopathy. Thirty-three patients diagnosed to have primary overt hypothyroidism were enrolled in the study. All subjects were assigned to underwent central corneal thickness (CCT), anterior chamber volume, depth and angle measurements with the Scheimpflug camera (Pentacam, Oculus) and cup to disc ratio (C/D), mean retinal thickness and mean retinal nerve fiber layer (RNFL) thickness measurements with optical coherence tomography (OCT) in addition to ophthalmological examination preceeding the replacement therapy and at the 1(st), 3(rd )and 6(th )months of treatment. The mean age of the patients included in the study were 40.58 +/- 1.32 years. The thyroid hormone levels return to normal levels in all patients during the follow-up period, however the mean intraocular pressure (IOP) revealed no significant change. The mean CCT was 538.05 +/- 3.85 mu initially and demonstrated no statistically significant change as the anterior chamber volume, depth and angle measurements did. The mean C/D ratio was 0.29 +/- 0.03 and the mean retinal thickness was 255.83 +/- 19.49 mu initially and the treatment did not give rise to any significant change. The mean RNFL thickness was also stable during the control visits, so no statistically significant change was encountered. Neither hypothyroidism, nor its replacement therapy gave rise to any change of IOP, CCT, anterior chamber parameters, RNFL, retinal thickness and C/D ratio.

  3. Ocular changes in primary hypothyroidism

    Directory of Open Access Journals (Sweden)

    Pekel Hamiyet

    2009-12-01

    Full Text Available Abstract Background To determine the ocular changes related to hypothyrodism in newly diagnosed patients without orbitopathy. Findings Thirty-three patients diagnosed to have primary overt hypothyroidism were enrolled in the study. All subjects were assigned to underwent central corneal thickness (CCT, anterior chamber volume, depth and angle measurements with the Scheimpflug camera (Pentacam, Oculus and cup to disc ratio (C/D, mean retinal thickness and mean retinal nerve fiber layer (RNFL thickness measurements with optical coherence tomography (OCT in addition to ophthalmological examination preceeding the replacement therapy and at the 1st, 3rd and 6th months of treatment. The mean age of the patients included in the study were 40.58 ± 1.32 years. The thyroid hormone levels return to normal levels in all patients during the follow-up period, however the mean intraocular pressure (IOP revealed no significant change. The mean CCT was 538.05 ± 3.85 μ initially and demonstrated no statistically significant change as the anterior chamber volume, depth and angle measurements did. The mean C/D ratio was 0.29 ± 0.03 and the mean retinal thickness was 255.83 ± 19.49 μ initially and the treatment did not give rise to any significant change. The mean RNFL thickness was also stable during the control visits, so no statistically significant change was encountered. Conclusions Neither hypothyroidism, nor its replacement therapy gave rise to any change of IOP, CCT, anterior chamber parameters, RNFL, retinal thickness and C/D ratio.

  4. Update on Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Jenny Heathcote

    2000-01-01

    Full Text Available The diagnosis of primary biliary cirrhosis (PBC is most often made in the asymptomatic phase, sometimes before the development of abnormal liver biochemistry. The antimitochondrial antibody remains the predominant hallmark, although not all patients test positive, even when the most sensitive techniques are used. The etiology of PBC remains elusive; studies suggest that the interlobular bile duct destruction is immune based, and associated autoimmune diseases are common. There are no surrogate markers that predict outcome in asymptomatic patients, whose chance of survival is less than that of age- and sex-matched populations but much better than the median survival of eight years in patients with symptomatic PBC. Symptoms common in this disease are fatigue, pruritus and xanthelasma, as well as complications of portal hypertension and osteoporosis. Treatment includes symptomatic and preventive measures, as well as specific therapeutic measures. Immunosuppressive therapy has yielded disappointing results in the long term management of PBC, and the only therapy shown to improve survival is the hydrophobic dihydroxy bile acid ursodeoxycholic acid. Treatment at a dose of 13 to 15 mg/kg/day is optimal, given in separate doses or as a single dose at least 4 h from giving the oral anion exchange resin cholestyramine, which may be used to control pruritus. However, liver transplantation remains the only cure for this disease, and the best postoperative survival is seen in patients whose serum bilirubin does not exceed 180 µmol/L at the time of liver transplantation. Recurrence takes place but is rarely symptomatic and does not deter from the benefits of transplantation.

  5. Primary hyperparathyroidism in North India

    International Nuclear Information System (INIS)

    Bhansali, Anil; Masoodi, Shariq Rashid; Reddy, K.S.S.; Dash, Jiban Radharaman; Behera, Aruanshu; Katariya, Rabinder Nath; Mittal, Bhagwant Rai

    2005-01-01

    Primary hyperparathyroidism (PHPT) has a variable clinical expression. Symptomatic PHPT is still predominant form of the disease in many parts of the world, especially developing countries. Because the clinical profile of the disease has changed from that described in the past we sought to improve our understanding of the disease in patients in North India. We summarized the clinical presentation, biochemical and radiological features, and operative findings from the case records from the last 13 years of 52 patients at a tertiary care center in North India who had documented PHPT. The male: female was 1:3.3 with ages ranging from 6 to 60 years (mean+-SD, 36.38+-12.73). Bone disease (46%), recurrent renal stones (21%) and body aches and pains (21%) were the most common modes of the presentation. The lag time varied ranged from 1 month to 16 years. Common clinical manifestations included bone pain (67%), weakness/fatigue (56%), fracture of long bones (48%), abdominal pain (39%), polyuria (37%) and psychiatric manifestations (23.1%). Hypertension was observed in 42% and a palpable nodule in the neck in 19%. Biochemical features included hypercalcemia (86.5%), hypophosphatemia (65.4%) and hyperphosphatasia (67.3%). Mean intact PTH (+-SD)was 809.0+-696.3 ng/L with levels significantly lower in patients who had only kidney stone diseases compared with those with bone disease (P=0.017). A single parathyroid was localized in 50(98%) patients. Hungry bone disease was seen in 59% patients. (author)

  6. Scintigraphic Evaluation in Primary Hyperparathyroidism

    International Nuclear Information System (INIS)

    Ghita, S.; Mazilu, C.; Marinescu, G.; Mititelu, R.; Rambu, A.; Murgoci, P.; Codorean, I.

