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Taco W Kuijpers
University of Amsterdam, Amsterdamo, North Holland, Netherlands
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Phenotypic Variation in Aicardi-Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release.
Eloy Cuadrado
Iliana Michailidou
Emma J van Bodegraven
Machiel H Jansen
Jacqueline A Sluijs
Dirk Geerts
Pierre-Olivier Couraud
Lidia De Filippis
Angelo L Vescovi
, Taco W Kuijpers,
Elly M Hol
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Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5. Mutations in those genes affect normal RNA/DNA intracellular metabolism and detection, triggering an autoimmune response with an increase in cerebral IFN-α production by astrocytes. Microangiopathy and vascular disease also contribute to the neuropathology in AGS. In this study, we report that AGS gene silencing of TREX1, SAMHD1, RNASEH2A, and ADAR1 by short hairpin RNAs in human neural stem cell-derived astrocytes, human primary astrocytes, and brain-derived endothelial cells leads to an antiviral status of these cells compared with nontarget short hairpin RNA-treated cells. We observed a distinct activation of the IFN-stimulated gene signature with a substantial increase in the release of proinflammatory cytokines (IL-6) and chemokines (CXCL10 and CCL5). A differential impact of AGS gene silencing was noted; silencing TREX1 gave rise to the most dramatic in both cell types. Our findings fit well with the observation that patients carrying mutations in TREX1 experience an earlier onset and fatal outcome. We provide in the present study, to our knowledge for the first time, insight into how astrocytic and endothelial activation of antiviral status may differentially lead to cerebral pathology, suggesting a rational link between proinflammatory mediators and disease severity in AGS. Copyright © 2015 by The American Association of Immunologists, Inc.
TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2
Mischa P. Keizer
Richard B. Pouw
Angela M. Kamp
Sanne Patiwael
Gerben Marsman
Margreet H. Hart
Sacha Zeerleder
, Taco W. Kuijpers,
Diana Wouters
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The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.This article is protected by copyright. All rights reserved
European Journal of Immunology 02/2015; 45(2). DOI:10.1002/eji.201445070
· 4.52 Impact Factor
Available from: Abbas Hawwari
DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients.
Susanne E Aydin
Sara Sebnem Kilic
Caner Aytekin
Ashish Kumar
Oscar Porras
Leena Kainulainen
Larysa Kostyuchenko
Ferah Genel
Necil Kütükcüler
Neslihan Karaca
, [......],
Beate Hagl
Benjamin Gathmann
Bernd H Belohradsky
Hans D Ochs
Talal Chatila
Ellen D Renner
Helen Su
Alexandra F Freeman
Karin Engelhardt
Michael H Albert
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Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.
Available from: Isabella Quinti
On the dark side of therapies with immunoglobulin concentrates: the adverse events.
Peter J Späth
Guido Granata
Fabiola La Marra
, Taco W Kuijpers,
Isabella Quinti
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Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.
Frontiers in Immunology 01/2015; 6:11. DOI:10.3389/fimmu.2015.00011
Available from: Dasja Pajkrt
Poorer Cognitive Performance in Perinatally HIV-Infected Children Versus Healthy Socioeconomically Matched Controls
Sophie Cohen
Jacqueline A Ter Stege
Gert J Geurtsen
Henriette J Scherpbier
, Taco W Kuijpers,
Peter Reiss
Ben Schmand
Dasja Pajkrt
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Background: Despite the declined incidence of severe neurological complications such as HIV‐encephalopathy, HIV‐infection in children is still associated with a range of cognitive problems. Studies comparing HIV‐infected children to socioeconomically (SES)‐matched controls are lacking, while most HIV‐infected children in industrialized countries are immigrants with a relatively low SES. Methods: This cross‐sectional study included perinatally HIV‐infected children and controls matched for age, gender, ethnicity and SES, who completed a neuropsychological assessment (NPA) evaluating intelligence, information processing speed, attention, memory, executive‐ and visual‐motor functioning. Multivariate normative comparison (MNC) was used to assess the prevalence of cognitive impairment in the HIV‐infected group. Multivariable regression analyses were performed to identify HIV‐ and cART‐related factors associated with cognitive performance. Results: In total, 35 perinatally HIV‐infected (median age: 13.8 years, median CD4+ T‐cells: 770*106/L, 83% with an undetectable HIV VL) and 37 healthy children (median age: 12.1 years) were included. HIV‐infected children scored lower than the healthy controls on all cognitive domains (e.g. intelligence quotient (IQ): 76 [SD 15.7] and 87.5 [SD 13.6] for HIV‐infected versus healthy children; P=0.002). Cognitive impairment was found in 6 HIV‐infected children (17%). The CDC clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC C: coefficient ‐22.98, P=0.010). Conclusion: Our results show that cognitive performance of HIV‐infected children is poor as compared to SES‐matched healthy controls. Gaining insight in these cognitive deficits is essential as subtle impairments may progress to more pronounced complications, that will influence future intellectual performance, job opportunities and community participation of HIV‐infected children.
Clinical Infectious Diseases 12/2014; DOI:10.1093/cid/ciu1144
· 9.42 Impact Factor
Available from: Hans-Hartmut Peter
Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe.
Kerr J
Quinti I
Eibl M
Chapel H
Späth PJ
Sewell WA
Salama A
van Schaik IN
, Kuijpers TW,
Peter HH
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REVIEW ARTICLE published: 12December2014 doi: 10.3389/fimmu.2014.00629 Isdosingoftherapeuticimmunoglobulinsoptimal?Areviewofathree-decadelongdebateinEurope JacquelineKerr 1, IsabellaQuinti 2, MarthaEibl 3, HelenChapel 4, PeterJ.Späth5,W.A.CarrockSewell 6, AbdulgabarSalama7, IvoN.vanSchaik 8,TacoW.Kuijpers9 and Hans-HartmutPeter 10* 1 Section Poly-andMonoclonalAntibodies,PaulEhrlichInstitut,Langen,Germany 2 Department ofMolecularMedicine,SapienzaUniversityofRome,Rome,Italy 3 ImmunologischeTagesklinik,Vienna,Austria 4 NuffieldDepartmentofMedicine,UniversityofOxford,Oxford,UK 5 InstituteofPharmacology,UniversityofBern,Bern,Switzerland 6 Hull YorkMedicalSchool,UniversityofLincoln,Lincoln,UK 7 ZentrumfürTransfusionsmedizinu.Zelltherapie,Charité,Berlin,Germany 8 Department ofNeurology,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,Netherlands 9 Department ofPediatricHematology,ImmunologyandInfectiousdisease,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,Netherlands 10 CentrumfürchronischeImmunodeficienz(CCI),UniversityMedicalCentre,UniversityofFreiburg,FreiburgimBreisgau,Germany Editedby: Albert Farrugia,UniversityofWestern Australia,Australia Reviewedby: Antonio Condino-Neto,Universityof São Paulo,Brazil Alessandro Plebani,Universityof Brescia, Italy *Correspondence: Hans-Hartmut Peter,Centrumfür chronischeImmundefizienz(CCI), Engesserstr.4,D-79108Freiburgim Breisgau, Germany e-mail: hans-hartmut.peter@ uniklinik-freiburg.de