Differential Induction of Functional IgG Using the Plasmodium falciparum Placental Malaria Vaccine Candidate VAR2CSA

BACKGROUND: In Plasmodium falciparum malaria endemic areas placental malaria (PM) is an important complication of malaria. The recurrence of malaria in primigravidae women irrespective of acquired protection during childhood is caused by the interaction between the parasite-expressed VAR2CSA antigen and chondroitin sulfate A (CSA) in the placental intervillous space and lack of protective antibodies. PM impairs fetal development mainly by excessive inflammation processes. After infections during pregnancy women acquire immunity to PM conferred by antibodies against VAR2CSA. Ideally, a vaccine against PM will induce antibody-mediated immune responses that block the adhesion of infected erythrocytes (IE) in the placenta. PRINCIPAL FINDINGS: We have previously shown that antibodies raised in rat against individual domains of VAR2CSA can block IE binding to CSA. In this study we have immunized mice, rats and rabbits with each individual domain and the full-length protein corresponding to the FCR3 VAR2CSA variant. We found there is an inherently higher immunogenicity of C-terminal domains compared to N-terminally located domains. This was irrespective of whether antibodies were induced against single domains or the full-length protein. Species-specific antibody responses were also found, these were mainly directed against single domains and not the full-length VAR2CSA protein. CONCLUSIONS/SIGNIFICANCE: Binding inhibitory antibodies appeared to be against conformational B-cell epitopes. Non-binding inhibitory antibodies reacted highly against the C-terminal end of the VAR2CSA molecule especially the highly polymorphic DBL6ε domain. Differential species-specific induction of antibody responses may allow for more direct analysis of functional versus non-functional B-cell epitopes

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

The effect of the mental health first-aid training course offered employees in Denmark:study protocol for a randomized waitlist-controlled superiority trial mixed with a qualitative study

BACKGROUND: Studies show a high and growing prevalence of mental disorders in the population worldwide. 25% of the general population in Europe will during their lifetime experience symptoms related to a mental disorder. The Mental Health First Aid concept (MHFA) was founded in 2000 in Australia by Kitchener and Jorm, in order to provide the population with mental health first aid skills. The aim of the concept is, through an educational intervention (course), to increase confidence in how to help people suffering from mental health problems. Further, secondary aims are to increase the mental health literacy of the public by increasing knowledge, reduce stigma and initiate more supportive actions leading towards professional care. An investigation of the effect of MHFA offered a Danish population is needed. METHODS: The design is a randomized waitlist-controlled superiority trial, in which 500 participants will be allocated to either the intervention group or the control group. The control group will attend the course six months later, hence waiting list design. From fall 2013 to spring 2014 participants will be educated to be “mental health first-aiders” following a manualized, two days MHFA course. All the participants will answer a questionnaire at base-line and at 6 months follow-up. The questionnaire is a back-translation of the questionnaire used in Australian trials. The trial will be complemented by a qualitative study, in which focus groups will be carried out. DISCUSSION: Outcomes measured are sensitive to interpretation, hence a challenge to uniform. This trial will add to the use of a mixed-methods design and exemplify how it can strengthen the analysis and take up the challenge of a sensitive outcome. TRIAL REGISTRATION: https://clinicaltrials.gov identifier NCT02334020

Traneksamsyre ved lokalbehandling av fremre epistaxis - en skånsom og mindre invasiv behandling ved neseblødning

Epistaxis er en vanlig medisinsk tilstand, som rammer nær 10 % av befolkningen minst en gang i livet. Da tilstanden også er hyppig forekommende hos barn og unge, er det svært viktig å gi god og skånsom behandling. I den forbindelse undersøker vi her muligheten for om den utbredte bruken av nesetamponade kan erstattes med en effektiv og mer skånsom behandling, ved bruk av topikal traneksamsyre (TXA). Vi har i vår oppgave valgt å se på to enkeltstudier som studerer behandling av fremre epistaxis med topikal TXA. Begge studier har vise gode resultater når det gjelder blødningsstans og reduksjon av reblødning første 7 dager. På bakgrunn av disse studiene anbefaler UpToDate TXA som et supplement til dagens behandling med nesetamponade. Da det generelle kunnskapsgrunnlaget om effekt av topikal behandling med TXA per i dag er utilstrekkelig, er det behov for videre randomiserte, kontrollerte studier for å nå en endelig konklusjon. All forskning som foreligger på behandling med topikal TXA tilsier at behandlingen er trygg, og det er ikke vist økt forekomst av komplikasjoner eller systemiske bivirkninger. Vi har i vår oppgave valgt Allmennlegevakten i Oslo som vårt mikrosystem. Ifølge Metodeboken for Legevakten i Oslo skal pasient først over telefon anbefales tiltak hjemme som kompresjon over nesebor, kjølig element over neseryggen og sette bomullsdott med olje inn i neseboret. Ved fortsatt blødning skal pasienten komme til legevakten for behandling. Der gjøres det kompresjon av neseboret og innsetting av nesetamponade. Ved manglende effekt skal pasienten henvises videre til ØNH-avdeling for videre behandling. Bruk av topikal TXA er ikke nevnt i nåværende retningslinjer. I dette kvalitetsforbedringsprosjektet ønsker vi å implementere TXA som topikal behandling av fremre epistaxis. Kvalitetsindikatorer valgt for prosjektet er andel konsultasjoner hvor behandling med topikal TXA gjennomføres. Videre vil vi kartlegge blødningsstans etter 10 minutter, andel henvisninger til ØNH-avdeling og behandling med nesetamponade som indikasjon på behandlingssvikt. I tillegg vil vi måle om det er forskjell i pasienttilfredshet hos pasienter som behandles med TXA sammenlignet med nesetamponade. Tiltakene som skal gjennomføres er (I) å oppdatere Metodeboken for Legevakten i Oslo, (II) informere ansatte via epost, samt under morgenmøter og fagdager (III) lage utstyrspakke for epistaxisbehandling og (IV) gjøre ny behandlingsalgoritme tilgjengelig på behandlingsrom. Vi anbefaler lokalbehandling med TXA til bruk ved fremre epistaxis før man igangsetter behandling med nesetamponade. Vår anbefaling begrenser seg til pasienter uten økt risiko for tromoemboliske episoder grunnet begrensninger i populasjonene studert i dagens forskning. Det er videre ønskelig med ytterligere forskning på området