    2006-01-01

    Full text: Primary hyperparathyroidism typically presents as an asymptomatic disorder. Classical findings of 'stones, bones, abdominal groans and psychic moans' are quite rare. Even in advanced cases symptoms may be seldom and unspecific, diagnosis being sometimes difficult to make. Case report. 35 year-old man, admitted in our hospital with left femoral neck fracture. The patient had a previous surgical intervention on the same femoral neck 10 months ago, for a benign tumor. Histopathology: 'Tissue rich in giant cells of osteoclastic type and blood vessels, areas of lysis and bony formation. Aneurismal bone cyst'. Radiographic exam of left hip at admission: 'Pathologic fracture of the left femoral neck. Sclerotic lesions in the proximal half of left femur with cortical thinning and internal septa'. Lab tests: ALP 803.94 IU/l (N: 38 - 126), Hb 9.7 g/dl, ESR 30/1h. Bone scan: Superscan with diffuse high uptake in both axial and appendicular skeleton. Extremely high uptake in the skull. Some focal uptakes in the left femur (proximal extremity neck, trochanteric region, and distal 1/3 of diaphysis), both patellae and right humerus. Conclusions: Super scan aspect suggesting the presence of changes in bone metabolism (hyperparathyroidism?). Focal changes which in such context may reflect the presence of osteitis fibrosa cystica / brown tumours. Further investigations: Rx confirms generalized demineralization. Serum calcium: 13.28 mg/dl indicating the probability of a primary hyper para-thyroidism. 99m Tc Tetrofosmin scan ('wash-out'): focal uptake in the left lower region of the neck, distal to the left thyroid lobe, visible on the early images, with almost complete normalization on late images (rapid wash-out). Probable diagnosis: adenoma of the left inferior parathyroid gland. Whole body acquisition performed immediately after the early acquisitions for parathyroid adenoma work-up revealed diffuse uptake in the skeleton reflecting a high metabolic rate; focal uptakes

  7. Multiple neoplasms, single primaries, and patient survival

    Directory of Open Access Journals (Sweden)

    Amer MH

    2014-03-01

    Full Text Available Magid H Amer Department of Medicine, St Rita's Medical Center, Lima, OH, USA Background: Multiple primary neoplasms in surviving cancer patients are relatively common, with an increasing incidence. Their impact on survival has not been clearly defined. Methods: This was a retrospective review of clinical data for all consecutive patients with histologically confirmed cancer, with emphasis on single versus multiple primary neoplasms. Second primaries discovered at the workup of the index (first primary were termed simultaneous, if discovered within 6 months of the index primary were called synchronous, and if discovered after 6 months were termed metachronous. Results: Between 2005 and 2012, of 1,873 cancer patients, 322 developed second malignancies; these included two primaries (n=284, and three or more primaries (n=38. Forty-seven patients had synchronous primaries and 275 had metachronous primaries. Patients with multiple primaries were predominantly of Caucasian ancestry (91.0%, with a tendency to develop thrombosis (20.2%, had a strong family history of similar cancer (22.3%, and usually presented with earlier stage 0 through stage II disease (78.9%. When compared with 1,551 patients with a single primary, these figures were 8.9%, 15.6%, 18.3%, and 50.9%, respectively (P≤0.001. Five-year survival rates were higher for metachronous cancers (95% than for synchronous primaries (59% and single primaries (59%. The worst survival rate was for simultaneous concomitant multiple primaries, being a median of 1.9 years. The best survival was for patients with three or more primaries (median 10.9 years and was similar to the expected survival for the age-matched and sex-matched general population (P=0.06991. Conclusion: Patients with multiple primaries are usually of Caucasian ancestry, have less aggressive malignancies, present at earlier stages, frequently have a strong family history of similar cancer, and their cancers tend to have indolent

  8. Primary progressive aphasia and apraxia of speech.

    Science.gov (United States)

    Jung, Youngsin; Duffy, Joseph R; Josephs, Keith A

    2013-09-01

    Primary progressive aphasia is a neurodegenerative syndrome characterized by progressive language dysfunction. The majority of primary progressive aphasia cases can be classified into three subtypes: nonfluent/agrammatic, semantic, and logopenic variants. Each variant presents with unique clinical features, and is associated with distinctive underlying pathology and neuroimaging findings. Unlike primary progressive aphasia, apraxia of speech is a disorder that involves inaccurate production of sounds secondary to impaired planning or programming of speech movements. Primary progressive apraxia of speech is a neurodegenerative form of apraxia of speech, and it should be distinguished from primary progressive aphasia given its discrete clinicopathological presentation. Recently, there have been substantial advances in our understanding of these speech and language disorders. The clinical, neuroimaging, and histopathological features of primary progressive aphasia and apraxia of speech are reviewed in this article. The distinctions among these disorders for accurate diagnosis are increasingly important from a prognostic and therapeutic standpoint. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  9. Ursodeoxycholic acid for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Gong, Y.; Huang, Z.B.; Christensen, Erik

    2008-01-01

    , and the references of identified studies. The last search was performed in January 2007. SELECTION CRITERIA: Randomised clinical trials evaluating UDCA versus placebo or no intervention in patients with primary biliary cirrhosis. DATA COLLECTION AND ANALYSIS: The primary outcomes were mortality and mortality......, trial duration, and patient's severity of primary biliary cirrhosis. We also used Bayesian meta-analytic approach to estimate the UDCA effect as sensitivity analysis. MAIN RESULTS: Sixteen randomised clinical trials evaluating UDCA against placebo or no intervention were identified. Data from three......BACKGROUND: Primary biliary cirrhosis is an uncommon autoimmune liver disease with unknown aetiology. Ursodeoxycholic acid (UDCA) has been used for primary biliary cirrhosis, but the effects remain controversial. OBJECTIVES: To evaluate the benefits and harms of UDCA on patients with primary...

  10. Primary uterine inertia in four labrador bitches.

    Science.gov (United States)

    Davidson, Autumn P

    2011-01-01

    Uterine inertia is a common cause of dystocia in the bitch and is designated as primary (i.e., uterine contractions fail to ever be initiated) or secondary (i.e., uterine contractions cease after a period of time but before labor is completed). The etiology of primary uterine inertia is not well understood. The accurate diagnosis of primary uterine inertia requires the use of tocodynamometry (uterine monitoring). Primary uterine inertia has been postulated to result from a failure of luteolysis resulting in persistently elevated progesterone concentrations. In this study, primary uterine inertia was diagnosed in a series of four bitches in which luteolysis was documented suggesting some other etiopathogenesis for primary uterine inertia.

  11. Primary leiomyosarcoma of the innominate vein.

    Science.gov (United States)

    Illuminati, Giulio; Miraldi, Fabio; Mazzesi, Giuseppe; D'urso, Antonio; Ceccanei, Gianluca; Bezzi, Marcello

    2007-01-01

    Primary venous leiomyosarcoma is rare. We report the case of a primary leiomyosarcoma of the left innominate vein, with neoplastic thrombus extending into the left jugular and subclavian veins. The tumor was curatively resected en bloc with anterior mediastinal and laterocervical lymphatics, through a median sternotomy prolonged into left cervicotomy. Primary venous sarcomas may be associated with prolonged survival in individual cases, with curative resection recommended as the standard treatment, in the absence of distant spread.

  12. Primary Oral Tuberculosis - A Case Report

    Directory of Open Access Journals (Sweden)

    B N Praveen

    2007-01-01

    Full Text Available Tuberculosis is most common disease in developing countries because of lack of public health awareness, poverty, nutritional deficiencies, absence of medical facilities. Primary oral lesions in tuberculosis are still exceedingly rare. Oral involvement may be primary or secondary to systemic involvement. Involvement of oral cavity is rare accounting for 0.2-1.5% of cases. A rare case report of primary oral tuberculosis is presented.