Theconsumptionofimmunoglobulins(Ig)isincreasingduetobetterrecognitionofantibodydeficiencies,anagingpopulation,andnewindications.Thisreviewaimstoexaminethevariousdosingregimensandresearchdevelopmentsintheestablishedandinsomeoftherelevantoff-labelindicationsinEurope.ThebackgroundtothecurrentregulatorysettingsinEuropeisprovidedasabackdropforthelatestdevelopmentsinprimaryandsecondaryimmunodefiienciesandinimmunomodulatoryindications.Intheseheterogeneousareas,clinicaltrialsencompassingdifferentroutesofadministration,varyingintervals,andinfusionratesarepavingthewaytowardmoreindividualizedtherapyregimens.Inprimaryantibodydeficiencies,adjustmentsindosingandintervalswilldependontheclinicalpresentation,effectiveIgGtroughlevelsandIgGmetabolism.Ideally,individualpharmacokineticpro-filesinconjunctionwiththeclinicalphenotypecouldleadtohighlytailoredtreatment.Inpractice,incrementaldosageincreasesarenecessarytotitratetheoptimaldoseformoreseverelyillpatients.Higherintravenousdosesinthesepatientsalsohavebenefi-cialimmunomodulatoryeffectsbeyondmereIgGreplacement.BetterunderstandingofthepharmacokineticsofIgtherapyisleadingtoamoveawayfromsimplistic"perkg"dosing.Defectiveantibodyproductioniscommoninmanysecondaryimmunodeficien-ciesirrespectiveofwhetherthecausativefactorwaslymphoidmalignancies(establishedindications),certainautoimmunedisorders,immunosuppressiveagents,orbiologics.Thisantibodyfailure,asshownbytestimmunization,maybeamenabletotreatmentwithreplacementIgtherapy.Incertainimmunomodulatorysettings[e.g.,idiopathicthrombo-cytopenicpurpura(ITP)],selectionofpatientsforIgtherapymaybeenhancedbyrelevantbiomarkersinordertoexcludenon-respondersandthusobtainhigherresponserates.Inthisreview,thedevelopmentsindosingoftherapeuticimmunoglobulinshavebeenlimitedtohighandsomemediumpriorityindicationssuchasITP,Kawasaki'disease,Guillain–Barrésyndrome,chronicinflammatorydemyelinatingpolyradiculoneuropathy,myastheniagravis,multifocalmotorneuropathy,fetalalloimmunethrombocytopenia,fetalhemolyticanemia,anddermatologicaldiseases. Keywords:IVIG,SCIG,replacementtherapy,immunomodulation,dosing INTRODUCTION Indicationsforintravenous(IVIG)andsubcutaneous(SCIG) immunoglobulin(Ig)therapiesaresteadilyincreasingandthe annualdemandhastripledinthelast15yearsreachingaworld- wideconsumptionof~130metrictonsin2012(1). Shortagesin supplyhaveoccurredinthepastandcostpressureonhealthsys- temsworldwideisgrowingTheincreaseddemandfortherapeutic Ighasbeenmetbyincreasingthenumberofplasmadonorsand byintroducingnewhigh-yieldfractionationprocedures,which in somecaseshavebeenaccompaniedbyincreasesinratesof hemolyticanemia. ReportsinvolvingalternativedosesgiveninbothIgreplace- mentandimmunomodulatoryindicationsarequestioningcur- rentpractice.These,togetherwithemergingbiomarkersassociated withIg-responderandnon-responderstatus,inviteclosescrutiny ofindicationsfor,andmethodsofadministering,IVIGandSCIG use inthefuture.TraditionaldosingofIghasreliedheavily ona"perkgofbodyweight"calculation,whichhasnowbeen www.frontiersin.org December 2014|Volume5|Article629| 1
Available from: Dasja Pajkrt
Country of birth does not influence long-term clinical, virological and immunological outcome of HIV-infected children living in the Netherlands
Sophie Cohen
Ward PH van Bilsen
Colette Smit
Pieter LA Fraaij
Adilia Warris
, Taco W Kuijpers,
Sibyl PM Geelen
Tom FW Wolfs
Henriette J Scherpbier
Dasja Pajkrt
on behalf of the Dutch Pediatric HIV Study Group
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BACKGROUND:: Immigrant HIV-infected adults in industrialized countries show a poorer clinical and virological outcome compared to native patients. We aimed to investigate potential differences in clinical, immunological and virological outcome in Dutch HIV-infected children born in the Netherlands (NL) versus born in Sub-Saharan Africa (SSA) in a national cohort-analysis. METHODS:: We included all HIV-infected children registered between 1996 and 2013. Descriptive statistics, mixed-effects models and Cox proportional hazard models were used to investigate differences between groups. RESULTS:: In total, 319 HIV-infected children were registered. The majority of these children were born in SSA (n=148, 47%) or NL (n=113, 36%) and most were black (n=158, 61%). Children born in NL were diagnosed at a median age of 1.2 years and initiated combination antiretroviral therapy (cART) at a median age of 2.6 years, compared to 3.7 and 5.3 years respectively for children born in SSA (HIV-diagnosis: P<0.001; cART initiation: P<0.001). Despite a lower initial CD4 T-cell Z-score in children born in SSA, their immunological reconstitution was similar to children from NL. Virological suppression was achieved in the majority of all cART-treated children (NL:96%, SSA:94%). There was no difference in the occurrence or timing of virological failure. CONCLUSIONS:: The majority of immigrant HIV-infected children living in NL were born in SSA. Children born in SSA were diagnosed and initiated cART at an older age than children born in NL. Despite initial differences in CD4 T-cell counts and HIV viral load, the long-term immunological and virological response to cART was similar in both groups.
JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2014; Nov. DOI:10.1097/QAI.0000000000000431
· 4.39 Impact Factor
Incidence of invasive group B streptococcal disease and pathogen genotype distribution in newborn babies in the Netherlands over 25 years: a nationwide surveillance study
Vincent Bekker
Merijn W Bijlsma
Diederik van de Beek
, Taco W Kuijpers,
Arie van der Ende
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Group B streptococcus is the most common cause of neonatal infections. We studied the clinical and molecular epidemiology of invasive group B streptococcus infection in children younger than 3 months in the Netherlands over 25 years. We assessed the effect of the Dutch guidelines, introduced in 1999, for prevention of group B streptococcus, consisting of intravenous antibiotic prophylaxis during labour in cases of premature labour, prolonged rupture of membranes, or fever during delivery. We did this nationwide surveillance study with data from 1987 to 2011, from the Netherlands Reference Laboratory for Bacterial Meningitis. We included data for patients aged 3 months or younger with positive blood culture or cerebrospinal fluid culture for group B streptococcus and Escherichia coli infection. Early onset was defined as less than 7 days after birth and late onset was defined as 7 or more days after birth. We did multilocus sequence typing of a random subset of group B streptococcus samples to assess changes in sequence type (Mann-Kendall trend test) and the distribution of clonal complexes (χ(2) and Fisher exact test) before the introduction of prevention guidelines (1987-99) and afterwards (2000-11). We compared incidences and the distribution of clonal complexes before and after the introduction of guidelines. Most cases of group B streptococcus had early onset (696/1075; 65%). The incidence of invasive group B streptococcus infection increased from 0·20 per 1000 livebirths in 1987, to 0·32 per 1000 livebirths in 2011 (p<0·0001). The incidence of early-onset disease increased from 0·11 per 1000 livebirths to 0·19 per 1000 livebirths (p<0·0001). The incidence of invasive Escherichia coli infection was 0·05 in 1987, and 0·16 in 2011 (p=0·17). Early-onset group B streptococcus infection caused by isolates belonging to clonal complex 17 was more common in the post-implementation period than in the pre-implementation period (p=0·002). The introduction of prevention guidelines for invasive group B streptococcus disease in 1999 did not reduce the incidence of disease in neonates. The guidelines should be reassessed and alternative approaches to prevent infant invasive group B streptococcus disease should be sought. National Institute of Public Health and the Environment, the European Union's seventh framework programme, Netherlands Organization for Health Research and Development, Academic Medical Center, and the European Research Council. Copyright © 2014 Elsevier Ltd. All rights reserved.
The Lancet Infectious Diseases 11/2014; 14(11):1083-9. DOI:10.1016/S1473-3099(14)70919-3
· 19.45 Impact Factor
Available from: Iwan Kustiawan
Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages.