  13. Primary multifocal osseous lymphoma in a child

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Takashi S.P. [University of Iowa, Carver College of Medicine, Iowa City, IA (United States); Ferguson, Polly J. [University of Iowa, Department of Pediatrics, Iowa City, IA (United States); Khanna, Geetika [Washington University, Mallinckrodt Institute of Radiology, St Louis, MO (United States)

    2008-12-15

    We report a case of primary multifocal osseous lymphoma in a 6-year-old girl presenting with multifocal osteolytic lesions without systemic symptoms or identifiable non-osseous primary tumor. The differential diagnoses for such a presentation include histiocytosis X, chronic recurrent multifocal osteomyelitis, acute lymphoblastic leukemia, metastatic disease, and primary bone lymphoma. Although non-Hodgkin lymphoma is common in the pediatric population, its presentation as a primary bone tumor, especially with multifocal disease, is extremely rare and is frequently misdiagnosed. We hope that awareness of this entity will help radiologists achieve timely diagnosis and intervention. (orig.)

  14. Blueprint for an Undergraduate Primary Care Curriculum.

    Science.gov (United States)

    Fazio, Sara B; Demasi, Monica; Farren, Erin; Frankl, Susan; Gottlieb, Barbara; Hoy, Jessica; Johnson, Amanda; Kasper, Jill; Lee, Patrick; McCarthy, Claire; Miller, Kathe; Morris, Juliana; O'Hare, Kitty; Rosales, Rachael; Simmons, Leigh; Smith, Benjamin; Treadway, Katherine; Goodell, Kristen; Ogur, Barbara

    2016-12-01

    In light of the increasing demand for primary care services and the changing scope of health care, it is important to consider how the principles of primary care are taught in medical school. While the majority of schools have increased students' exposure to primary care, they have not developed a standardized primary care curriculum for undergraduate medical education. In 2013, the authors convened a group of educators from primary care internal medicine, pediatrics, family medicine, and medicine-pediatrics, as well as five medical students to create a blueprint for a primary care curriculum that could be integrated into a longitudinal primary care experience spanning undergraduate medical education and delivered to all students regardless of their eventual career choice.The authors organized this blueprint into three domains: care management, specific areas of content expertise, and understanding the role of primary care in the health care system. Within each domain, they described specific curriculum content, including longitudinality, generalism, central responsibility for managing care, therapeutic alliance/communication, approach to acute and chronic care, wellness and prevention, mental and behavioral health, systems improvement, interprofessional training, and population health, as well as competencies that all medical students should attain by graduation.The proposed curriculum incorporates important core features of doctoring, which are often affirmed by all disciplines but owned by none. The authors argue that primary care educators are natural stewards of this curriculum content and can ensure that it complements and strengthens all aspects of undergraduate medical education.

  15. Ion transport by the amphibian primary ureter

    DEFF Research Database (Denmark)

    Møbjerg, Nadja

    2008-01-01

    putative ion transport mechanisms in the primary ureter of the freshwater amphibian Ambystoma mexicanum (axolotl). Primary ureters isolated from axolotl larvae were perfused in vitro and single cells were impaled across the basal cell membrane with glass microelectrodes. In 42 cells the membrane potential......+] steps from 3 to 20 mmol/l and a hyperpolarization of Vm upon lowering [Na+] from 102 to 2 mmol/l, indicating the presence of luminal K+ and Na+ conductances. This study provides the first functional data on the vertebrate primary ureter. The data show that the primary ureter of axolotl larvae...

  16. Primary data collection in health technology assessment.

    Science.gov (United States)

    McIsaac, Michelle L; Goeree, Ron; Brophy, James M

    2007-01-01

    This study discusses the value of primary data collection as part of health technology assessment (HTA). Primary data collection can help reduce uncertainty in HTA and better inform evidence-based decision making. However, methodological issues such as choosing appropriate study design and practical concerns such as the value of collecting additional information need to be addressed. The authors emphasize the conditions required for successful primary data collection in HTA: experienced researchers, sufficient funding, and coordination among stakeholders, government, and researchers. The authors conclude that, under specific conditions, primary data collection is a worthwhile endeavor in the HTA process.

  17. Primary intestinal lymphangiectasia (Waldmann's disease).

    Science.gov (United States)

    Vignes, Stéphane; Bellanger, Jérôme

    2008-02-22

    Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool alpha1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective

  18. Primary intestinal lymphangiectasia (Waldmann's disease

    Directory of Open Access Journals (Sweden)

    Bellanger Jérôme

    2008-02-01

    Full Text Available Abstract Primary intestinal lymphangiectasia (PIL is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other

  19. Primary health care in India.

    Science.gov (United States)

    Deodhar, N S

    1982-03-01

    relative neglect of development of health manpower for nursing, environmental engineering, and other technical and paramedical personnel. Community involvement and participation were at a minimum if they existed at all. The basic concern about primary health care for all continued unabated however. To realize the goal of health care for all, 3 programs will have to be pursued simultaneously during the next 2 decades: integrated overall development including family planning; improvement in nutrition, environment, and health education; and the provision of adequate health care services for all, particularly the poor and underprivileged. It is necessary to redefine the roles of the central and state governments in view of the large power powers delegated to local bodies at the district level and below. Voluntary agencies will have to function within the overall plan/aid down by the state.

  20. Primary School Teachers' Perceptions of Adequacy and Quality of Physical Facilities in Public Primary Schools under Free Primary Education

    Science.gov (United States)

    Muthima, Ndirangu Wahome; Udoto, Maurice O.; Anditi, Zephania O.

    2016-01-01

    The Free Primary Education (FPE) programme was commissioned in Kenya in January 2003 to provide basic education to all children of school going age and to ease the burden of cost sharing from the parents. However, even though the public primary school class teachers were to shoulder the greatest responsibility in the implementation of this…

  1. The primary care amplification model: taking the best of primary care forward

    Directory of Open Access Journals (Sweden)

    Nicholson Caroline

    2008-12-01

    Full Text Available Abstract Background Primary care internationally is approaching a new paradigm. The change agenda implicit in this threatens to de-stabilise and challenge established general practice and primary care. Discussion The Primary Care Amplification Model offers a means to harness the change agenda by 'amplifying' the strengths of established general practices around a 'beacon' practice. Conclusion Such 'beacon' practices can provide a mustering point for an expanded scope of practice for primary care, integrated primary/secondary service delivery, interprofessional learning, relevant local clinical research, and a focus on local service innovation, enhancing rather than fragmenting the collective capacity of existing primary care.

  2. Primary care in Switzerland gains strength.

    Science.gov (United States)

    Djalali, Sima; Meier, Tatjana; Hasler, Susann; Rosemann, Thomas; Tandjung, Ryan

    2015-06-01

    Although there is widespread agreement on health- and cost-related benefits of strong primary care in health systems, little is known about the development of the primary care status over time in specific countries, especially in countries with a traditionally weak primary care sector such as Switzerland. The aim of our study was to assess the current strength of primary care in the Swiss health care system and to compare it with published results of earlier primary care assessments in Switzerland and other countries. A survey of experts and stakeholders with insights into the Swiss health care system was carried out between February and March 2014. The study was designed as mixed-modes survey with a self-administered questionnaire based on a set of 15 indicators for the assessment of primary care strength. Forty representatives of Swiss primary and secondary care, patient associations, funders, health care authority, policy makers and experts in health services research were addressed. Concordance between the indicators of a strong primary care system and the real situation in Swiss primary care was rated with 0-2 points (low-high concordance). A response rate of 62.5% was achieved. Participants rated concordance with five indicators as 0 (low), with seven indicators as 1 (medium) and with three indicators as 2 (high). In sum, Switzerland achieved 13 of 30 possible points. Low scores were assigned because of the following characteristics of Swiss primary care: inequitable local distribution of medical resources, relatively low earnings of primary care practitioners compared to specialists, low priority of primary care in medical education and training, lack of formal guidelines for information transfer between primary care practitioners and specialists and disregard of clinical routine data in the context of medical service planning. Compared to results of an earlier assessment in Switzerland, an improvement of seven indicators could be stated since 1995. As a

  3. Primary extradural meningioma arising from the calvarium

    Directory of Open Access Journals (Sweden)

    N Ravi

    2013-06-01

    Full Text Available Meningiomas are the most common intracranial tumours. Meningiomas arising at other locations are termed primary extradural meningiomas (EDM and are rare. Here we report a case of EDM arising from the calvarium – a primary calvarial meningioma (PCM.

  4. [Primary childhood vasculitis new classification criteria

    DEFF Research Database (Denmark)

    Herlin, T.; Nielsen, Susan

    2008-01-01

    Primary vasculitis is seen in both adults and children, but some of the diseases like Kawasaki disease occur primarily in children. The Chapel Hill Classification Criteria for primary vasculitis refers to the size of vessels but has not been validated in children. Recently, new criteria...

  5. Oxidative stress in primary glomerular diseases

    DEFF Research Database (Denmark)

    Markan, Suchita; Kohli, Harbir Singh; Sud, Kamal

    2008-01-01

    To evaluate the status of oxidative stress in patients with different primary glomerular diseases (PGD) which have differential predisposition to renal failure.......To evaluate the status of oxidative stress in patients with different primary glomerular diseases (PGD) which have differential predisposition to renal failure....

  6. A Conceptual Framework for Primary Source Practices

    Science.gov (United States)

    Ensminger, David C.; Fry, Michelle L.

    2012-01-01

    This article introduces a descriptive conceptual framework to provide teachers with a means of recognizing and describing instructional activities that use primary sources. The framework provides structure for professional development programs that have been established to train teachers to access and integrate primary sources into lessons. The…

  7. Diversity of primary care systems analysed.

    NARCIS (Netherlands)

    Kringos, D.; Boerma, W.; Bourgueil, Y.; Cartier, T.; Dedeu, T.; Hasvold, T.; Hutchinson, A.; Lember, M.; Oleszczyk, M.; Pavlick, D.R.

    2015-01-01

    This chapter analyses differences between countries and explains why countries differ regarding the structure and process of primary care. The components of primary care strength that are used in the analyses are health policy-making, workforce development and in the care process itself (see Fig.

  8. Second primary tumours in oral cancer

    NARCIS (Netherlands)

    van der Waal, I.; de Bree, R.

    2010-01-01

    Second primary tumours in patients treated for oral cancer occur at a rate of 3% to 7% per year. The majority of these tumours show up at least six months after the detection of the primary and are often located in the upper aerodigestive tract. Cessation of smoking habits may reduce the risk of the

  9. Humor Climate of the Primary Schools

    Science.gov (United States)

    Sahin, Ahmet

    2018-01-01

    The aim of this study is to determine the opinions primary school administrators and teachers on humor climates in primary schools. The study was modeled as a convergent parallel design, one of the mixed methods. The data gathered from 253 administrator questionnaires, and 651 teacher questionnaires was evaluated for the quantitative part of the…

  10. An Introduction to Primary Physical Education

    Science.gov (United States)

    Griggs, Gerald, Ed.

    2012-01-01

    Physical Education is a core component of the primary school curriculum. The primary years are perhaps the most significant period for motor development in children, a time during which basic movement competencies are developed and which offers the first opportunity for embedding physical activity as part of a healthy lifestyle. This is the first…

  11. Standardization of Primary Education in Great Britain

    Science.gov (United States)

    Yarovaya, Yelena B.

    2015-01-01

    The article examines the standardization of primary education as one of the development trends of the British school at the present moment in the context of improving its efficiency and quality. It analyses the positive results of the standard-based reforms (modernization of primary education content, improvement of younger students' outcomes,…

  12. Primary School Principals' Self-Monitoring Skills

    Science.gov (United States)

    Konan, Necdet

    2015-01-01

    The aim of the present study is to identify primary school principals' self-monitoring skills. The study adopted the general survey model and its population comprised primary school principals serving in the city of Diyarbakir, Turkey, while 292 of these constituted the sample. Self-Monitoring Scale was used as the data collection instrument. In…

  13. Primary School Teachers' Perceptions of Mathematical Reasoning

    Science.gov (United States)

    Loong, Esther Yook-Kin; Vale, Colleen; Bragg, Leicha A.; Herbert, Sandra

    2013-01-01

    Little is known about how Australian teachers interpret, enact and assess reasoning. This paper reports on primary teachers' perceptions of reasoning prior to observation and subsequent trialling of demonstration lessons in a primary school. The findings indicate that while some teachers were able to articulate what reasoning means, others were…

  14. Melinda: De Facto Primary School Music Teacher

    Science.gov (United States)

    de Vries, Peter

    2013-01-01

    A series of reviews dating back to the 1960s and a body of research literature points to the inadequate delivery of music education by generalist primary school teachers in Australian schools. Despite recommendations for specialist music teachers to teach music in all Australian primary schools to counter this ongoing trend, such an approach has…

  15. Primary Immune Deficiency Treatment Consortium (PIDTC) report

    NARCIS (Netherlands)

    L.M. Griffith (Linda); M. Cowan (Morton); L.D. Notarangelo (Luigi Daniele); R. Kohn (Robert); J. Puck (Jennifer); S.-Y. Pai (Sung-Yun); B. Ballard (Barbara); S.C. Bauer (Sarah); J. Bleesing (Jack); M. Boyle (Marcia); R.W. Brower (Ronald); R.H. Buckley (Rebecca); M. van der Burg (Mirjam); L.M. Burroughs (Lauri); F. Candotti (Fabio); A. Cant (Andrew); T. Chatila (Talal); C. Cunningham-Rundles (Charlotte); M.C. Dinauer (Mary); J. Dvorak (Jennie); A. Filipovich (Alexandra); L.A. Fleisher (Lee); H.B. Gaspar (Bobby); T. Gungor (Tayfun); E. Haddad (Elie); E. Hovermale (Emily); F. Huang (Faith); A. Hurley (Alan); M. Hurley (Mary); S.K. Iyengar (Sudha); E.M. Kang (Elizabeth); B.R. Logan (Brent); J.R. Long-Boyle (Janel); H. Malech (Harry); S.A. McGhee (Sean); S. Modell (Sieglinde); S. Modell (Sieglinde); H.D. Ochs (Hans); R.J. O'Reilly (Richard); R. Parkman (Robertson); D. Rawlings (D.); J.M. Routes (John); P. Shearer (P.); T.N. Small (Trudy); H. Smith (H.); K.E. Sullivan (Kathleen); P. Szabolcs (Paul); A.J. Thrasher (Adrian); D. Torgerson; P. Veys (Paul); K. Weinberg (Kenneth); J.C. Zuniga-Pflucker (Juan Carlos)

    2014-01-01

    textabstractThe Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency

  16. Teaching Primary Science with Almost Nothing

    Science.gov (United States)