Sietse Q Nagelkerke
Gillian Dekkers
Iwan Kustiawan
Fleur S van de Bovenkamp
Judy Geissler
Rosina Plomp
Manfred Wuhrer
Gestur Vidarsson
Theo Rispens
Timo K van den Berg
, Taco W Kuijpers
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In immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA), circulating IgG-opsonized blood cells are cleared from the circulation by macrophages. Administration of intravenous immunoglobulin (IVIg) can prevent uptake, but the exact working mechanism is not known. The prevailing theory from murine studies, which states that Fc-sialylated IgG alters the balance between activating and inhibitory Fc-gamma receptors (FcγRs) by inducing upregulation of the inhibitory FcγRIIb on effector macrophages, is currently debated. We studied phagocytosis of IgG-opsonized blood cells in a human system, assessing the effect of IVIg and blocking anti-FcγR F(ab')2 fragments on uptake by monocyte-derived macrophages (both M1 and M2 macrophages). Phagocytosis was remarkably sensitive to administration of IVIg but unexpectedly, recombinant Fc-sialylated IgG or sialic acid-enriched IVIg were equally active as unsialylated IgG fractions in mediating this inhibition - independent of FcγRIIb expression. Instead, IVIg inhibited phagocytosis by direct blockade of FcγRs. IgG fractions enriched for IgG-dimers with enhanced avidity for FcγRs showed increased inhibition compared to monomeric IgG fractions. Together, our data demonstrate that inhibition of IgG-mediated phagocytosis in human macrophages by IVIg is dependent on the capacity to directly bind FcγRs but independent of FcγRIIb or sialylation of the Fc fragment in the human setting.
Blood 10/2014; 124(25). DOI:10.1182/blood-2014-05-576835
· 9.78 Impact Factor
Available from: Machiel H Jansen
Fetal exposure to HIV-1 alters chemokine receptor expression by CD4+T cells and increases susceptibility to HIV-1.
Madeleine J Bunders
John L van Hamme
Machiel H Jansen
Kees Boer
Neeltje A Kootstra
, Taco W Kuijpers
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Absolute numbers of lymphocytes are decreased in uninfected infants born to HIV-1-infected women (HIV-1-exposed). Although the exact mechanism is unknown, fetal exposure to maternal HIV-1-infection could prime the immune system and affect T cell trafficking. We compared the expression of chemokine receptors on cord blood CD4(+) T cells from HIV-1-exposed children and healthy controls. At baseline CD4(+) T cells had a largely naïve phenotype. However, stimulation with cytokines resulted in an upregulation of inflammatory response-related chemokine receptors on CD4(+) T cells, with HIV-1-exposed infants having a significantly higher frequency of CD4(+) T cells expressing, in particularly Th2 associated chemokine receptors (CCR3 p < 0.01, CCR8 p = 0.03). Numbers of naive CCR7(+) CD4(+) T cells were reduced (p = 0.01) in HIV-1-exposed infants. We further assessed whether the inflammatory phenotype was associated with susceptibility to HIV-1 and detected higher levels of p24 upon in in vitro infection of stimulated CD4(+) T cells of HIV-1-exposed infants. In summary, fetal exposure to HIV-1 primes the immune system in the infant leading to an enhanced immune activation and altered T cell homing, with potential ramifications regarding T cell responses and the acquisition of HIV-1 as an infant.
Scientific Reports 10/2014; 4:6690. DOI:10.1038/srep06690
· 5.08 Impact Factor
PKCδ is dispensible for oxLDL uptake and foam cell formation by human and murine macrophages.
Katka Szilagyi
Alexander B Meijer
Annette E Neele
Paul Verkuijlen
Michael Leitges
Sandrine Dabernat
Elisabeth Förster-Waldl
Kaan Boztug
Alexandre Belot
, Taco W Kuijpers,
Georg Kraal
Menno P J de Winther
Timo K van den Berg
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Uptake of oxLDL and foam cell formation by macrophages is one of the first steps in the development of atherosclerosis. Recently, PKCδ has been implicated as a regulator of oxLDL uptake and foam cell formation via down-regulation of PKCβ and scavenger receptors CD36 and SR-A expression. Here we describe studies in which we have re-evaluated the role of PKCδ in oxLDL uptake and foam cell formation.
Cardiovascular Research 09/2014; DOI:10.1093/cvr/cvu213
· 5.81 Impact Factor
Frequency of joint involvement in juvenile idiopathic arthritis during a 5-year follow-up of newly diagnosed patients: implications for MR imaging as outcome measure
Robert Hemke
Charlotte Nusman
Désirée M F M van der Heijde
Andrea S Doria
, Taco W. Kuijpers,
Mario Maas
Marion A.J. van Rossum
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To assess the sequence and type of active joints in a cohort of newly diagnosed juvenile idiopathic arthritis (JIA) patients with full access to current treatment at first visit and during a follow-up period of 5-years, in order to identify an index joint/group of joints for magnetic resonance imaging in JIA. Patient charts of all consecutive newly diagnosed JIA patients with a follow-up duration of at least 5 years were analyzed. Patients were derived from two tertiary pediatric rheumatology centers. Patient characteristics and data concerning the presence of joints with arthritis and the use of medication were recorded. Findings from 95 JIA patients [39 (41 %) oligoarticular and 56 (59 %) polyarticular] were analyzed. At first visit, distribution of active joints among patients was as follows: knee (n = 70, 74 %), ankle (n = 55, 58 %), elbow (n = 23, 24 %), wrist (n = 23, 24 %), metacarpophalangeal (MCP) (n = 20, 21 %), proximal interphalangeal (PIP) (n = 13, 14 %), hip (n = 6, 6 %), shoulder (n = 5, 5 %), and distal interphalangeal (DIP) (n = 4, 4 %) joints. After a follow-up period of 5 years, the cumulative percentage of patients with specific joint involvement changed into: knee (n = 88, 93 %), ankle (n = 79, 83 %), elbow (n = 43, 45 %), wrist (n = 38, 40 %), MCP (n = 36, 38 %), PIP (n = 29, 31 %), shoulder (n = 20, 21 %), hip (n = 17, 19 %), and DIP (n = 9, 10 %) joints. Despite changes in treatment strategies over the years, the knee remains the most commonly involved joint at onset and during follow-up in JIA, followed by the ankle, elbow, and wrist. For the evaluation of outcome with MRI, the knee appears the most appropriate joint in JIA.
Rheumatology International 08/2014; DOI:10.1007/s00296-014-3108-x
· 1.63 Impact Factor
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Health related quality of life and parental perceptions of child vulnerability among parents of a child with juvenile idiopathic arthritis: results from a web-based survey
Lotte Haverman
Hedy A van Oers
Heleen Maurice-Stam
, Taco W Kuijpers,
Martha A Grootenhuis
Marion Aj van Rossum
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A chronic illness, such as Juvenile Idiopathic Arthritis (JIA), has an impact on the whole family, especially on parents caring for the ill child. Therefore the aim of this study is to evaluate parental Health Related Quality of Life (HRQOL) and parental perceptions of child vulnerability (PPCV) and associated variables in parents of a child with JIA.
Pediatric Rheumatology 08/2014; 12:34. DOI:10.1186/1546-0096-12-34
· 1.62 Impact Factor
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FcγRIIa cross-talk with TLRs, IL-1R, and IFNγR selectively modulates cytokine production in human myeloid cells
Lisa T. C. Vogelpoel
Ivo S. Hansen
Marijke W. Visser
Sietse Q. Nagelkerke
, Taco W. Kuijpers,
Martien L. Kapsenberg
Esther C. de Jong
Jeroen den Dunnen
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Myeloid antigen-presenting cells (APCs) tailor immune responses to the pathogen involved through the production of specific pro- and anti-inflammatory cytokines. It is becoming increasingly clear that the ultimate cytokine profile produced by myeloid APCs crucially depends on interaction between multiple pathogen recognizing receptors. In this respect, we recently identified an important role for cross-talk between Fc gamma receptor IIa (FcγRIIa) and Toll-like receptors (TLRs) in human dendritic cells (DCs), which induces anti-bacterial immunity through the selective induction of TNFα and Th17-promoting cytokines. Here, we show that FcγRIIa-TLR cross-talk is not restricted to DCs, but is a common feature of various human myeloid APC subsets including monocytes and macrophages. Interestingly, FcγRIIa-TLR cross-talk in monocytes resulted in the induction of a cytokine profile distinct from that in DCs and macrophages, indicating that FcγRIIa stimulation induces cell-type and tissue specific responses. Surprisingly, we show that the FCGR2A H131R single nucleotide polymorphism (SNP), which is known to greatly affect FcγRIIa-mediated uptake of IgG2-opsonized bacteria, did not affect FcγRIIa-dependent cytokine production, indicating that these processes are differently regulated. In addition, we demonstrate that FcγRIIa selectively synergized with TLRs, IL-1R, and IFNγR, but did not affect cytokine production induced by other receptors such as C-type lectin receptor Dectin-1. Taken together, these data demonstrate that FcγRIIa-dependent modulation of cytokine production is more widespread than previously considered, and indicate that cross-talk of FcγRIIa with various receptors and in multiple cell types contributes to the induction of pathogen and tissue-specific immunity.
Immunobiology 07/2014; 220(2). DOI:10.1016/j.imbio.2014.07.016
· 2.81 Impact Factor
Available from: Alan Nurden
Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding
Matthias Canault
Dorsaf Ghalloussi
Charlotte Grosdidier
Marie Guinier
Claire Perret
Nadjim Chelghoum
Marine Germain
Hana Raslova
Franck Peiretti
Pierre E Morange
Noemie Saut
Xavier Pillois
Alan T Nurden
François Cambien
Anne Pierres
Timo K van den Berg
, Taco W Kuijpers,
Marie-Christine Alessi
David-Alexandre Tregouet
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The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis.
Journal of Experimental Medicine 06/2014; 211(7). DOI:10.1084/jem.20130477
· 13.91 Impact Factor
Available from: Roel P Gazendam
Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects
Roel P Gazendam
John L van Hamme
Anton T J Tool
Michel van Houdt
Paul J J H Verkuijlen
Martin Herbst
Johannes G Liese
Frank L van de Veerdonk
Dirk Roos
Timo K van den Berg
, Taco W Kuijpers
[Show abstract]
[Hide abstract]
Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use two distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized Candida albicans was found to be dependent on Complement Receptor 3 (CR3), the signaling proteins phosphatidylinositol-3-kinase (PI3K) and CARD9, but was independent of NADPH oxidase activity. The second mechanism for the killing of opsonized Candida albicans was strictly dependent on Fc-gamma receptors, protein kinase C (PKC) and Reactive Oxygen Species (ROS) production by the NADPH oxidase system. Each of the two pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensible for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency or Chronic Granulomatous Disease (CGD).
Blood 06/2014; 124(4). DOI:10.1182/blood-2014-01-551473
· 9.78 Impact Factor
Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies
Eloy Cuadrado
Adeline Vanderver
Kristy J Brown
Annie Sandza
Asako Takanohashi
Machiel H Jansen
Jasper Anink
Brian Herron
Simona Orcesi
Ivana Olivieri
Gillian I Rice
Eleonora Aronica
Pierre Lebon
Yanick J Crow
Elly M Hol
, Taco W Kuijpers
[Show abstract]
[Hide abstract]
Objectives Aicardi–Goutières syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. Methods Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. Results Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGS patients bind epitopes present in the cerebral white matter. Conclusions Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype.
Annals of the Rheumatic Diseases 06/2014; DOI:10.1136/annrheumdis-2014-205396
· 9.27 Impact Factor
Conference Paper:
THU0025 Complement Deficiencies in A Cohort of Pediatric Onset Lupus: A Preliminary Study from A Tertiary Care Centre in North India
Sagar Bhattad
Amit Rawat
Surjit Singh
Anju Gupta
Deepti Suri
Ravinder Garg
Martin de Boer
, Taco W Kuijpers
EULAR 2014, Paris, France; 06/2014
Distribution Pattern of MRI Abnormalities Within the Knee and Wrist of Juvenile Idiopathic Arthritis Patients: Signature of Disease Activity
Charlotte M Nusman
Robert Hemke
Dieneke Schonenberg
Koert M Dolman
Marion A J van Rossum
J Merlijn van den Berg
, Taco W Kuijpers,
Mario Maas
[Show abstract]
[Hide abstract]
OBJECTIVE. The aim of this study in clinically active juvenile idiopathic arthritis (JIA) was to assess the frequency and distribution pattern of synovitis as hallmark of disease and additional soft-tissue and bony abnormalities on MRI in the knee and wrist as two target joints. MATERIALS AND METHODS. MRI datasets of 153 clinically active JIA patients (110 with knee and 43 with wrist involvement) were evaluated independently by two readers for the presence of literature-based imaging features: "synovial hypertrophy," "bone marrow changes," "bone erosions," "tenosynovitis" (only in the wrist), and "cartilage lesions" (only in the knee) in accordance with validated definitions and scoring locations. RESULTS. Synovial hypertrophy was most frequently observed-both in the knee and in the wrist (61.8-65.1% of cases). For the knee, the most frequently involved locations were the cruciate ligaments (46/183 locations [25.1%] affected with synovial hypertrophy) and medial patella (18/62 locations [29.0%] with bone marrow changes). Cartilage lesions and bone erosions were rare (5.5-7.3% of cases). For the wrist, most frequently involved were the radiocarpal joint (21/64 locations [32.8%] with synovial hypertrophy), lunate (7/46 locations [15.2%] with bone marrow changes), and capitate or triquetrum (6/28 locations [21.4%] with bone erosions). Tenosynovitis was a common wrist-specific feature (46.5% of cases). MRI showed no abnormalities in a subgroup of patients with clinically active knee (23.6%) and wrist (16.3%) involvement. CONCLUSION. The distribution pattern of MRI abnormalities in the knee and wrist of active JIA patients provides a practical tool to detect a signature of JIA disease activity in target joints.
American Journal of Roentgenology 05/2014; 202(5):W439-46. DOI:10.2214/AJR.13.11314
· 2.74 Impact Factor
Available from: Rachel H Giles
Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway.
Harry F Heijnen
Richard van Wijk
Tamara C Pereboom
Yvonne J Goos
Cor W Seinen
Brigitte A van Oirschot
Rowie van Dooren
Marc Gastou
Rachel H Giles
Wouter van Solinge
, Taco W Kuijpers,
Hanna T Gazda
Marc B Bierings
Lydie Da Costa
Alyson W MacInnes
[Show abstract]
[Hide abstract]
Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies.
PLoS Genetics 05/2014; 10(5):e1004371. DOI:10.1371/journal.pgen.1004371
· 8.52 Impact Factor
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Timo K van den Berg
Sanquin Blood Supply Foundation
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Dirk Roos
Sanquin Blood Supply Foundation
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Martin de Boer
Sanquin Blood Supply Foundation
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Henriëtte J Scherpbier
Academisch Medisch Centrum Universiteit van Amsterdam
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René A W van Lier
Sanquin Blood Supply Foundation
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The Journal of Immunology
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University of Amsterdam
• Faculty of Medicine AMC
• Department of Paediatrics
Amsterdamo, North Holland, Netherlands
Academic Medical Center (AMC)
Amsterdamo, North Holland, Netherlands
Academisch Medisch Centrum Universiteit van Amsterdam
• Academic Medical Center
• Department of Paediatrics
Amsterdamo, North Holland, Netherlands
University of Freiburg
Faculty of Biology
Freiburg, Baden-Württemberg, Germany
Genome Institute of Singapore
Tumasik, Singapore
Sanquin Blood Supply Foundation
Phagocyte Laboratory
Amsterdamo, North Holland, Netherlands
VU University Amsterdam
Department of Clinical Chemistry
Amsterdamo, North Holland, Netherlands
Hong Kong Red Cross Blood Transfusion Service
Hong Kong, Hong Kong
Infectious Diseases
Clinical Immunology
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Camela Hotel & Resort
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Heavenly Halong
The journey to Halong bay from Hanoi takes 3 hours with an obligatory stop at some craft shop to attempt to part tourists with their money. To be fair these warehouses are for people disabled as a result of Agent Orange, the toxic spray used by the Americans during the Vietnam war. It is predicted that the birth defects caused by the chemicals will last 3 generations so many children are born with mental or physical handicaps and these are the people who ...