    Kelly, Lois; Schofield, Kathy

    2012-01-01

    In the summer of 2010 the authors spent two weeks helping teachers in a primary school near Kampala to develop their science curriculum. In common with many primary schools in Uganda science was taught as "facts to be learnt." This was partly because the teachers had had little or no first-hand experience of practical science or science…

  17. Teaching Primary Science: How Research Helps

    Science.gov (United States)

    Harlen, Wynne

    2010-01-01

    The very first edition of "Primary Science Review" included an article entitled "Teaching primary science--how research can help" (Harlen, 1986), which announced that a section of the journal would be for reports of research and particularly for teachers reporting their classroom research. The intervening 24 years have seen…

  18. Sensitivity to friction for primary explosives

    International Nuclear Information System (INIS)

    Matyáš, Robert; Šelešovský, Jakub; Musil, Tomáš

    2012-01-01

    Highlights: ► The friction sensitivity of 14 samples of primary explosives was determined. ► The same apparatus (small scale BAM) and the same method (probit analysis) was used. ► The crystal shapes and sizes were documented with microscopy. ► Almost all samples are less sensitive than lead azide, which is commercially used. ► The organic peroxides (TATP, DADP, HMTD) are not as sensitive as often reported. - Abstract: The sensitivity to friction for a selection of primary explosives has been studied using a small BAM friction apparatus. The probit analysis was used for the construction of a sensitivity curve for each primary explosive tested. Two groups of primary explosives were chosen for measurement (a) the most commonly used industrially produced primary explosives (e.g. lead azide, tetrazene, dinol, lead styphnate) and (b) the most produced improvised primary explosives (e.g. triacetone triperoxide, hexamethylenetriperoxide diamine, mercury fulminate, acetylides of heavy metals). A knowledge of friction sensitivity is very important for determining manipulation safety for primary explosives. All the primary explosives tested were carefully characterised (synthesis procedure, shape and size of crystals). The sensitivity curves obtained represent a unique set of data, which cannot be found anywhere else in the available literature.

  19. Sensitivity to friction for primary explosives

    Energy Technology Data Exchange (ETDEWEB)

    Matyas, Robert, E-mail: robert.matyas@upce.cz [Institute of Energetic Materials, Faculty of Chemical Technology, University of Pardubice, Pardubice 532 10 (Czech Republic); Selesovsky, Jakub; Musil, Tomas [Institute of Energetic Materials, Faculty of Chemical Technology, University of Pardubice, Pardubice 532 10 (Czech Republic)

    2012-04-30

    Highlights: Black-Right-Pointing-Pointer The friction sensitivity of 14 samples of primary explosives was determined. Black-Right-Pointing-Pointer The same apparatus (small scale BAM) and the same method (probit analysis) was used. Black-Right-Pointing-Pointer The crystal shapes and sizes were documented with microscopy. Black-Right-Pointing-Pointer Almost all samples are less sensitive than lead azide, which is commercially used. Black-Right-Pointing-Pointer The organic peroxides (TATP, DADP, HMTD) are not as sensitive as often reported. - Abstract: The sensitivity to friction for a selection of primary explosives has been studied using a small BAM friction apparatus. The probit analysis was used for the construction of a sensitivity curve for each primary explosive tested. Two groups of primary explosives were chosen for measurement (a) the most commonly used industrially produced primary explosives (e.g. lead azide, tetrazene, dinol, lead styphnate) and (b) the most produced improvised primary explosives (e.g. triacetone triperoxide, hexamethylenetriperoxide diamine, mercury fulminate, acetylides of heavy metals). A knowledge of friction sensitivity is very important for determining manipulation safety for primary explosives. All the primary explosives tested were carefully characterised (synthesis procedure, shape and size of crystals). The sensitivity curves obtained represent a unique set of data, which cannot be found anywhere else in the available literature.

  20. The relationship between primary school teachers extrinsic ...

    African Journals Online (AJOL)

    The study investigated the relationship between primary school teacher's extrinsic motivation and pupils' academic performance in Cross river State, Nigeria. Ex Post Facto research design was adopted for the study. The population of the study consisted of 17,221 teachers and 68,201 Primary Six Pupils in the three ...

  1. Problem Solving Strategies among Primary School Teachers

    Science.gov (United States)

    Yew, Wun Thiam; Lian, Lim Hooi; Meng, Chew Cheng

    2017-01-01

    The purpose of this article was to examine problem solving strategies among primary school teachers. The researchers employed survey research design to examine their problem solving strategies. The participants of this study consisted of 120 primary school teachers from a public university in Peninsula Malaysia who enrolled in a 4-year Graduating…

  2. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2011-01-01

    Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients...

  3. Primary Education and Dropout in Nepal

    Science.gov (United States)

    Devkota, Shree Prasad; Bagale, Shiba

    2015-01-01

    This article tries to highlight the dropout rate of primary education of Nepal. The main essence of the article is to explore the situation of dropout of primary education. There are several programs and policies to reduce the dropout, out of the school children and so on but still there are several issues that are left behind. Educational budget…

  4. Leading Change in the Primary Science Curriculum

    Science.gov (United States)

    Waller, Nicky; Baker, Chris

    2014-01-01

    Nicky Waller and Chris Baker believe that change can be a good thing and explain how their training has helped others to adjust to the new science curriculum. In September 2013, teachers across England received the definitive version of the new primary curriculum "Leading Change in the Primary Science Curriculum." This course aimed to…

  5. Distribution of nutrients, chlorophyll and phytoplankton primary ...

    African Journals Online (AJOL)

    Distribution of nutrients, chlorophyll and phytoplankton primary production in ... Two cruises were undertaken in the vicinity of the Cape Frio upwelling cell ... and concentrations of nitrate, phosphate, silicate, oxygen and chlorophyll a. ... Estimates of the annual primary production for each of the water bodies were calculated.

  6. Primary School Leadership Today and Tomorrow

    Science.gov (United States)

    Southworth, Geoff

    2008-01-01

    The article provides a retrospective and prospective view of primary school leadership. It begins with an analytic description of primary school leadership in the recent past. The second part looks at school leadership today, identifies contemporary issues and examines role continuities and changes. The third part looks at what the future might…

  7. Method for the production of primary amines

    NARCIS (Netherlands)

    Baldenius, Kai-Uwe; Ditrich, Klaus; Breurer, Michael; Navickas, Vaidotas; Janssen, Dick; Crismaru, Ciprian; Bartsch, Sebastian

    2014-01-01

    The present invention relates to a novel enzymatically catalyzed method for the production of aliphatic primary amines, which method comprises the enzymatic oxidation of a primary aliphatic alcohol catalyzed by an alcohol dehydrogenase, amination of the resulting oxocompound catalyzed by a

  8. Primary Science Quality Mark--2016 Update

    Science.gov (United States)

    Turner, Jane

    2016-01-01

    Back in May 2011, an article in "Primary Science" described how the idea for a quality mark for primary science was developed from an initial conversation at an Association for Science Education annual conference (Turner, Marshall and Elsmore, 2011). Its intention then, as now, was to support and champion good practice and raise the…

  9. Gender Preference in Primary School Enrolment among ...

    African Journals Online (AJOL)

    2017-05-01

    May 1, 2017 ... The benefits of equal enrolment and retention in primary schools cannot be underestimated for ... Gender Preference in Primary School Enrolment among Households in Northern Region, Ghana decisions ... is a major decision maker in issues of education (Akaguri, 2011; Al-Samarrai & Peasgood,. 1998).