Back to Hanoi
... rolls. We had lunch on the boat while we sailed back to Halong dock.
We stayed at The same hotel as before the tour for one last night, tomorrow we go to Hoi An and will hopefully get some clothes made.
(I apologise for the lack of photos, now that smart phones and tablets are the norm, its hard to find internet caf�, and I have no means of uploading from the SLR to my mob or tablet. Pics to follow) :-)
Ha Long Bay Tour day 2
... tough and we passed lots of locals who were working up the sides of the mountain, carrying huge bags of sand for making concrete paths. They laughed at us as we struggled up and nearer the top, it became a full on rock climb. Trying to hold onto any rock or bit of rope that looked steady enough, we finally made it to the top and had an amazing view. Such a sweaty and probably very dangerous journey but it was worth it. We got back to the ...
Meeting an Old Friend and Many New, Hai Phong
Hai Phong is quite a drive from Hanoi, luckily it was better then my first trip to the location in 2012. On my first trip the road was under construction and we felt beat up by the time we got there! This trip to Hai Phong wasn't without it's issues. The amount of large vehicle traffic on this thoroughfare is very heavy. Large vehicle drivers in Vietnam do not hold the same chaotic, but responsive driving attitude as many of the majority of drivers ...
Castaway #2
... night, DT shagged Zeus, some pengy pengy Dutch bird and everyone went skinny dipping at midnight. Most the birds got their titties and fanny's out which was appreciated. Also mid way through the night, there was an attempted bukake, some minging fat bird had been asking everyone to jizz on her. Bird was an absolute freak, kept touching peoples nobs and being a general freak. Obviously Suarez was ...

subset: commoncrawl


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snacker Review
Cultured Freshwater Pearl Stud Earrings Set (2pc)
These look better in real life than they did on the websight. They are very nice, and if you have multiple piercings, can wear both sets at the same time, if both colors are called for. Very nice for the price.
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I have a recipe I've come up with and would appreciate comments to see if I am going to brewing what i think I am.
please make some guesses at how this will smell taste ect.
Help is greatly appreciated. i'll reveal what I am going for after a few comments. Thanks.
5 lbs munich, 3.5 Amer2-row, 2.5 6-row, 1.0 40L crystal, 0.5 Caramunich, 0.5 Aromatic Malt
Step mash: 15min at 122, 20min at 149, 45' at 157 (or until Iodine is neg)
Hops: 10z Chinook at 60min, 0.5 Centennial at 20min, 1.0 Cent at 10 min, 1.0 Csacade dry-hpped
California ale yeast
thanks, justin
I fail to see any reason to use a step mash. You probably need something darker in the grain bill (but I have not ran the numbers.) An amber should have a initial malty-sweetness that may be lost with such a low mash temp.
I would dump the munich malt.. add some more two row.. then add more 40L and 60L crystal malt. Maybe a couple ounces of chocolate malt for color. The crystal malts are whats really gonna get you that malty sweetness your looking for in an amber.
=============My Cheap Stainless Element HousingSqare1 R2 Panel Build (110v 6gal E-BIAB)
thanks for the comments. I am definitely going for some sweet malt flavor. I also really prefer the american hops (like much of sierra nevadas stuff). Though I don't want an IPA. Just a little bitterness and a stronger aroma on the level of a craft brew plae ale/maber. Going to more crystall malt ans less munich may be the way to go.
Thanks for the replies.
Why the 6-row? I don't think it'll hurt the flavor, I'm just wondering.
By the way, amber is one of my favorite styles! Here's the wiki article on ambers: http://www.homebrewtalk.com/wiki/ind...ican_Amber_Ale
The AAA usualy uses 2-row (~65%) and crystal (~25%) for its base plus maybe up to ~10% munich. I would lower the hops to maybe 2 oz total. I like centennial in mine, it does a good job for this style of beer. Here is mine: http://www.homebrewtalk.com/f66/scoobys-red-ale-134981/
I thought this would help conversion. I have only done a couple all-grain batches but had good conversion with a decoction and a 3-step mash. I thought I might need more enzymes to reduce the mash time and steps and to eliminate harsher flavors from a longer mash.
I want a little more complex malt flavor than a typical amber. I like Manchester Brewing's Marzen, but I want some more American hops aroma and it has to be an ale. So my style description may not have been perfect. I definitiely like the idea of backing off the caramunich to get more sweetness out of a crystal 60L.
Thanks again for the comments. I don't get many shots at brewing, so i've got to make it count when I get one. Thanks - justin


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The 27th Amendment is the most recent amendment to the Constitution, and its existence today can be traced to a college student who proposed the idea in a term paper and was given a C by his professor for the idea.
Scott Bomboy's posts.
Supreme Court denies potential major guns rights case
The United States Supreme Court said on Monday morning it will not consider a case that would define rights related to concealed gun permits in New Jersey and potentially across the country.
Scalia's factual error not only one in recent Supreme Court decisions
The legal press is up in arms over a factual mistake made by Justice Antonin Scalia in a Supreme Court decision this week. But Scalia isn't alone among justices who've been corrected by academics and even a few bloggers.
It was 225 years ago today: America gets its first President
It was on this day in 1789 that George Washington placed his hand on a bible in New York and became the first President of the Unites States under our Constitution – setting another of many traditions still in use today.
The latest controversy about Under God in the Pledge of Allegiance
New lawsuits in New Jersey and Massachusetts are seeking to eliminate the words "under God" from being used by public school students taking the Pledge of Allegiance. But how did the words get added to the Pledge and what have the courts already said?
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A chilled out corner of Central, Hong Kong:
Ring Jacket Navy Suit in our Armoury Model
Farfalla Slippers in Denim
A chilled out corner of Central, Hong Kong:
Ring Jacket Navy Suit in our Armoury Model
Farfalla Slippers in Denim
Cade & Co
Cade and Co shot by Carmen Chan
Ring Jacket Double Breasted Linen Fresco
Liverano Buttondown
Drake's Brown Grenadine
Choose Nissan
Ring Jacket Double Breasted in Wool Linen
End of day hustle by Jagnelli
The many sides of Jagnelli:
Ring Jacket Brown Check Sportsjacket
Ring Jacket Chinos
Carmina String Loafers
Tweed Check Brothers
Ring Jacket hit it out of the park with this piece - They chose sumptuous colors and weight not able to be found in books nowadays, and also a nice big scale on the check. Next to the vintage piece by Liverano - you can see the reference to colorful pieces from the past
Justo Jackets from Spain now in the Armoury, Navy & Green.
Perfect for the elegant weekend out
Stand tall:
Orazio Luciano Double Breasted Suit
Ascot Chang White Shirt
Drake's Knit Tie
Crockett & Jones Tassel Loafers
Jagnelli meal #jagnelli #armoury
Jagnelli in a cream vintage Barbera DB by Ring Jacket


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I second that. and what's worse is that I sold GNW to buy this spec. I broke my rule of never buying biotech or pharma. crap.
Unfortunately, with all the "rah-rah" postings on this board last week, you probably missed my WARNING calls here.
A little different attitude than you had last week, no? You have to learn how to trust the charts.


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We never used to look forward to scrubbing, but all that changed when we found this natural exfoliating cleanser. It keeps skin looking fresh and smooth without the irritation of other sloughs. The star ingredient is rice starch, which binds with water molecules to banish dirt and dead skin.
I bought this with a gift card, based on the rave reviews and it did not disappoint! It smells great, very moisturizing and gives a great scrub at the same time (without being too abrasive). I actually leave mine on like a mask for about 10 minutes; my skin feels fresh and soft afterwards!
I did receive the Vasanti BrightenUp! scrub as a sample, which was great but I still went back to my 'Origins' (see what I did there!)


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Browse by Study
Charting The Here of There: French & American Poetry in Translation in Literary Magazines, 1850-2002, a book which chronicles the ongoing history of Franco-American literary exchanges.Author City: Los Angeles, CA USABorn in Orleans, France in 1966, Béatrice Mousli in the author of many books including Valery Larbaud (1998), and Max Jacob (2005). Mousli has collaborated with her husband, Guy Bennett, on many projects, most recently Beyond the Iconic at the L.A. Central Library. Mousli currently resides in Los Angeles, where she teaches at both USC aand Otis College of Art and Design.
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Careers and Worklife
Navigating happily through your professional life
Being the "Best Of" — you …
"Whatever you are, be a good one." Abraham Lincoln Many publications have been running their "Best Of" contests, providing reader's rankings of restaurants, services, stores etc. It is fun to read, and congratulations to the winners. Along this theme of "Best Of" I thought I would take a difference approach …. What makes a person […] [Read More]
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By connecting with someone in your field of interest, you nurture a professional relationship where you can learn a great deal. Pairing up with a seasoned professional can help the less experienced individual avoid stumbling blocks. Your mentor can open doors for you, teach you new skills and facilitate career transitions. They are someone that […] [Read More]
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Abraham Lincoln was born 202 years ago, on February 12th — his inspiration lives on … He has a right to criticize, who has a heart to help. – Abraham Lincoln Some people criticize – non-stop. They pick out problems. They always have a "better" way – or at least they think. But oftentimes, you […] [Read More]
How to be a Great Mentor
Mentoring is a buddy system that builds relationships. It facilitates the sharing of knowledge, experience and wisdom. Mentoring is a two way street and an active collaboration between committed individuals. It's a partnership dedicated to empowering each other to achieve professional growth. As a mentor, you are a catalyst for change and personal development. You […] [Read More]
There is Work-Life Balance… but what about Life-Work Balance?
When most of us think about work-life balance, it usually refers to being able to carve out enough time for your personal life and finding a way of disallowing your career to consume everything else. However, what about those times when life outside of work creeps into your work time? Maybe you have had a […] [Read More]
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Just about everyone needs a mentor at some point in their career. A mentor is a trusted seasoned professional who guides a less experienced individual in his/her development through listening, instruction, advice and encouragement. This can also include being a coach for better career decision-making. The mentor can be someone internally or outside the organization […] [Read More]
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Once a new technology rolls over you, if you're not part of the steamroller, you're part of the road." – Stewart Brand Over the past few years, with the onslaught of layoffs, plant closings and other grim economic news, many, many workers have become displaced. Now, as business conditions are steadily improving with companies hiring […] [Read More]


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Took our money....never called back....never say any results.....never returned phone calls or texts after the initial process....was a bad mistake to trust him to handle our case.....he got paid to do nothing...
I was never able to stay in contact with Mr. Smith. He wouldn't return phone calls and messages left by me or my family. I was never exactly sure where we stood with the case because he wouldn't maintain communication. He kept putting off very important matters and then having the court date postponed. I was not satisfied with his services.


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The Kids' Rooms of HGTV Dream Home
Take a telescope to these exciting kids' bedrooms, playrooms and bathrooms from HGTV Dream Homes past.
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An approximately 2,000-square-foot residence in the heart of Atlanta, Georgia


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In 1-quart saucepan bring water and salt to boiling.
Stir in uncooked brown rice.
Cover and simmer for 45 to 50 minutes or till tender.
If using frozen pea pods, rinse under hot water to separate; drain.
Heat wok over high heat; add oil.
Stir-fry carrots 2 minutes.
Add onions, green pepper, and garlic; stir-fry 2 minutes.
Add more oil, if needed.
Add mushrooms, pea pods, and cooked rice to wok; stir-fry 2 to 3 minutes more.
Stir in soy sauce.


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from £79 /night help
Estimated nightly price based on a weekly stay. Contact the advertiser to confirm the total cost.
Availability Your dates are available
House | 4 bedrooms | sleeps 8
|Key Info
This fabulous accommodation is in a great location for taking local walks through the marshes or along Bude Canal,or equally for families looking for that luxury seaside holiday house.
Just a 15 minute walk and you can be on Summerleaze Beach.Perfect for families looking for a luxury seaside house with all mod cons and in a fabulous location.You will be staying in the main part of this gorgeous house,with your own private gardens.
Faraway provides an excellent base for some fantastic walks. A gentle fifteen minute stroll along the canal path and through the River Neet nature reserve takes you into Bude. Alternatively try the circular walk- should take about an hour - takes in canal path, breakwater, sea lock, cliffs and coastal path - gorgeous. For the more adventurous, head the other way - wander up through Upton, pick up the coastal path and head east or west as far as the eye can see - rugged, spiritual, stunningly beautiful and quite magnificent.
|Sleeps up to 8, 4 bedrooms
|Car advised
|Family friendly
|Great for children of all ages, Suitable for people with restricted mobility
|No pets allowed, No smoking at this property
Features and Facilities
|DVD player
|Central heating, TV, Satellite TV, Wi-Fi available
|Kettle, Toaster, Iron, Hair dryer
|Clothes dryer, Dishwasher, Cooker, Microwave, Fridge, Freezer, Washing machine
|4 bedrooms, 3 bathrooms of which 1 En suites and 2 Shower rooms
|Double beds (2), Single beds (4), Dining seats for 8, Lounge seats for 8
|Linen provided, Towels provided, High chair
|Private garden, BBQ
|Further details indoors
The property has been refurbished to an extremely high standard with acacia wood floors thoughout a large open plan kitchen dining and living area . There is a large plasma tv, leather sofas and chairs. Patio doors opening onto a decked area for al fresco dining.
There is also a children's snug area within the large entrance hall ,with large flat screen tv and 'Wii' games console.
Please note this property has 3 shower rooms (no bath)
|Further details outdoors
The house has extremely well kept gardens,some laid to lawn and a lovely decked area with BBQ for Al Fresco dining.
There is private parking for up to 3 vehicles.
|Further details
You will be staying in the main part of this gorgeous with its own private gardens entrance.
About this location
The Cornwall region
North Cornwall is home to stunning rugged coastlines,coupled with beautiful sandy beaches.
It is in the perfect location to explore both Cornwall and Devon with The Eden Project,Exeter,Plymouth and Truro are all about an hours drive.
Bude is gorgeous. A small town dramatically perched on the edge of England. Visit once and we guarantee you'll be back. The town is incredibly popular year round and yet manages to be effortlessly charming whilst offering something for everyone.
Some of the most beautiful beaches and inspiring views in the world await you in Bude. From the tiniest coves to the widest stretches of gorgeous sands all have unrivalled scenic beauty; stunning coastal and inland paths await and are yours to enjoy.
Carnivals, fetes, jazz festivals and life saving demonstrations jostle to grab your attention. Golf, horse riding, surfing, fishing and mountain boarding are all on offer here (with loads more too) and all set against spectacular natural scenery.
About the owner
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22 Apr 2014
"Amazing house"
There was a family of 8, 4 adults and 4 children stayed at Easter 2014. What an amazing house. The rooms were beautifully decorated and very clean. The showers were lovely, beds so comfortable. The o… More
Thank you so much for your comments. We are really pleased you enjoyed your stay!
4 Nov 2013
"Brilliant 5 star property!"
We were a group of 6 adults who stayed for a week at Faraway - a beautiful immaculate home. The welcome pack with scones etc was a nice surprise and very welcome - they went down well with a cuppa as … More
Thank you so much for taking the time to review Faraway. We are so pleased you enjoyed your stay.
23 Aug 2013
"Great family house located close to Bude town"
We stayed here for a week with our family and grandchildren. The house is very modern, spacious (large open plan living area), clean and extremely comfortable bedrooms and has everything you need for … More
Thank you so much for taking the time to post a review. We are really pleased you enjoyed your stay and hope to welcome you back at some point in the future.
This advert is created and maintained by the advertiser; we can only publish adverts in good faith as we don't own, manage or inspect any of the properties. We advise you to familiarise yourself with our terms of use.