  10. Information communication technology policy and public primary ...

    African Journals Online (AJOL)

    The main objective of this study was to correlate Information Communication Technology with public primary schools' efficiency in Rwanda. The study employed the descriptive survey and descriptive co-relational design. One hundred and forty-four primary teachers participated in the study. The level of ICT was poor (M ...

  11. 16 CFR 316.3 - Primary purpose.

    Science.gov (United States)

    2010-01-01

    ....3 Primary purpose. (a) In applying the term “commercial electronic mail message” defined in the CAN-SPAM Act, 15 U.S.C. 7702(2), the “primary purpose” of an electronic mail message shall be deemed to be... does not intend for these criteria to treat as a “commercial electronic mail message” anything that is...

  12. Suicidal ideation in German primary care

    NARCIS (Netherlands)

    Wiborg, J.F.; Gieseler, D.; Lowe, B.

    2013-01-01

    OBJECTIVE: To examine suicidal ideation in a sample of German primary care patients. METHODS: We conducted a cross-sectional study and included 1455 primary care patients who visited 1 of 41 general practitioners (GPs) working at 19 different sites. Suicidal ideation and psychopathology were

  13. Photodynamic therapy for multiple primary lung cancer

    International Nuclear Information System (INIS)

    Konaka, C.; Okunaka, T.; Sakai, H.; Furukawa, K.; Hayata, Y.; Kato, H.

    1992-01-01

    In recent years, multiple primary lung cancers have been reported with greater frequency. As for the treatment of multiple primary lung cancer, operative excision is usually difficult for all lesions due to problems of pulmonary function. PDT is a good therapeutic modality in the treatment of multiple primary lung cancer, especially central type lung cancer, for preservation of lung function. Since 1980, 50 patients of endoscopically-evaluated early stage lung cancers have been treated with PDT at Tokyo Medical College. Within this group, 16 patients were classified as having multiple primary lung cancers. This paper evaluates the effectiveness of PDT in the treatment of these patients with multiple primary bronchogenic carcinoma. (author). 6 refs., 2 tabs

  14. Bilateral primary adrenocortical carcinoma complicated by Addisonian crisis: case report

    International Nuclear Information System (INIS)

    Foster, M.; Nolan, R.L.; Hong, H.H.

    2001-01-01

    Primary adrenal carcinoma is a rare malignancy. Primary adrenal insufficiency (i.e. Addison's disease) is a rare complication of bilateral infiltration. We report a case of primary bilateral adrenal carcinoma complicated by an episode of primary adrenal insufficiency. (author)

  15. VHA Support Service Center Primary Care Management Module (PCMM)

    Data.gov (United States)

    Department of Veterans Affairs — The Primary Care Management Module (PCMM) was developed to assist VA facilities in implementing Primary Care. PCMM supports both Primary Care and non-Primary Care...

  16. HANPP Collection: Human Appropriation of Net Primary Productivity as a Percentage of Net Primary Productivity

    Data.gov (United States)

    National Aeronautics and Space Administration — The Human Appropriation of Net Primary Productivity (HANPP) as a Percentage of Net Primary Product (NPP) portion of the HANPP Collection represents a map identifying...

  17. Integrated primary health care in Australia

    Directory of Open Access Journals (Sweden)

    Gawaine Powell Davies

    2009-10-01

    Full Text Available Introduction: To fulfil its role of coordinating health care, primary health care needs to be well integrated, internally and with other health and related services. In Australia, primary health care services are divided between public and private sectors, are responsible to different levels of government and work under a variety of funding arrangements, with no overarching policy to provide a common frame of reference for their activities. Description of policy: Over the past decade, coordination of service provision has been improved by changes to the funding of private medical and allied health services for chronic conditions, by the development in some states of voluntary networks of services and by local initiatives, although these have had little impact on coordination of planning. Integrated primary health care centres are being established nationally and in some states, but these are too recent for their impact to be assessed. Reforms being considered by the federal government include bringing primary health care under one level of government with a national primary health care policy, establishing regional organisations to coordinate health planning, trialling voluntary registration of patients with general practices and reforming funding systems. If adopted, these could greatly improve integration within primary health care. Discussion: Careful change management and realistic expectations will be needed. Also other challenges remain, in particular the need for developing a more population and community oriented primary health care.

  18. Integrated primary health care in Australia.

    Science.gov (United States)

    Davies, Gawaine Powell; Perkins, David; McDonald, Julie; Williams, Anna

    2009-10-14

    To fulfil its role of coordinating health care, primary health care needs to be well integrated, internally and with other health and related services. In Australia, primary health care services are divided between public and private sectors, are responsible to different levels of government and work under a variety of funding arrangements, with no overarching policy to provide a common frame of reference for their activities. Over the past decade, coordination of service provision has been improved by changes to the funding of private medical and allied health services for chronic conditions, by the development in some states of voluntary networks of services and by local initiatives, although these have had little impact on coordination of planning. Integrated primary health care centres are being established nationally and in some states, but these are too recent for their impact to be assessed. Reforms being considered by the federal government include bringing primary health care under one level of government with a national primary health care policy, establishing regional organisations to coordinate health planning, trialling voluntary registration of patients with general practices and reforming funding systems. If adopted, these could greatly improve integration within primary health care. Careful change management and realistic expectations will be needed. Also other challenges remain, in particular the need for developing a more population and community oriented primary health care.

  19. Interprofessional Competencies in Integrative Primary Healthcare

    Science.gov (United States)

    Brooks, Audrey J.; Maizes, Victoria; Goldblatt, Elizabeth; Klatt, Maryanna; Koithan, Mary S.; Kreitzer, Mary Jo; Lee, Jeannie K.; Lopez, Ana Marie; McClafferty, Hilary; Rhode, Robert; Sandvold, Irene; Saper, Robert; Taren, Douglas; Wells, Eden; Lebensohn, Patricia

    2015-01-01

    In October 2014, the National Center for Integrative Primary Healthcare (NCIPH) was launched as a collaboration between the University of Arizona Center for Integrative Medicine and the Academic Consortium for Integrative Health and Medicine and supported by a grant from the Health Resources and Services Administration. A primary goal of the NCIPH is to develop a core set of integrative healthcare (IH) competencies and educational programs that will span the interprofessional primary care training and practice spectra and ultimately become a required part of primary care education. This article reports on the first phase of the NCIPH effort, which focused on the development of a shared set of competencies in IH for primary care disciplines. The process of development, refinement, and adoption of 10 “meta-competencies” through a collaborative process involving a diverse interprofessional team is described. Team members represent nursing, the primary care medicine professions, pharmacy, public health, acupuncture, naturopathy, chiropractic, nutrition, and behavioral medicine. Examples of the discipline-specific sub-competencies being developed within each of the participating professions are provided, along with initial results of an assessment of potential barriers and facilitators of adoption within each discipline. The competencies presented here will form the basis of a 45-hour online curriculum produced by the NCIPH for use in primary care training programs that will be piloted in a wide range of programs in early 2016 and then revised for wider use over the following year. PMID:26421232

  20. Third sector primary care for vulnerable populations.

    Science.gov (United States)