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Bridget Reps (Property Manager Breakwater Holidays)
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About Jerry Noyce
Jerry Noyce played varsity tennis at the University of Minnesota (UM) and coached the varsity men's tennis team for 15 years. As co-founder of the UM Baseline Club, Jerry was instrumental in endowing all men's tennis scholarships at UM and securing significant contributions to construct an on campus tennis facility. As a tennis professional, Jerry coached playing professionals David Wheaton and Ann Henricksson. Here he discusses what coaches look for in their recruits.
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Is a Post-Graduate Year a Good Idea for Me?
There are many reasons why prospective college tennis players, in
partnership with their parents, might consider taking an extra year
before starting college. A gap year can certainly provide extra time
to improve academic standing, physical or emotional maturity, and/or
level of play with the hope of providing more options. But what are
the implications? And what should you do with that year? Knowing the
rules and planning ahead is critical in making a sensible decision.
Tips from D-II Players and Parents
At High-Tech Tennis, we're in a unique position because we have access
to information that can help you transition from junior tennis to
college tennis. We have interacted with dozens of junior tennis
coaches who have walked the walk and are now talking the talk to help
you navigate the very exciting - but sometimes confusing - recruiting
process. Here are interesting HIGH-TECH TIPS that might help you if
you're thinking about Division II schools.
Five Vital Tips for Student Athletes in Their College Search
Each year student athletes make the transition from high school to
college. Some student athletes and their families have a good idea of
when and how to start, while others have little or no idea at all.
Regardless of the category you fall in, every athlete can make use of
these five helpful tips...
About Scholarship for Athletes
Scholarship for Athletes
is an independent consulting company that guides high school athletes
and their families through the recruiting process while assisting with
the scholarship search and negotiation process. Alongside consulting,
SFA consistently provides educational content, such as this
video series,
to high school athletes and their families.
Full Listings: Boys' Commits & Girls' Commits


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Wagan 7 Liter 12v Auto Personal Fridge/Warmer
Gifting note: This item ships in the manufacturer's original packaging. If intended as a gift, the packaging may reveal the contents.
About this item
The Wagan 7 Liter 12v Auto Personal Fridge/Warmer allows you to keep food and beverages cool&or warm them up with the flip of a switch. This product offers convenience and comfort on the road - no messy ice required! Seven liter capacity can hold 9 cans. The Wagan 7 Liter 12v Auto Personal Fridge/Warmer's cooling capacity is 40 degrees below room temperature and can heat up to 140 degrees. Simply plug it into your vehicle's cigarette lighter to use. The Wagan 7 Liter 12v Auto Personal Fridge/Warmer features two built-in cup holders, a hot/cold/off switch, and a padded armrest. A convenient shoulder strap provides easy and safe transport on the go. The Wagan 7 Liter 12v Auto Personal Fridge/Warmer is designed to fit in front console or back seat. There is an optional AC adapter available for home and office use (Wagan item EL9903). Now you can pack your own food and beverages to take with you instead of stopping for fast food during your busy day.
Wagan 7 Liter 12v Auto Personal Fridge/Warmer:
- Seven liter capacity
- Holds up to nine cans
- Cooling capacity of 40-degrees below room temperature
- Heats up to 140-degrees
- Plugs into vehicle's cigarette lighter
- Two built-in cup holders
- Padded armrest
- Convenient shoulder strap
- Fits front console or back seat
- Optional AC adapter available - Wagan item EL9903
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|Does Not Contain a Battery
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Home |
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Mothers Day Menu 2015
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Daily Menu
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Weddings, Parties, Events and Wakes
Wines Spirits Beers
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Welcome to The Waters Edge Bar and Restaurant
Open to everyone all day every day of the year
Book now for Mothers Day and Easter 2015
The Waters Edge is set on the famous river Hamble with its attractive and wide variety of wildlife interacting with the bustle of the yachting fraternity.
If you are looking for the perfect setting for that day or evening out it is definitely worth a visit to see the stunning views, enjoy a meal and drink and meet the friendly staff.
The restaurant seats 60 people comfortably and with a large bar and conservatory, plus an outside terrace and large patio area there are plenty of places to sit and enjoy the view and soak up the atmosphere.
We are open all day everyday throughout the year.
Should you require a special function, please contact us. We are able to cater for weddings, anniversaries and birthdays as well as other occasions.
Througout the year there are special events so keep coming back to our website to see what we've got laid on and what's happening.
Many thanks
James and Nick
Wedding Catalogue
Click here to download catalogue
Wedding Gallery
Introducing San Miguel
£3.80 per pint
Easter 2015 Menu
Waters Edge Bar & Restaurant, Mercury Yacht Harbour, Satchell Lane, Hamble, Southampton,
Hampshire, SO31 4HQ. Tel: 02380 457220
Itseeze Websites (Fareham, Hampshire) - www.itseeze-fareham.co.uk
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Audubon mom and daughter saved by seat belts
On July 7, Melissa Conley and her daughter Erica were traveling east on Highway 10 in Audubon, when their vehicle was struck by another car.
The mother and daughter were both spared serious injury -- despite the fact that their vehicle was a total loss. The reason? According to Trooper Andy Schmidt of the Minnesota State Patrol, it's because they were both wearing seat belts.
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The National Geospatial-Intelligence Agency's Map of the World provides an ever-expanding set of searchable databases using, among other sources, commercial and classified satellite data. (Photo: NGA)
The National Geospatial-Intelligence Agency might be the most important U.S. intelligence agency your mother's never heard of. It has little public name recognition compared to the CIA or the National Security Agency and yet, with a sprawling Springfield, Va., campus and an ample budget, NGA is remaking how the intelligence community processes data gathered in the field.
Underpinning the IC's shift to more integrated geospatial intelligence is NGA's Map of the World, a set of searchable databases available to agencies and contractors that NGA is gradually expanding. The "map" taps into a trove of commercial and classified satellite data, among many other sources. When fully implemented, it will give analysts an ever-updated view of intelligence gathered around the world.
FCW recently visited NGA headquarters for a demonstration of the Map of the World and an update on the project in which Director of National Intelligence James Clapper has taken a strong personal interest.
The man in charge of the map is John Goolgasian, a two-decade veteran of NGA who said the project is taking flight in part because of the widespread commercialization of geographic information systems. Some 85 percent of transportation-related data for the map comes from the commercial sector rather than government, he estimated.
"What we're doing is giving the [intelligence community] a consistent content set to work from spatially that has not really existed before," Goolgasian said. "Because up until then, yes we were providing information, but there was no one governing what information was going to be used in any individual application."
NGA was in the map business well before the Internet, which posed both a challenge and an opportunity to make its reams of maps easily accessible to intelligence analysts.
"For 34 years we had been creating standard products for our customer base: air information products for Air Force and other aviators, navigational charts for maritime … [and] topographic maps," Goolgasian said.
"And then when we started moving from the paper world to the digital world, we really didn't change the business process," he added. "And what we ended up with was a number of different databases based on the products that we created."
The multiple databases bred "conflicting and duplicative data over the same areas," he explained. Eight different databases contributed information on an airfield in Africa, for example. The data was accurate but didn't present a unified, discernable picture to intelligence analysts.
The shift from paper to digital did not have high-tech beginnings: Goolgasian said he and a colleague drew up the Map of the World on a piece of scrap paper.
NGA unveiled the first iteration of Map of the World in December 2013. Nine data layers were available when FCW spoke with NGA Director Letitia Long in April, with a topographic layer added shortly after, and two more to come in August to round out the first operational version of the map.
A demo showed maritime data with changing depths off the coast of Haiti. The maritime data had markings indicating a shipwreck to warn vessels of danger. An analyst more interested in aeronautical data can draw that up.
Goolgasian explained how adding variables to a search can increase the value of intelligence. "Show me North Korea, show me North Korean missiles, show me North Korean missiles active in the last three days, click on it and I see all of the intelligence information that is known on that missile facility in the last three days," he said.
Though the NGA developed the map, it needn't reside within the agency. It is meant to be portable so that once accessed by another agency or intelligence firm, it does not have to be downloaded again. "So I don't have to come to NGA's website to get this information. I can just touch a service end point and embed the information at any one of the agencies," Goolgasian explained.
The data can be published in multiple formats so users can view it with Google Earth or another interface. NGA is trying to enable this by using open standards when possible.
The bigger picture offered by the map is one of operational intelligence for some of the biggest U.S. foreign policy decisions.
"How do you make that difficult decision about a manhunt or about what is happening in Iraq today, or are the Russians going to come over the border into the Ukraine?" Goolgasian asked. "You need that foundation to immerse yourself with all of the intelligence information. … And we believe we're building a foundation to do that that the entire community can learn from."
About the Author
Sean Lyngaas is a staff writer covering defense, cybersecurity and intelligence issues. Connect with him on Twitter: @snlyngaas.
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Meet 100 women and men who are doing great things in federal IT.
Click here for the full list
Unisys Federal Systems' Venkatapathi Puvvada, this year's Eagle award winner for industry, stresses the importance of community.
Experts tell committee that business models, not technology, are the main obstacle to better sharing across systems.
Protests have delayed SEWP V, but industry experts say the contract vehicle offers agencies service and value that are hard to find.
The power of the individual informs FCW's coverage each and every day, but with the Federal 100, we take time to really spotlight and celebrate it. Get to know each of this year's winners.
The latest version of the Cybersecurity Information Sharing Act purportedly protects companies from liability and individuals from government intrusion.
Popular CIO is headed for the private sector.
The Census Bureau hasn't established a time frame for its cloud computing plans, including testing for scalability, security, and privacy protection, as well as determining a budget for cloud services.
President Obama's proposal to boost government coordination with the private sector got a warm welcome in the House Homeland Security Committee.
The spy agency wants to better integrate cybersecurity into its traditional human intelligence operations.
The significant positive impact NGA MoW offers not only supports the intelligence community, but aids warfighters, map producers, allied partners and those responding to natural or humanitarian crisis. This open service-oriented GEOINT foundation will enable anticipatory Analytics driven by the crowd, hosted in the cloud, and kept fresh via change services or your locally protected personal enhancements, if desired.
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Asian Studies MA Student, Greg Bryan, will be defending his Master's Thesis ("Examining Perspectives on China's Near-Monopoly of Rare Earths") on Tuesday, March 24, 2015 at 1:00 PM in SIPA 502.
Study Abroad Programs are offered this Summer 2015 in China. Click here to learn about the Summer A 2015 program to Zhejiang Gongshang University in Hangzhou.
World acclaimed contemporary Chinese artist Xu Bing will open his exhibition Writing Between Heaven and Earth at the Patricia & Phillip Frost Art Museum on Saturday, February 21st. The exhibition is curated by Dr. Lidu Yi, Assistant Professor at the College of Architecture + The Arts. Click here to view the article.
The FIU Chinese Club, Korean Culture Club and the Asian Studies Program present the "Asian Film Festival 2015" from February 11th to April 1st. Click on the flyer to view the list of films.
"Literature & Crisis" Conference - April 9 and 10, 2015. Crisis, war, state of emergency, catastrophe: the recurrence of these terms has become increasingly obsessive in contemporary debates on the state of the planet. Join us for a conference with the keynote speakers Dr. Mihoko Suzuki and Dr. Joshua Landy. Click here to view the flyer
Lecture by Prof. Jingping Guo, MDC Confucius Institute.
Asian Studies Program
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Planting Sweet Peas
mainerose(4)April 30, 2006
My husband just put up a beautiful white lattice fence next to our patio. I am already envisioning sweet peas growing all over it, but am not sure when to plant the seeds. Any suggestions as to planting time or sweet pea culture in general will be appreciated. Any favorite varieties?


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Is Warren Buffett Unpatriotic?
A tax inversion happens when a firm relocates its headquarters to another country and declares that country as its domicile for the foreign country's lower tax rate.
A tax inversion happens when a firm relocates its headquarters to another country and declares that country as its domicile for the foreign country's lower tax rate.
Spiritual wisdom like mindfulness coexists in unconventional ways with traditional business models resulting in positive outcomes for the organization.
An implicit challenge is to coordinate the efforts of groups with different interests to realize expected gains. This means that acquisitions quickly go from numbers to considering the impacts on people, as achieving synergy requires clear communication of the implications of an acquisition to those impacted.
Decisions involving issues of sustainability tend to include an array of objective attributes along with highly subjective value judgments. Managers must find a way to factor qualitative attributes such as environmental, social, and ethical impact into the decision-making process.
Management in a connected, interdependent, and information intensive world requires new thinking and innovative approaches. The increasing interdependence and complexity of organizations and institutions call for transorganizational thinking.
Learn from the successes and failures of two technical teams with a focus on transfer of tacit knowledge and co-location strategies.
ITIL and BSM, and the adoption of BSM concepts in an IT department and a business service unit of a regional healthcare provider.
If computers are always getting faster, but people are not, how can we maximize employee productivity when it comes time to upgrade computer systems?
This article explores why headcount reporting problems exist and will likely worsen, especially for multinational companies, unless improved workforce planning frameworks are implemented.
This article discusses the current Supply chain management directions, strategies, and tactics, and how organizations can improve their processes.


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Google releases digital wallet app for iPhones
Google is bringing its digital wallet to the iPhone in its latest attempt to upstage Apple on its own popular device.
Google is bringing its digital wallet to the iPhone in its latest attempt to upstage Apple on its own popular device.
Activist investor Carl Icahn said Thursday he would meet Apple chief executive Tim Cook in September and discuss the "magnitude" of a share repurchase plan.
Crowdfunding gets a new twist Thursday with the launch of an online platform that offers startups ideas and expertise as well as cash.
A study led by a Michigan State University scholar questions whether higher education ranking systems are creating competition simply for the sake of competition at a time when universities are struggling financially.
Why do shopping addicts keep spending even in the face of harmful financial, emotional and social consequences? A new study suggests poor credit management and a belief that new purchases will create a happier life fuel compulsive ...
Even the healthiest relationships include arguments, but the topic of the argument could predict risk of divorce, according to a Kansas State University researcher.
He's not heading out to pasture, but the CEO of "FarmVille" maker Zynga Inc. is stepping aside as the troubled online game company looks to revive itself and lift its stalled stock price.
The word "money" triggers a slew of negative connotations, often including corruption, greed, power, and, most dramatically, the "root of all evil." But while we often associate money and vice, can the mere ...
Travel ratings website TripAdvisor said Wednesday it has acquired US start-up GateGuru, a mobile app focused on flight and airport information.
Consumers are more likely to pursue goals when they are ambitious yet flexible, according to a new study in the Journal of Consumer Research.
Men with a partner and children at home work longer hours than other men in full-time work, but the number of hours they work has been in decline over the last 10 years, according to new research published ...
(Phys.org) —A study suggests that money will continue to be wasted on research into social and psychological interventions unless the methods used by the researchers are fully reported in academic journals.
The United States is studying the potential risk from online payment mechanisms like PayPal and Bitcoin, a top US Federal Reserve official told an international conference on Monday.
Like some humans, chimpanzees and bonobos exhibit emotional responses to outcomes of their decisions by pouting or throwing angry tantrums when a risk-taking strategy fails to pay off, according to research ...
The United States on Tuesday unveiled what it said was the world's "largest" money laundering probe against the digital currency operator Liberty Reserve.


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seeding onions
Can someone give me an idea how thick to sow onion seed in flats to be transplanted in 8-10 weeks? The containers will be 5"x5". Thanks
Here's a guy who's in business who does 200 seeds in what looks like a 5 inch pot. He's transplanting them to plugs before putting them out.
Here is a link that might be useful: Dense planting seeds
I agree that they can be sown very thickly and then separated after germination. I used to do it that way but have gotten lazy in my old age.:)
Now I sow in 1" squares - just use a stick to cut a 1" grid on top the soil and plant a couple of seeds in each square. The roots will form a thin mat of roots that is then easily cut into 1" squares for transplanting.
If transplanting them for green salad onions you plant them in large matted chunks.