    Crampton, P; Dowell, A; Woodward, A

    2001-12-01

    This paper aims to describe and explain the development of third sector primary care organisations in New Zealand. The third sector is the non-government, non-profit sector. International literature suggests that this sector fulfils an important role in democratic societies with market-based economies, providing services otherwise neglected by the government and private for-profit sectors. Third sector organisations provided a range of social services throughout New Zealand's colonial history. However, it was not until the 1980s that third sector organisations providing comprehensive primary medical and related services started having a significant presence in New Zealand. In 1994 a range of union health centres, tribally based Mäori health providers, and community-based primary care providers established a formal network -- Health Care Aotearoa. While not representing all third sector primary care providers in New Zealand, Health Care Aotearoa was the best-developed example of a grouping of third sector primary care organisations. Member organisations served populations that were largely non-European and lived in deprived areas, and tended to adopt population approaches to funding and provision of services. The development of Health Care Aotearoa has been consistent with international experience of third sector involvement -- there were perceived "failures" in government policies for funding primary care and private sector responses to these policies, resulting in lack of universal funding and provision of primary care and continuing patient co-payments. The principal policy implication concerns the role of the third sector in providing primary care services for vulnerable populations as a partial alternative to universal funding and provision of primary care. Such an alternative may be convenient for proponents of reduced state involvement in funding and provision of health care, but may not be desirable from the point of view of equity and social cohesion

  1. Primary lymphocytic lymphoma of lacrimal gland.

    Science.gov (United States)

    Romero-Caballero, M D; Lozano-García, I; Gómez-Molina, C; Gil-Liñán, A I; Arcas, I

    2017-02-01

    We report a case of primary small-cell lymphocytic lacrimal gland lymphoma in a male diagnosed with primary antiphospholipid syndrome. These rare lymphomas are usually presented in the clinic as disseminations secondary to chronic lymphocytic leukaemia, and the primary site is rare in the orbit. Non-Hodgkin lymphomas are a heterogeneous group of tumours. Although treatment in the IE stage is usually radiotherapy, due to its association with antiphospholipid syndrome, systemic treatment with rituximab was administered. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Aging mourning doves by outer primary wear

    Science.gov (United States)

    Wight, H.M.; Blankenship, L.H.; Tomlinson, R.E.

    1967-01-01

    Many immature mourning doves (Zenaidura macroura) cannot be aged by the conventional white-tipped primary covert method if molt has proceeded beyond the 7th primary. A new method of aging doves in this group is based on the presence (immature) or absence (adult) of a buff-colored fringe on the tips of the 9th and 10th primaries. Experienced biologists were nearly 100 percent accurate in aging wings of 100 known-age doves from eastern and midwestern states. The technique is not as reliable for doves from southwestern United States because of added feather wear, apparently from harsh vegetative and soil conditions.

  3. Renal involvement in primary antiphospholipid syndrome.

    Science.gov (United States)

    Marcantoni, Carmelita; Emmanuele, Carmela; Scolari, Francesco

    2016-08-01

    Antiphospholipid syndrome is an autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or pregnancy-related problems associated with persistently elevated levels of antiphospholipid antibodies. The kidney is a major target organ in both primary and secondary antiphospholipid syndrome. This review describes several aspects of the renal involvement in the primary form of the syndrome, in particular the histological pattern of the so-called antiphospholipid syndrome nephropathy (APSN). APSN is a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries, recanalizing thrombi in arteries and arterioles, and focal atrophy, a constellation of morphological lesions suggestive of primary antiphospholipid syndrome.

  4. Etiological evaluation of primary congenital hypothyroidism cases.

    Science.gov (United States)

    Bezen, Diğdem; Dilek, Emine; Torun, Neşe; Tütüncüler, Filiz

    2017-06-01

    Primary congenital hypothyroidism is frequently seen endocrine disorder and one of the preventable cause of mental retardation. Aim of study was to evaluate the frequency of permanent/transient hypothyrodism, and to detect underlying reason to identfy any marker which carries potential to discriminate permanent/transient form. Forty eight cases older than 3 years of age, diagnosed as primary congenital hypothyroidism and started thyroxin therapy in newborn-period, and followed up between January 2007-June 2013 were included in the study. Thyroid hormon levels were evaluated and thyroid ultrasonography was performed in cases who are at the end of their 3 years of age, after 6 weeks of thyroxine free period. Thyroid sintigraphy was performed if serum thyroid-stimulating hormone was high (≥ 5 mIU/mL) and perchlorate discharge test was performed if uptake was normal or increased on sintigraphy. Cases with thyroid-stimulating hormone levels ≥ 5 mIU/mL were defined as permanent primary congenital hypothyroidism group and as transient primary congenital hypothyroidism group with normal thyroid hormones during 6 months. The mean age was 3.8±0.7 years. Mean diagnosis age was 16.6±6.5 days and 14 cases (29.2%) were diagnosed by screening program of Ministry of Health. There were 23 cases (14F, 9M) in permanent primary congenital hypothyroidism group and 12 (52.2%) of them were dysgenesis (8 hypoplasia, 4 ectopia), and 11 (47.8%) dyshormonogenesis. In transient primary congenital hypothyroidism group, there were 25 cases (17M, 8F). The mean thyroid-stimulating hormone levels at diagnosis were similar in two groups. The mean thyroxin dose in permanent primary congenital hypothyroidism group was significantly higher than transient group at the time of thyroxin cessation (2.1±0.7, 1.5±0.5 mg/kg/d, respectively, p=0.004). Thyroxin dose ≥1.6 mcg/kg/d was 72% sensitive and 69.6% specific for predicting permenant primary congenital hypothyroidism. Transient primary

  5. Primary Mural Endocarditis Without Valvular Involvement.

    Science.gov (United States)

    Tahara, Mai; Nagai, Tomoo; Takase, Yoshiyuki; Takiguchi, Shunichi; Tanaka, Yoshiaki; Kunihara, Takashi; Arakawa, Junko; Nakaya, Kazuhiro; Hamabe, Akira; Gatate, Youdou; Kujiraoka, Takehiko; Tabata, Hirotsugu; Katsushika, Shuichi

    2017-03-01

    Primary mural endocarditis is an extremely rare infection in which nonvalvular endocardial involvement is seen without any cardiac structural abnormalities such as ventricular septal defects. The rapid and precise diagnosis of this disease remains challenging. We present 2 cases (67- and 47-year-old male patients) of pathologically confirmed primary mural endocarditis that could have been detected by initial transthoracic echocardiography in the emergency department. Transthoracic echocardiography and transesophageal echocardiography play critical roles in the early recognition and confirmation of primary mural endocarditis. © 2017 by the American Institute of Ultrasound in Medicine.

  6. Brown tumor of mandible with primary hyperparathyroidism

    International Nuclear Information System (INIS)

    Ali, S.K.; Khan, F.A.; Siddiq, A.; Hanif, M.S.

    2011-01-01

    Parathyroid hormone (PTH) is secreted and released by the parathyroid glands, the activity of which is controlled by the ionized serum calcium level. Increased PTH secretion results in hyperparathyroidism. Hyperparathyroidism is classified as primary, secondary and tertiary types. Primary hyperparathyroidism is characterized by increased parathyroid hormone secretion occurring as a result of abnormality in one or more of the parathyroid glands. Brown tumors are non-neoplastic lesions as a result of abnormal bone metabolism in cases of hyperparathyroidism, creating a local destructive phenomenon. A rare case of a young female patient with brown tumors in her mandible associated with primary hyperparathyroidism, is reported. (author)

  7. Inferior limbal conjunctival autografting in primary pterygium

    Directory of Open Access Journals (Sweden)

    Farouk M Othman

    2015-01-01

    In patients with primary pterygium, conjunctival limbal autografting from the lower bulbar conjunctiva is an effective technique with a low recurrence rate. It can be a suitable treatment for glaucomatous patients with pterygium to leave the upper bulbar conjunctiva untouched.

  8. Primary xanthoma of calcaneus bone: Case report

    Directory of Open Access Journals (Sweden)

    Ghalib Ahmed

    2014-01-01

    CONCLUSION: We present this case to raise the suspicion of this lesion that is rarely described in the literatures. This is the first case of primary xanthoma of calcaneus bone that has been reported in Qatar.

  9. Factors influencing the prevalence of primary dysmenorrhoea ...

    African Journals Online (AJOL)

    ... of primary dysmenorrhoea amongst Abia State university medical students, South ... its impact on school and social activities and the students' management strategies. ... is high, and not consistently associated with demographic risk factors.

  10. Political Broadcast Advertising and Primary Election Voting

    Science.gov (United States)

    Wanat, John

    1974-01-01

    Results of a research project which hypothisized that: Other things being equal, the heavier a candidate's usage of broadcast advertising in a primary election campaign, the greater will be his share of the votes in the election. (Author/HB)

  11. primary prevention of mental, neurological and psychosocial

    African Journals Online (AJOL)

    92-4-. 154516X. This well written book addresses the primary prevention of ... a broad, public health perspective. ... suicide include gun control, gas detoxification and responsible ... It will be most useful for policy makers, and professionals and.

  12. Primary effluent filtration for coastal discharges

    Energy Technology Data Exchange (ETDEWEB)

    Cooper-Smith, G.D. [Yorkshire Water Services, Huddersfield (United Kingdom); Rundle, H. [The Capital Controls Group, Nottingham (United Kingdom)

    1998-12-31

    The use of a Tetra Deep Bed filter demonstration unit to treat primary effluent (Primary Effluent Filtration, PEF) was investigated. PEF proved capable of achieving the UWWTD primary standard, even when the primary stage performs poorly, but is not a cost-effective alternative to chemically assisted settlement. Results demonstrated that using a 1.5 to 2.2 mm grade medium, a filtration rate of 5 m/h, three backwashes a day and dosing 40 mg/l of PAXXL60 (a polyaluminium silicte) an average effluent quality of 20 mg/l BOD and 15 mgl/l total solid could be achieved. UV disinfection produced an effluent which complied with the Bathing Water Directive imperative requirement. A high enterovirus kill was also achieved. However, considerable additional work would be required before PEF could be considered suitable for full-scale applications. (orig.)

  13. Six elements of integrated primary healthcare.

    Science.gov (United States)

    Brown, Lynsey J; Oliver-Baxter, Jodie

    2016-03-01

    Integrated care has the potential to deliver efficiencies and improvements in patient experiences and health outcomes. Efforts towards integrated care, especially at the primary and community health levels, have increasingly been under focus, both nationally and internationally. In Australia, regional integration is a priority, and integration of care is a task for meso-level organisations such as Primary Health Networks (PHNs). This paper seeks to provide a list of elements and questions for consideration by organisations working across primary healthcare settings, looking to enact and improve the delivery of integrated care. Six elements that consistently emerged during the development of a series of rapid reviews on integrated primary healthcare in Australia are presented in this paper. The elements identified are context, governance and leadership, infrastructure, financing, engagement, and communication. They offer a starting point for reflection in the planning and practices of organisations in their drive for continuous improvements in integrated care.

  14. Rotary endodontics in primary teeth - A review.

    Science.gov (United States)

    George, Sageena; Anandaraj, S; Issac, Jyoti S; John, Sheen A; Harris, Anoop

    2016-01-01

    Endodontic treatment in primary teeth can be challenging and time consuming, especially during canal preparation, which is considered one of the most important steps in root canal therapy. The conventional instrumentation technique for primary teeth remains the "gold-standard" over hand instrumentation, which makes procedures much more time consuming and adversely affects both clinicians and patients. Recently nickel-titanium (Ni-Ti) rotary files have been developed for use in pediatric endodontics. Using rotary instruments for primary tooth pulpectomies is cost effective and results in fills that are consistently uniform and predictable. This article reviews the use of nickel-titanium rotary files as root canal instrumentation in primary teeth. The pulpectomy technique is described here according to different authors and the advantages and disadvantages of using rotary files are discussed.

  15. Multiple Primary Cancers: Simultaneously Occurring Prostate ...

    African Journals Online (AJOL)

    2016-05-20

    May 20, 2016 ... occurring prostate cancer and other primary tumors-our experience and literature ..... thyroid cancers, pancreatic tumors, renal cancers, and melanoma. ... Hsing AW, Yeboah E, Biritwum R, Tettey Y, De Marzo AM,. Adjei A, et ...

  16. Attention Deficit Disorder (ADHD): Primary school teachers ...

    African Journals Online (AJOL)

    Hennie

    The participants were 200 South African primary school teachers (178 female, 22 male; mean age = 43 years) of children enrolled in ... education reforms would be the training of teachers in classroom management. ..... Assistive technology.

  17. EJSCREEN Version 1, Primary EJ Index

    Data.gov (United States)

    U.S. Environmental Protection Agency — The primary EJ index measures how much a particular place contributes to overall nationwide differences in environmental indicator values between demographic groups....

  18. Primary renal osteosarcoma: A case report

    African Journals Online (AJOL)

    C. Ahomadégbé

    Primitive renal osteosarcoma is a rare sarcoma of the kidney with only 27 cases reported in the literature. Its histogenesis .... low-grade extraskeletal osteosarcoma. Skeletal ... et al. Primary Ewing's sarcoma/primitive neuroectodermal tumor of.

  19. Primary ventral or groin hernia in pregnancy

    DEFF Research Database (Denmark)

    Oma, E; Bay-Nielsen, M; Jensen, K K

    2017-01-01

    BACKGROUND: Prevalence, management, and risk of emergency operation for primary ventral or groin hernia in pregnancy are unknown. The objective of this study was to estimate the prevalences of primary ventral or groin hernia in pregnancy and the potential risks for elective and emergency repair...... was conducted to identify patients registered with a primary ventral or groin hernia in pregnancy. Follow-up was conducted by review of medical record notes within the Capital Region of Denmark supplemented with structured telephone interviews on indication. RESULTS: In total, 20,714 pregnant women were...... included in the study cohort. Seventeen (0.08%) and 25 (0.12%) women were registered with a primary ventral and groin hernia, respectively. None underwent elective or emergency repair in pregnancy, and all had uncomplicated childbirth. In 10 women, the groin bulge disappeared spontaneously after delivery...

  20. Bisphosphonates for osteoporosis in primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Rudic, Jelena; Giljaca, Vanja; Krstic, Miodrag N

    2011-01-01

    Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis...