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Δευτέρα, 2 Ιανουαρίου 2017

Psykogene ikke-epileptiske anfall hos barn

Psykogene ikke-epileptiske anfall er anfall av epilepsilignende karakter som ikke har et hjerneorganisk korrelat. Som navnet indikerer, antar man at psykologiske prosesser spiller en rolle. Vårt inntrykk ved Spesialsykehuset for epilepsi er at forekomsten av slike anfall blant barn og unge har økt de siste årene.

Psykogene ikke-epileptiske anfall, i internasjonal litteratur gjerne forkortet PNES (psychogenic non-epileptic seizures), er som den viktigste differensialdiagnosen til epilepsi godt kjent i voksennevrologien og er tidligere omtalt i Tidsskriftet (1, 2). Vårt inntrykk er at slike anfall er mindre kjent blant pediatere, skoleleger og fastleger.

Man antar at psykogene ikke-epileptiske anfall hovedsakelig er et symptom på en konversjonslidelse (3, 4). I diagnoseklassifikasjonssystemene DSM-5 og ICD-10 blir tilstanden kategorisert som henholdsvis en konversjons- og dissosiasjonstilstand. I motsetning til i ICD-10 kreves det ikke at man har holdepunkter for en psykisk årsak for å sette diagnosen i det nylig reviderte amerikanske DSM-5. Klinisk kan det, særlig i den første utredningsfasen, være vanskelig å oppdage bakenforliggende psykiske belastninger.

Anfallene ses noe sjeldnere hos barn enn hos voksne (5). De er imidlertid en stor belastning ikke bare for den det gjelder, men også for familie, skole og samfunn. Barna er ofte gjenstand for gjentatte akuttinnleggelser og mange unødvendige undersøkelser. Mange får dessuten etter hvert et stort forbruk av lite virksomme legemidler (4).

Psykogene ikke-epileptiske anfall hos barn skiller seg fra slike anfall hos voksne på flere måter, blant annet er de bakenforliggende årsakene (3, 6 – 8), anfallsutformingen (9, 10) og prognosen noe forskjellig (11).

Hensikten med denne artikkelen er å gi en kort oversikt over forekomst, risikofaktorer, ytringsformer, diagnostikk og behandling av slike anfall hos barn. Artikkelen er basert på søk i PubMed med søkeordet «psychogenic non-epileptic seizures» og forfatternes kliniske erfaring.

Forekomst

Den eksakte prevalensen av psykogene ikke-epileptiske anfall blant barn er ikke kjent (5). Første anfall opptrer som oftest i 8 – 15-årsalderen (10, 12, 13), men diagnostiseringen er gjerne forsinket (10, 14). Tilstanden er sett hos barn helt ned til 4 – 5-årsalderen.

Hos barn hvor man mistenker epilepsi, er prevalensen av psykogene ikke-epileptiske anfall funnet å være 5 – 13 % (5, 15). I materialer bestående av barn henvist til video-EEG for en diagnostisk utredning av forskjellige typer anfall, har man funnet tilstanden hos 3,5 – 20 % (12, 16, 17). Blant barn henvist til pediatriske epilepsisentra for intraktabel epilepsi er det funnet en forekomst av barn med slike anfall på 10 – 23 % (8, 18).

Blant ungdom og voksne med tilstanden er 70 – 80 % kvinner (4, 19, 20). Kjønnsforskjellen er ikke så uttalt blant barn (18).

Som hos voksne er det ikke helt uvanlig at psykogene ikke-epileptiske anfall koeksisterer med epilepsi (18). Men hvor ofte en blanding av begge anfallsformer forekommer, er usikkert og angis svært forskjellig (21).

Risikofaktorer

Psykogene ikke-epileptiske anfall ses på som et symptom på underliggende kroniske konflikter eller stressorer (22). Oppvekst i en dysfunksjonell familie, faglige vansker på skolen, mobbing eller andre problemer i kameratflokken er hyppig assosiert med tilstanden hos barn (4, 22). Fysisk eller seksuelt misbruk er ikke like vanlig blant barn med slike anfall som hos voksne (23), selv om en studie viste at 21 % og 6 % hadde opplevd henholdsvis seksuelt eller fysisk misbruk (3).

I en kontrollert studie ble 55 barn med psykogene ikke-epileptiske anfall sammenlignet med sine søsken (4). Gjennomsnittsalderen var 14,3 år, og 71 % var jenter. Man fant at alle barna hadde en konversjonslidelse. Sammenlignet med kontrollgruppene hadde de en signifikant økt nevrologisk (inkludert epilepsi), medisinsk og psykiatrisk morbiditet, økt medisinbruk, hyppigere intensivbehandling, en innadvendt mestringsstrategi, flere skolevansker, mer skolefravær, de var mer utsatt for mobbing, og de hadde større interpersonlige problemer (4).

I en spørreundersøkelse blant danske barnenevrologer var det en alminnelig oppfatning at slike anfall var assosiert med stress, fysiske og/eller psykiske traumer og seksuelt misbruk (24).

Personlighetstester har vist at mange barn med slike anfall har et høyt spenningsnivå med mye angst, depresjon og mistilpassede personlighetstrekk (24). Opptil en tredel av barna har en forsinket psykomotorisk utvikling (21).

Anfallsutforming

Det er funnet interessante forskjeller i anfallssemiologien, dvs. hvordan anfallene ytrer seg klinisk, mellom barn og voksne (8 – 10, 12, 19, 24). Anfallene hos barna er gjerne «fredeligere» og mer stereotype enn hos voksne. Hos voksne ses ofte lukkede øyne, voldsomme bevegelser, vokalisering og opistotonus. Anfallene hos barn er ofte av dialektisk art, dvs. at de ytrer seg ved langvarig kontaktløshet. Er det motoriske symptomer, dreier det seg oftest om tremor eller grove, asynkrone bevegelser av ekstremitetene samt et fluktuerende forløp (22). Når barna kommer i puberteten, blir anfallsutformingen mer lik den som man ser hos voksne. Anfallene starter og slutter gjerne abrupt (21).

Som hos voksne varer anfallene lenger enn de epileptiske anfallene. En pediatrisk studie viste en gjennomsnittlig varighet av psykogene ikke-epileptiske anfall på 269 sekunder mot 83 sekunder for epileptiske anfall (12).

Ifølge danske barnenevrologer er typiske trekk hos barn med slike anfall lukkede øyne, motstand mot å åpne øynene, sjelden anfallsrelaterte skader, anfallene kommer som oftest i sosiale settinger, fravær av postiktale symptomer og manglende effekt av antiepileptiske legemidler (24).

I tabell 1 kan man se noen forskjeller mellom psykogene ikke-epileptiske anfall hos barn, psykogene ikke-epileptiske anfall hos voksne og epileptiske anfall.

Tabell 1  Noen forskjeller mellom psykogene ikke-epileptiske anfall hos barn og hos voksne og genuine epileptiske anfall. Tabellen er dels basert på egne erfaringer og dels på sentrale artikler fra området, bl.a. Alessi og medarbeidere (9)

 

Psykogene ikke-epileptiske anfall hos barn

Psykogene ikke-epileptiske anfall hos voksne

Genuine epileptiske anfall

Anfallsutforming

Ofte «stille» anfall, manglende kontakt

Ofte dramatiske anfall med motorisk uro, asynkrone rykninger, eventuelt opistotonus

Mange typer anfall – fra absenser til tonisk-kloniske anfall

Varierende intensitet av anfallet underveis

Vanlig

Vanlig

Sjelden

Hodebevegelser fra side til side

Vanlig

Vanlig

Sjelden

Motstand mot passive bevegelser, inkludert øyelokk

Vanlig

Vanlig

Sjelden

Lukkede øyne under anfallet

Vanlig

Vanlig

Sjelden

Gråt under anfallet

Forekommer

Forekommer

Sjelden

Rask oppvåkning etter anfallet

Vanlig

Vanlig

Sjelden

Nattlige anfall

Svært sjelden

Svært sjelden

Forekommer, avhengig av epilepsiformen

Anfallsvarighet

Som oftest mer enn to minutter

Som oftest mer enn to minutter

Som oftest mindre enn to minutter

Effekt av antiepileptika

Ingen

Ingen

Som oftest god

Iktale EEG-funn

Ingen epileptiform aktivitet

Ingen epileptiform aktivitet

Som regel epileptiform aktivitet

Anfallsprognose

Som regel god

Varierende, men dårligere enn hos barn

Avhengig av epilepsiform

Diagnostikk

Alle barn med hyppige epilepsilignende anfall til tross for behandling, anfall som for epilepsi er atypiske når det gjelder ytringsform og varighet, samt flere normale EEG, bør vekke mistanke om psykogene ikke-epileptiske anfall (21).

Det finnes ingen internasjonale retningslinjer for diagnostikk og behandling av slike anfall hos barn (24). Mange av barna får epilepsidiagnose og årelang behandling med antiepileptika. I en studie fra India var det tilfelle hos 33 av 56 barn med slike anfall (10). De som først får epilepsidiagnose, har gjerne lært at anfallene resulterer i økt oppmerksomhet, noe som kan vedlikeholde anfallstendensen.

En spørreundersøkelse blant danske barnenevrologer viste ingen enighet verken når det gjaldt terminologi eller kodebruk. Kun 49 % av barnenevrologene anga at de brukte video-EEG i diagnostikken (25).

Etter vårt skjønn bør diagnostikken av slike anfall hovedsakelig bygge på en grundig sykehistorie, inkludert komparentopplysninger, med nøyaktig kartlegging av omstendighetene rundt anfallsopptredenen, selve anfallsutformingen og registrering av typiske anfall på video-EEG. Det bør være holdepunkter for at pasienten har emosjonelle belastninger som kan forklare utviklingen av anfallene, selv om dette altså ikke er obligatorisk ifølge DSM-5.

Spesialsykehuset for epilepsi har landsfunksjon for diagnostisering og initial oppfølging av barn og voksne med psykogene ikke-epileptiske anfall. Alle pasienter med epilepsilignende anfall av uklar natur kan henvises til et kartleggingsopphold ved sykehuset.

I det første oppholdet inngår en grundig anamnese med særlig oppmerksomhet rettet mot barnets psykososiale miljø, omstendighetene rundt anfallene og selve anfallsutformingen. I tillegg foretas langtids video-EEG med målsetting om å registrere anfallene. Dersom anfallene ikke har EEG-korrelat, og sykehistorie og anfallssemiologi gir mistanke om psykogene ikke-epileptiske anfall, er vi rimelig sikre på anfallenes natur.

Det er imidlertid viktig å understreke at man ikke kan bygge diagnosen på manglende iktalt EEG-korrelat alene. Det finnes nemlig flere typer epileptiske anfall, særlig utgående fra frontallappen, der man ikke finner slikt korrelat (26).

Behandling

Generelt bør behandlingen være rettet mot det man i hvert tilfelle antar ligger til grunn for anfallene. Både hos voksne og barn har psykoedukasjon, stressreduserende tiltak samt læring av avspenningsteknikker og fysioterapi vist seg effektivt (27). Mange har nytte av å lære bedre og mer adekvate mestringsstrategier. I noen tilfeller kan familieterapi, kognitiv terapi og støttebehandling være indisert (27).

Dersom barnet bruker antiepileptiske legemidler bør disse trappes gradvis ned til full seponering. I tilfeller der det foreligger en blanding av epileptiske og psykogene ikke-epileptiske anfall kan det være aktuelt å forenkle medikasjonen fordi mange av disse etter hvert får en omfattende multifarmasi.

Under det andre oppholdet ved Spesialsykehuset for epilepsi bearbeides barnets og pårørendes reaksjon på diagnosen av et spesialtrenet team. Det blir foretatt en tverrfaglig kartlegging av barnets psykisk helse, trivsel i hjem og skole og skoleprestasjoner. Den psykiske helsen kartlegges ved hjelp av spørreskjemaer, og de kognitive evnene måles av spesialpedagog i samarbeid med nevropsykolog. Mot slutten av oppholdet arrangeres det en videokonferanse med barnets lokale hjelpeapparat med tanke på informasjonsoverføring og råd om videre behandling samt takling av eventuelle fremtidige anfall. Avdekker man symptomer på psykisk sykdom, henvises pasienten til lokal barne- og ungdomspsykiatrisk poliklinikk.

Dersom det har vært mye dramatikk på barnets skole i forbindelse med anfallene og mange akuttinnleggelser på sykehus, besøker deler av teamet skolen for å trygge lærere og eventuelt medelever. Dersom barnet har et høyt stressnivå på grunn av faglig tilkortkomming, kan det være aktuelt med spesielt tilrettelagt undervisning.

Barn og unge med slike anfall føler seg ofte stigmatisert og mistrodd (28). Noen opplever dette så vanskelig at de trekker seg tilbake sosialt, eller de blir overbeskyttet av foreldrene. Dersom ungdommene selv har en god sykdomsforståelse, er det lettere å håndtere reaksjonene fra omgivelsene. Det er derfor viktig å bruke god tid på formidling av diagnosen. Dette bør gjøres på en empatisk og ikke-konfronterende måte. Diskusjoner om de mulige underliggende mekanismene ved slike anfall er helt essensielt for barnas mestring (28). Vi benytter en biopsykososial forklaringsmodell som bygger på en forståelse av at både psykososiale og biologiske forhold kan være predisponerende, utløsende og vedlikeholdende faktorer. En slik forklaring kan gjøre det enklere for barna selv å forstå hvorfor de har utviklet anfall og å identifisere seg med diagnosen (29).

For noen barn og pårørende oppleves det som en lettelse å høre at anfallene ikke er ledd i en hjerneorganisk sykdom som krever årelang medisinering, og at anfallene opptrer ubevisst, dvs. at de ikke er viljestyrte.

De sammensatte problemene som ofte ligger bak slike anfall, fordrer en multidisiplinær tilnærming (13). Vi søker å oppnå en terapeutisk allianse og en felles forståelse med pasient og pårørende om hva som forårsaker og vedlikeholder anfallene.

I noen særlig terapiresistente tilfeller kan det være behov for langvarig behandling. Slik behandling må foregå lokalt.

Prognose

Sammenlignet med voksne med psykogene ikke-epileptiske anfall er utsiktene til anfallsfrihet bedre blant barn og unge med slike anfall, kanskje fordi det hos disse er lettere å identifisere en ytre årsak (6). Rundt 70 – 80 % av barna blir kvitt anfallene (11, 13).



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Validation of the LittlEARS Auditory Questionnaire in cochlear implanted infants and toddlers

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Publication date: February 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 93
Author(s): Anita Obrycka, Artur Lorens, José-Luis Padilla García, Anna Piotrowska, Henryk Skarzynski
ObjectivesThe LittlEARS Auditory Questionnaire (LEAQ) has so far been validated to assess auditory development in groups of normal-hearing children in over 20 different languages. Considering the huge variability in auditory development of CI children, especially since candidacy criteria have been relaxed, additional evidence to validate the use of LEAQ scores in this particular population is needed. The aim of this study is to provide evidence for the reliability and validity of LEAQ scores for assessing the auditory development of CI infants and toddlers based on an evaluation of LEAQ's internal structure and its relation to other variables.MethodsThe study was prospective, with sequential enrolment and within-subject repeated measures. It included 122 children with profound bilateral sensorineural hearing loss implanted at 6–22 months of age. All children were evaluated with the Polish version of LEAQ on the first day of CI activation and at each of four follow-up visits related to sound processor fitting.The study was undertaken in the light of current psychometric thinking about how assessment instruments should be validated. The main aim of the study was to obtain evidence for the validity of interpreting LEAQ measures from CI children in terms of auditory development. First, in order to collect evidence for score reliability and validity based on LEAQ's internal structure, the psychometric properties of LEAQ scores from CI children were determined. A second step was to confirm validity by investigating the effect of concomitant variables on LEAQ scores. Correlations between LEAQ score and duration of hearing aid (HA) use, and between LEAQ score and duration of CI use, were investigated. Additionally, group differences in LEAQ scores between: 1) early and late implanted children; 2) children with long and short HA experience prior to implantation; and 3) children who showed responses over a wide frequency range from using their HAs (prior to implantation) vs those who did not.ResultsOn each of the five administrations of LEAQ, the item difficulty indices increased (meaning the items became easier) and over the series they progressively increased with a range of: 0.01–0.62, 0.03–0.92, 0.09–1.00, 0.26–1.00, and 0.52–1.00. At the same time, item–total correlations were in the ranges: 0.09–0.77, 0.26–0.62, 0.00–0.65, 0.00–0.65, and 0.00–0.67. Cronbach's alpha values were above 0.80 for all administrations. A positive correlation between LEAQ score and duration of HA use, and subsequent duration of CI use (hearing experience) was found. When the children were stratified into groups according to age at cochlear implantation, duration of HA use before implantation, and audibility provided by HAs prior to implantation, the differences between the groups were reflected in both their rate of auditory development and their LEAQ score.ConclusionThe interpretation of LEAQ scores from CI children in terms of auditory development was supported by the validity evidence of internal structure and from a logical relationship to other variables. (1) Psychometric properties – item difficulty, item–total correlations, and Cronbach's alpha values – indicate that LEAQ measures are highly consistent and reliably gauge the level of a CI child's auditory development. (2) There was a positive correlation between LEAQ scores and the duration of hearing experience with HAs and a later CI; similarly, there were significant differences between groups of children stratified according to the age at cochlear implantation, duration of HA use before implantation, and audibility provided by HAs prior to implantation, all of which demonstrate the expected relation between LEAQ score and concomitant variables.



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Chondrodysplasia punctata presenting with tracheal obstruction

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Publication date: February 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 93
Author(s): Claudia Schweiger, Michel N. Nassar, Debora Goebel, Michael J. Rutter
Chondrodysplasia punctata is a group of congenital bone and cartilage disorders characterized by erratic calcification during development. Laryngeal and tracheal calcification and subsequent stenosis, while being reported in several cases of chondrodysplasia punctata, are not frequent findings and there are no proposed management techniques. We describe here a case of an infant with chondrodysplasia punctata associated to tracheal stenosis that was successfully treated with balloon dilation, and with long term follow-up.



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Diagnostic Value of Serum Baseline Tryptase Levels in Childhood Asthma and Its Correlation with Disease Severity

Background: The aim of this study was to explore whether serum baseline tryptase (sBT) levels might be a useful marker not only for the accurate diagnosis of childhood asthma, but also for the prediction of disease severity. Methods: A total of 114 asthmatic children were enrolled in this study, 36 of whom had mild intermittent asthma, 38 had mild persistent asthma, and 40 had moderate to severe persistent asthma. Additionally, 34 age-matched healthy children were enrolled as controls. The sBT levels of these populations were measured using a fluoroenzymeimmunoassay kit. The diagnostic performance of sBT levels and their correlation with asthma severity were systematically investigated using receiver operating characteristic (ROC) analysis and correlation analysis. Results: Children with mild and moderate to severe persistent asthma had significantly increased sBT levels as compared to those with mild intermittent asthma and healthy controls. ROC analysis further demonstrated that sBT levels not only appear to be highly sensitive and specific for distinguishing asthmatic children from healthy controls, but also show good accuracy for the differentiation of various asthmatic subgroups. Correlation analysis revealed that in all asthmatic subgroups sBT levels were significantly correlated with a variety of key markers that reflect the disease severity of asthma, including childhood asthma control test scores, serum IgE and interleukin-13 levels, blood eosinophil counts, and pulmonary test parameters. Conclusions: sBT levels may have a potential use in supporting a diagnosis of asthma in children and as a predictor of disease severity.
Int Arch Allergy Immunol 2016;171:194-202

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Association of Polysensitization, Allergic Multimorbidity, and Allergy Severity: A Cross-Sectional Study of School Children

Background: Aeroallergen sensitization is related to the coexistence of allergic diseases, but the nature of this relationship is poorly understood. The aim of this study was to clarify the relationship of polysensitization with allergic multimorbidities and the severity of allergic diseases. Methods: This study is a cross-sectional analysis of 3,368 Korean children aged 6-7 years-old. We defined IgE-mediated allergic diseases based on structured questionnaires, and classified the sensitivity to 18 aeroallergens by logistic regression and the Ward hierarchical clustering method. The relationship of polysensitization (positive IgE responses against 2 or more aeroallergens classes) with allergic multimorbidities (coexistence of 2 or more of the following allergic diseases: asthma, rhinitis, eczema, and conjunctivitis) and severity of allergic diseases was determined by ordinal logistic regression analysis. Results: The rate of polysensitization was 13.6% (n = 458, 95% CI 12.4-14.8) and that of allergic multimorbidity was 23.5% (n = 790, 95% CI 22.0-24.9). Children sensitized to more aeroallergens tended to have more allergic diseases (rho = 0.248, p p Conclusion: Polysensitization was weakly related to multimorbidity. However, the number of allergens to which a child is sensitized is related to the severity of IgE-mediated symptoms.
Int Arch Allergy Immunol 2016;171:251-260

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Association of Toll-Like Receptor 3 Single-Nucleotide Polymorphisms and Hepatitis C Virus Infection

Toll-like receptor 3 (TLR3) plays a key role in innate immunity by recognizing pathogenic, double-stranded RNAs. Thus, activation of TLR3 is a major factor in antiviral defense and tumor eradication. Although downregulation of TLR3 gene expression has been mainly reported in patients infected with hepatitis C virus (HCV), the influence of TLR3 genotype on the risk of HCV infection, HCV-related cirrhosis, and/or hepatocellular carcinoma (HCC) remains to be determined. Single-nucleotide polymorphisms (SNPs) within the TLR3 gene and their associations with HCV-related disease risk were investigated in a Saudi Arabian population in this study. Eight TLR3 SNPs were analyzed in 563 patients with HCV, which consisted of 437 patients with chronic HCV infections, 88 with HCV-induced liver cirrhosis, and 38 with HCC. A total of 599 healthy control subjects were recruited to the study. Among the eight TLR3 SNPs studied, the rs78726532 SNP was strongly associated with HCV infection when compared to that in healthy control subjects. The rs5743314 was also strongly associated with HCV-related liver disease progression (cirrhosis and HCC). In summary, these results indicate that distinct genetic variants of TLR3 SNPs are associated with HCV infection and HCV-mediated liver disease progression in the Saudi Arabian population.

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Study about Doping Ion La3+ onto Surface of Pyrolusite Ore for Removing Simultaneously Both Fluoride and Phosphate from Wastewater

Lanthanum has been doped onto the surface of the natural Pyrolusite for simultaneous removal of phosphate and fluoride in aqueous solution. The adsorbent characterization of the materials was observed by the SEM, BET, and XRD techniques. The dynamics and isotherms models of fluoride and phosphate adsorption, with respect to pH, pHPZC, adsorbent dose, and effect of coexisting ions, were studied. The results showed that lanthanum doped Pyrolusite ore (LDPO) relatively highly adsorbed amount of phosphate and fluoride from aqueous solution. Phosphate and fluoride removal efficiencies of LDPO are approximately 97% and 95%, respectively. Pseudo-first order for kinetic studies of phosphate and fluoride removal of the LDPO was observed with high correlations for fluoride but weak correlations for phosphate. However, pseudo-second order for kinetic studies was high correlation for both phosphate and fluoride. The phosphate and fluoride adsorption capacities of the LDPO significantly decreased with the existence of coions (sulfate, chloride, and nitrate) in the aqueous solution.

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Different Characterizations of Large Submodules of QTAG-Modules

A module over an associative ring with unity is a -module if every finitely generated submodule of any homomorphic image of is a direct sum of uniserial modules. The study of large submodules and its fascinating properties makes the theory of QTAG-modules more interesting. A fully invariant submodule of is large in if , for every basic submodule of The impetus of these efforts lies in the fact that the rings are almost restriction-free. This motivates us to find the necessary and sufficient conditions for a submodule of a QTAG-module to be large and characterize them. Also, we investigate some properties of large submodules shared by -modules, summable modules, -summable modules, and so on.

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Mercury and Organic Matter Concentrations in Lake and Stream Sediments in relation to One Another and to Atmospheric Mercury Deposition and Climate Variations across Canada

This article focuses on analyzing the Geological Survey of Canada (GSC) data for total mercury concentrations (THg) in lake and stream sediments. The objective was to quantify how sediment THg varies by (i) sediment organic matter, determined by loss on ignition (LOI) at 500∘C, (ii) atmospheric Hg deposition (atm.) as derived from the Global/Regional Atmospheric Heavy Metals Model GRAHM2005, and (iii) mean annual precipitation and mean monthly July and January temperatures (, ). Through regression analyses and averaging by National Topographic System tiles (NTS, 1:250,000 scale), it was found that 40, 70, and 80% of the sediment THg, LOI, and atm. variations were, respectively, related to precipitation, , and . In detail, lake sediment THg was related to atm. and precipitation, while stream sediment THg was related to sediment LOI and . Plotting sediment THg versus sediment LOI revealed a curvilinear pattern, with highest Hg concentrations at intermediate LOI values. Analysing the resulting 10th and 90th log10THg percentiles within each 10% LOI class from 0 to 100% revealed that (i) atm. contributed to the organic component of sediment THg and (ii) this was more pronounced for lakes than for streams.

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Successful Management of Refractory Type 1 Renal Tubular Acidosis with Amiloride

A 28-year-old female with history of hypothyroidism, Sjögren’s Syndrome, and Systemic Lupus Erythematosus (SLE) presented with complaints of severe generalized weakness, muscle pain, nausea, vomiting, and anorexia. Physical examination was unremarkable. Laboratory test showed hypokalemia at 1.6 mmol/l, nonanion metabolic acidosis with HCO3 of 11 mmol/l, random urine pH of 7.0, and urine anion gap of 8 mmol/l. CT scan of the abdomen revealed bilateral nephrocalcinosis. A diagnosis of type 1 RTA likely secondary to Sjögren’s Syndrome was made. She was started on citric acid potassium citrate with escalating dosages to a maximum dose of 60 mEq daily and potassium chloride over 5 years without significant improvement in serum K+ and HCO3 levels. She had multiple emergency room visits for persistent muscle pain, generalized weakness, and cardiac arrhythmias. Citric acid potassium citrate was then replaced with sodium bicarbonate at 15.5 mEq every 6 hours which was continued for 2 years without significant improvement in her symptoms and electrolytes. Amiloride 5 mg daily was added to her regimen as a potassium sparing treatment with dramatic improvement in her symptoms and electrolyte levels (as shown in the figures). Amiloride was increased to 10 mg daily and potassium supplementation was discontinued without affecting her electrolytes. Her sodium bicarbonate was weaned to 7.7 mEq daily.

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Declining Physical Performance Associates with Serum FasL, miR-21, and miR-146a in Aging Sprinters

Aging is associated with systemic inflammation and cellular apoptosis accelerating physiological dysfunctions. Whether physically active way of life affects these associations is unclear. This study measured the levels of serum inflammatory and apoptotic molecules, their change over 10 years, and their associations with physical performance in sprint-trained male athletes. HsCRP, cell counts, HGB, FasL, miR-21, and miR-146a were measured cross-sectionally (, 18–90 yrs) and serum FasL, miR-21, and miR-146a and their aging-related associations with physical performance were assessed over a 10-year follow-up (, 50–90 yrs). The cross-sectional study showed positive age correlations for neutrophils and negative for lymphocytes, red blood cells, HGB, FasL, and miR-146a. During the 10-year follow-up, FasL decreased () and miR-21 () and miR-146a () levels increased. When combining the molecule levels, aging, and physical performance, FasL associated with countermovement jump and bench press (), miR-21 and miR-146a with knee flexion (; ), and bench press (; ) and miR-146a with sprint performance (). The studied serum molecules changed in an age-dependent manner and were associated with declining physical performance. They have potential as biomarkers of aging-related processes influencing the development of physiological dysfunctions. Further research is needed focusing on the origins and targets of circulating microRNAs to clarify their function in various tissues with aging.

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Role of Phosphorylated HDAC4 in Stroke-Induced Angiogenesis

Acetylation or deacetylation of chromatin proteins and transcription factors is part of a complex signaling system that is involved in the control of neurological disorders. Recent studies have demonstrated that histone deacetylases (HDACs) exert protective effects in attenuating neuronal injury after ischemic insults. Class IIa HDAC4 is highly expressed in the brain, and neuronal activity depends on the nucleocytoplasmic shuttling of HDAC4. However, little is known about HDAC4 and its roles in ischemic stroke. In this study, we report that phosphorylation of HDAC4 was remarkably upregulated after stroke and blockade of HDAC4 phosphorylation with GÖ6976 repressed stroke-induced angiogenesis. Phosphorylation of HDAC4 was also increased in endothelial cells hypoxia model and suppression of HDAC4 phosphorylation inhibited the tube formation and migration of endothelial cells in vitro. Furthermore, in addition to the inhibition of angiogenesis, blockade of HDAC4 phosphorylation suppressed the expression of genes downstream of HIF-VEGF signaling in vitro and in vivo. These data indicate that phosphorylated HDAC4 may serve as an important regulator in stroke-induced angiogenesis. The protective mechanism of phosphorylated HDAC4 is associated with HIF-VEGF signaling, implicating a novel therapeutic target in stroke.

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En mann med feber og leddsmerter

Leddsmerter kan ha mange årsaker. Traumatiske, immunologiske og infeksiøse lidelser må vurderes. En god anamnese kan sette oss på rett spor tidlig.

En norsk mann i 60-årene ble innlagt i medisinsk avdeling på grunn av sterke smerter i høyre ankel. Smertene var ledsaget av intermitterende feber over 39 °C. Han var tidligere stort sett frisk, bortsett fra at han var innlagt med malaria i 2011. Pasienten brukte Albyl-E 75 mg 1 · 1 som fast medikasjon som primærprofylakse mot hjertesykdom. Han kom hjem til Norge fra et utenlandsopphold fem dager i forveien. Under reisen og to uker før innleggelsen hadde han merket forbigående nesetetthet og ubehag i svelg. Ved innleggelsen hadde han tiltagende smerter fra høyre ankel. Han hadde tråkket over og forstuet ankelen en måned i forveien, men det var ingen større traumer i historien. Han oppga også generelle smerter i skuldre, rygg og venstre hofte. Pasienten var ved ankomst til sykehuset høyfebril med temperatur 39 °C, normalt blodtrykk (119/65), og puls var 86, regelmessig. Det var normale auskultasjonsfunn over hjerte og lunger. Han hadde diffus rubor både på medialsiden og lateralsiden av høyre ankel, samt varmeøkning og petekkialt utslett over ankelleddet (fig 1).

Blodprøver ved innkomst viste CRP 248 (9/l) med 19,4 nøytrofile granulocytter (1,7 – 8,2 · 10**9/l), trombocytter 186 (145 – 348 · 10**9/l), INR 1,3 (

Det ble rekvirert tilsyn fra ortoped i akuttmottak. Blodprøvesvar forelå da, og det ble funnet indikasjon for diagnostisk punksjon av ankelleddet. Det ble ikke funnet indikasjon for røntgenundersøkelse av ankelen. Det ble tappet 2 – 3 ml blakket leddvæske fra høyre ankel rundt midnatt innkomstdagen. På grunn av smerter fikk vi ikke tappet ut all leddvæske. Leddvæsken ble sendt til dyrking og mikroskopi, men ikke til celletelling.

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Figur 1  Høyre ankel ved innkomst. Foto: Astrid Rykkje Heien

På dette tidspunktet valgte vi på empirisk grunnlag å dekke septisk artritt med kloksacillin og gentamicin intravenøst. Vi trodde initialt mest på reaktiv artritt, men en høy CRP-verdi og leukocytose med nøytrofili, i tillegg til høy feber, gjorde at vi i tillegg dekket med antibiotika.

Morgenen etter var pasienten fremdeles febril, og CRP-nivået hadde steget til 317. Omtrent samtidig kom det preliminært svar fra Mikrobiologisk avdeling om at mikroskopi av leddvæsken viste gramnegative kokker i par og rikelig med leukocytter. Mikrobene kunne ses intracellulært (fig 2).

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Figur 2  Mikroskopifunn. Grampreparat som viser gramnegative diplokokker funnet ved punksjon av høyre ankel

Dette gjorde de klart hyppigste årsakene til septisk artritt – Staphylococcus aureus og Streptococcus species – mindre sannsynlig. Vi mistenkte nå ut fra mikroskopifunnet gonokokkinfeksjon og endret antibiotika til ceftriaxon 2 g intravenøst 1 · 1.

På bakgrunn av dette ble pasienten henvist poliklinikk for seksuelt overførbare sykdommer. Dette ble gjort første innleggelsesdag. Han var nå subfebril og hadde mindre smerter i ankelen.

Det ble tatt prøver fra urethra og tonsilleregionen med tanke på gonokokker og klamydia, i tillegg til serologi med tanke på syfilis, hiv og hepatittvirus. Anamnestisk kom det etter hvert frem at pasienten hadde hatt sex uten kondom i land utenfor Europa ved et par tilfeller det siste året.

Ankelen var hoven og rød, men med god bevegelighet to dager etter innleggelse. Vi punkterte ankelen på nytt, og det kom ut 1 ml blank væske. To dager etter gjentok vi punksjon av ankel og tappet 3 ml pussbefengt væske. I høyre kne ble pasienten på grunn av økende hevelse tappet for 5 ml strågul væske. På dette tidspunktet forelå også endelig mikrobiologisk svar med oppvekst av Neisseria gonorrhoeae, fra leddvæsken fra høyre ankel tappet ved innleggelsen, både på blodagar og sjokoladeagar. Mikroben var katalasepositiv og agglutinerte i serogruppe WI. Bekreftende identifikasjon av bakteriene ble gjort med både systemet Vitek II og massespekterbasert teknologi med systemet MaldiTof (bioMérieux). Mikroben var resistent for penicillin G, ampicillin og ciprofloxacin, men sensitiv for ceftriaxon, azitromycin og spectinomycin.

Vi vurderte fortløpende behovet for artroskopisk skylling. Imidlertid tilkom det biokjemisk og lokal bedring, så dette ble ikke gjort.

Etter ti dager med antibiotikabehandling hadde pasienten fremdeles feber og smerter. CRP-nivået var fortsatt forhøyet til 145. Vi valgte da å gi en prednisolonkur, initialt 40 mg 1 · 1 i fire dager, deretter gradvis nedtrapping over tre uker. To dager etter oppstart av prednisolon ble pasienten afebril, og CRP-nivået falt raskt. Syv dager etter dette kunne pasienten skrives ut med peroral azitromycin, og prednisolon i nedtrappende dosering. CRP-nivået var da 6. Han fikk belaste ankelen til smertegrensen og fikk instruks om øvelser av fysioterapeut.

Det ble ikke påvist gonokokker i sekret fra urethra og hals, og blodkulturer var negative. Chlamydia trachomatis DNA ble ikke påvist i urinprøve, og serologiske tester for syfilis (Treponema pallidum spesifikke antistoff) og hiv-antigen/antistoff var negative. Pasienten ble kontrollert ukentlig på poliklinikken. Hevelsen bedret seg gradvis, CRP-nivået forble normalt, og pasienten hadde mindre smerter. Prednisolon og antibiotika ble seponert etter henholdsvis 3 og 4,5 ukers behandling (18 dager intravenøst ceftriaxon, azitromycin · 3/uke i 2,5 uker).

Etter avsluttet behandling tilkom økende hydrops og smerter i høyre kne, ledsaget av CRP-stigning til 43. Han ble reinnlagt, og kneleddet ble tappet for 15 ml gulaktig væske. Denne ble analysert med celletelling (leukocytter 5,7 · 109/l), men var mikroskopi- og dyrkingsnegativ. Revmatolog satte inn 2 ml Lederspan (et kortikosteroidpreparat) da vi antok at han nå hadde en postinfeksiøs reaktiv artritt. CRP-nivået falt da til 1 ved kontroll én uke senere. Senere fikk han på ny lett CRP-stigning til 17, og han ble behandlet med diklofenak 50 mg 1 · 3 i én uke. Ved avsluttende kontroll var CRP-verdien

Diskusjon

Ved feber og monoartritt overveies i første omgang septisk artritt, reaktiv artritt eller krystallartritt. Med polyartralgi i tillegg vil også systemsykdom som adult Stills sykdom eller virusinfeksjon med leddaffinitet være aktuelt. Hvis symptomene har oppstått ved reise til et tropisk område, øker de differensialdiagnostiske mulighetene. Det er avgjørende å punktere leddet for leddvæskeanalyser og ta blodkulturer.

Gonokokkartritt er en kjent, men forholdsvis sjelden årsak til septisk artritt. I Norge påvises årlig 1 – 2 tilfeller med gonokokker i leddvæske (Øyvind Nilsen, MSIS, Folkehelseinstituttet, personlig meddelelse). Gonokokker forårsaker vanligvis uretritt og cervisitt, men fra litteraturen er det kjent at mellom 0,5 – 3 % av personer med mukosal gonokokkinfeksjon utvikler disseminert gonokokkinfeksjon (1 – 3). Flertallet av disseminerte gonokokkinfeksjoner, 42 – 85 %, vil presentere seg med artritt (2). I Norge har det de siste ti årene vært påvist 12 tilfeller av gonokokker i leddvæske, av totalt 3 682 tilfeller av gonokokkinfeksjon, tilsvarende 0,3 % (Øyvind Nilsen, personlig meddelelse).

Ved disseminert gonokokksykdom foreligger hovedsakelig purulent artritt eller et syndrom med tenosynovitt, dermatitt og polyartralgi, eventuelt en kombinasjon av dette (4, 5).

Denne pasienten hadde åpenbart septisk artritt, med purulent leddvæske og oppvekst av bakterier. I tillegg hadde han klinisk tenosynovitt, dermatitt og polyartralgi. Hovedsymptomene var sterke smerter i høyre ankel, ledsaget av høy feber og generelle smerter i kroppen. I tillegg fant vi ved undersøkelse erytem på høyre legg, petekkialt utslett på høyre fot og hydrops i høyre kne. Han hadde også generelle smerter i skuldre, rygg og venstre hofte.

Invasiv gonokokksykdom er assosiert med komplementmangel og systemisk lupus erythematosus (SLE). Pasienten hadde ikke hatt dette. Prøve på antinukleære antistoffer (ANA) var negativ, og komplementtest var normal.

Diagnostikk, resistens og behandlingslengde

Direkte mikroskopi av leddvæske har en høy forekomst av falskt negative funn ved septiske artritter, og sensitivitetstall fra under 50 % til 78 % er oppgitt (6, 7).

Metoden brukes likevel ved alvorlige infeksjoner der funn ved mikroskopi vil kunne ha konsekvens for valg av behandling. For vår pasient sikret metoden at det raskt ble skiftet behandling til korrekt antibiotika. Flere mikrobiologiske laboratorier i Norge kan nå også hurtig påvise gonokokker med nukleinsyreamplifiseringstester (PCR).

Isolatet var resistent for ampicillin og ciprofloksacin. Av antibiotika som isolatet var følsomt for, var kun ceftriaxon og azitromycin registrert i Norge, mens spectinomycin måtte bestilles med en leveringstid på cirka tre uker.

I litteraturen er det angitt at 7 – 10 dager samlet behandlingstid vanligvis er nok for gonokokkartritt (8). Vi valgte å gi betydelig lengre behandling på grunn av vedvarende smerter, febrilia og høye inflammasjonsmarkører. Vi valgte derfor intravenøs ceftriaxon initialt mens vi dekket med peroral azitromycin så lenge han fikk adjuvant steroidbehandling.

Adjuvant steroidbehandling ble valgt da vi oppfattet vedvarende febrilia til å være immunologisk utløst og hans hydrops i høyre kne til å være reaktiv artritt (8).

Kirurgisk behandling: Tapping versus skylling

Generelt anbefales artroskopisk skylling ved septisk artritt. Ved gonokokkartritt er det anbefalt enten skylling eller gjentatte punksjoner. Vi valgte gjentatte punksjoner (8). Det forelå svært beskjeden mengde leddvæske, slik at risikoen for leddskade syntes lav.

Årlig antas det å forekomme minst 78 millioner nye gonorétilfeller globalt (9). Funn av Neisseria gonorrhoeae er i Norge meldepliktig til Meldingssystem for smittsomme sykdommer (MSIS). Folkehelsesinstituttet har i de senere årene rapportert om stadig økende forekomst (10) (fig 3).

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Figur 3  Oversikt over antall meldte gonorétilfeller, forekomst etter påvisningsmetode (10). Illustrasjonen er basert på Folkehelseinstituttets figur og gjengitt med tillatelse fra Øivind Nilsen

Man har også lenge sett en bekymringsfull økning i ciprofloksacinresistente isolat både i Norge og internasjonalt, noe som førte til at ciprofloksacin ble forlatt som empirisk behandling i norske retningslinjer fra 2013 (11, 12). Også cefalosporinresistens er økende globalt, og sykdommen blir stadig vanskeligere å behandle (13).

Vår pasient presenterte seg med atypisk klinisk bilde. Sykdommen er økende, og det er viktig at både helsearbeidere og personer i risikogruppene er oppmerksomme på sykdommen, også ved atypiske symptomer.



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A Group Decision-Making Model Based on Regression Method with Hesitant Fuzzy Preference Relations

In recent years, the decision-making models with hesitant fuzzy preference relations (HFPRs) have received a lot of attention by some researchers. Meanwhile, the previous studies normally adopt normalization technical means to ensure the same number for all elements, which biases original information of decision-makers. In order to overcome this problem, in this paper, the multiplicative consistency of HFPRs is defined and the highest consistent reduced HFPRs are obtained by means of fuzzy linear programming method from given HFPRs. The proposed regression method eliminates the unreasonable information and retains the reasonable information from a given HFPR. In addition, the proposed method overcomes drawbacks of Zhu and Xu’s regression method and is more simple and effective. On account of the obtained reduced HFPRs by the proposed regression method, a GDM model is established. Finally, a supplier selection problem was researched to present the effectiveness and pragmatism of the proposed approach, which proved that the method could offer beneficial insights into the GDM procedure.

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Photomediated Larvicidal Activity of Pheophorbide a against Cercaria Larvae of Fasciola gigantica

Fasciolosis is a parasitic disease caused by Fasciola gigantica. The freshwater snail Lymnaea acuminata is the intermediate host of F. gigantica which cause endemic fasciolosis in the northern part of India. To investigate larvicidal activity of pure and laboratory extracted pheophorbide a (Pa) against cercaria larvae of F. gigantica, data were analyzed in different spectra of visible light, sunlight, and laboratory conditions. Photostimulation of chlorophyll derivative pheophorbide a (Pa) caused time and concentration dependent larvicidal activity against cercaria larvae of F. gigantica. Larvicidal activity of pure Pa under 650 nm and 400–650 nm (8 h LC50 0.006 mg/10 mL) was more pronounced than extracted Pa under same irradiations (650 nm LC50 0.12 mg/10 mL, 400–650 nm LC50 0.14 mg/10 mL). Lowest toxicity of pure (8 h LC50 0.14 mg/10 mL) and extracted Pa (8 h LC50 1.25 mg/10 mL) was noted under 400 nm. Pa was found to be toxic in laboratory conditions also. The results presented in this paper indicate that pheophorbide a possess potential larvicidal activity against Fasciola gigantica larvae in different wavelengths of visible light, sunlight, and laboratory conditions.

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High Prevalence of Metabolic Syndrome in Patients with Discoid Lupus Erythematosus: A Cross-Sectional, Case-Control Study

Although it is known that systemic form of lupus erythematosus (LE) and metabolic syndrome (MetS) are frequently observed together, there are no published reports on MetS in patients with skin-restricted LE. We aimed to compare the frequencies of MetS and its components in discoid LE (DLE) with the non-DLE control group. Additionally, we intended to determine the differences of sociodemographic and clinical data of the DLE patients with MetS compared to the patients without MetS. This was a cross-sectional, case-control study, including 60 patients with DLE and 82 age- and gender-matched control subjects. In DLE group, the presence of MetS was observed as more frequent (48.3% versus 24.4%, ), and hypertriglyceridemia (43.3% versus 22.0%, ) and reduced HDL-cholesterol (61.7% versus 23.2%, ) among the MetS components were found significantly higher when compared to the control group. DLE patients with MetS were at older age ( versus , ), and hypertension, hyperlipidemia/dyslipidemia, and cardiovascular disease histories were observed at a higher ratio when compared to the patients without MetS. Between the DLE patients with and without MetS, no significant difference was observed in terms of clinical characteristics of DLE. Moreover, further large case-control studies with follow-up periods would be required to clearly assess the impact of MetS on the clinical outcomes of DLE.

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Characterization of Rain Specific Attenuation and Frequency Scaling Method for Satellite Communication in South Korea

The attenuation induced by rain is prominent in the satellite communication at Ku and Ka bands. The paper studied the empirical determination of the power law coefficients which support the calculation of specific attenuation from the knowledge of rain rate at Ku and Ka band for Koreasat 6 and COMS1 in South Korea that are based on the three years of measurement. Rain rate data was measured through OTT Parsivel which shows the rain rate of about 50 mm/hr and attenuation of 10.7, 11.6, and 11.3 dB for 12.25, 19.8, and 20.73 GHz, respectively, for 0.01% of the time for the combined values of rain rate and rain attenuation statistics. Comparing with the measured data illustrates the suitability for estimation of signal attenuation in Ku and Ka band whose validation is done through the comparison with prominent rain attenuation models, namely, ITU-R P.618-12 and ITU-R P. 838-3 with the use of empirically determined coefficient sets. The result indicates the significance of the ITU-R recommended regression coefficients of rain specific attenuation. Furthermore, the overview of predicted year-wise rain attenuation estimation for Ka band in the same link as well as different link is studied which is obtained from the ITU-R P. 618-12 frequency scaling method.

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En mann med feber og leddsmerter

Leddsmerter kan ha mange årsaker. Traumatiske, immunologiske og infeksiøse lidelser må vurderes. En god anamnese kan sette oss på rett spor tidlig.

En norsk mann i 60-årene ble innlagt i medisinsk avdeling på grunn av sterke smerter i høyre ankel. Smertene var ledsaget av intermitterende feber over 39 °C. Han var tidligere stort sett frisk, bortsett fra at han var innlagt med malaria i 2011. Pasienten brukte Albyl-E 75 mg 1 · 1 som fast medikasjon som primærprofylakse mot hjertesykdom. Han kom hjem til Norge fra et utenlandsopphold fem dager i forveien. Under reisen og to uker før innleggelsen hadde han merket forbigående nesetetthet og ubehag i svelg. Ved innleggelsen hadde han tiltagende smerter fra høyre ankel. Han hadde tråkket over og forstuet ankelen en måned i forveien, men det var ingen større traumer i historien. Han oppga også generelle smerter i skuldre, rygg og venstre hofte. Pasienten var ved ankomst til sykehuset høyfebril med temperatur 39 °C, normalt blodtrykk (119/65), og puls var 86, regelmessig. Det var normale auskultasjonsfunn over hjerte og lunger. Han hadde diffus rubor både på medialsiden og lateralsiden av høyre ankel, samt varmeøkning og petekkialt utslett over ankelleddet (fig 1).

Blodprøver ved innkomst viste CRP 248 (9/l) med 19,4 nøytrofile granulocytter (1,7 – 8,2 · 10**9/l), trombocytter 186 (145 – 348 · 10**9/l), INR 1,3 (

Det ble rekvirert tilsyn fra ortoped i akuttmottak. Blodprøvesvar forelå da, og det ble funnet indikasjon for diagnostisk punksjon av ankelleddet. Det ble ikke funnet indikasjon for røntgenundersøkelse av ankelen. Det ble tappet 2 – 3 ml blakket leddvæske fra høyre ankel rundt midnatt innkomstdagen. På grunn av smerter fikk vi ikke tappet ut all leddvæske. Leddvæsken ble sendt til dyrking og mikroskopi, men ikke til celletelling.

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Figur 1  Høyre ankel ved innkomst. Foto: Astrid Rykkje Heien

På dette tidspunktet valgte vi på empirisk grunnlag å dekke septisk artritt med kloksacillin og gentamicin intravenøst. Vi trodde initialt mest på reaktiv artritt, men en høy CRP-verdi og leukocytose med nøytrofili, i tillegg til høy feber, gjorde at vi i tillegg dekket med antibiotika.

Morgenen etter var pasienten fremdeles febril, og CRP-nivået hadde steget til 317. Omtrent samtidig kom det preliminært svar fra Mikrobiologisk avdeling om at mikroskopi av leddvæsken viste gramnegative kokker i par og rikelig med leukocytter. Mikrobene kunne ses intracellulært (fig 2).

/sites/http://ift.tt/2hOFMbc

Figur 2  Mikroskopifunn. Grampreparat som viser gramnegative diplokokker funnet ved punksjon av høyre ankel

Dette gjorde de klart hyppigste årsakene til septisk artritt – Staphylococcus aureus og Streptococcus species – mindre sannsynlig. Vi mistenkte nå ut fra mikroskopifunnet gonokokkinfeksjon og endret antibiotika til ceftriaxon 2 g intravenøst 1 · 1.

På bakgrunn av dette ble pasienten henvist poliklinikk for seksuelt overførbare sykdommer. Dette ble gjort første innleggelsesdag. Han var nå subfebril og hadde mindre smerter i ankelen.

Det ble tatt prøver fra urethra og tonsilleregionen med tanke på gonokokker og klamydia, i tillegg til serologi med tanke på syfilis, hiv og hepatittvirus. Anamnestisk kom det etter hvert frem at pasienten hadde hatt sex uten kondom i land utenfor Europa ved et par tilfeller det siste året.

Ankelen var hoven og rød, men med god bevegelighet to dager etter innleggelse. Vi punkterte ankelen på nytt, og det kom ut 1 ml blank væske. To dager etter gjentok vi punksjon av ankel og tappet 3 ml pussbefengt væske. I høyre kne ble pasienten på grunn av økende hevelse tappet for 5 ml strågul væske. På dette tidspunktet forelå også endelig mikrobiologisk svar med oppvekst av Neisseria gonorrhoeae, fra leddvæsken fra høyre ankel tappet ved innleggelsen, både på blodagar og sjokoladeagar. Mikroben var katalasepositiv og agglutinerte i serogruppe WI. Bekreftende identifikasjon av bakteriene ble gjort med både systemet Vitek II og massespekterbasert teknologi med systemet MaldiTof (bioMérieux). Mikroben var resistent for penicillin G, ampicillin og ciprofloxacin, men sensitiv for ceftriaxon, azitromycin og spectinomycin.

Vi vurderte fortløpende behovet for artroskopisk skylling. Imidlertid tilkom det biokjemisk og lokal bedring, så dette ble ikke gjort.

Etter ti dager med antibiotikabehandling hadde pasienten fremdeles feber og smerter. CRP-nivået var fortsatt forhøyet til 145. Vi valgte da å gi en prednisolonkur, initialt 40 mg 1 · 1 i fire dager, deretter gradvis nedtrapping over tre uker. To dager etter oppstart av prednisolon ble pasienten afebril, og CRP-nivået falt raskt. Syv dager etter dette kunne pasienten skrives ut med peroral azitromycin, og prednisolon i nedtrappende dosering. CRP-nivået var da 6. Han fikk belaste ankelen til smertegrensen og fikk instruks om øvelser av fysioterapeut.

Det ble ikke påvist gonokokker i sekret fra urethra og hals, og blodkulturer var negative. Chlamydia trachomatis DNA ble ikke påvist i urinprøve, og serologiske tester for syfilis (Treponema pallidum spesifikke antistoff) og hiv-antigen/antistoff var negative. Pasienten ble kontrollert ukentlig på poliklinikken. Hevelsen bedret seg gradvis, CRP-nivået forble normalt, og pasienten hadde mindre smerter. Prednisolon og antibiotika ble seponert etter henholdsvis 3 og 4,5 ukers behandling (18 dager intravenøst ceftriaxon, azitromycin · 3/uke i 2,5 uker).

Etter avsluttet behandling tilkom økende hydrops og smerter i høyre kne, ledsaget av CRP-stigning til 43. Han ble reinnlagt, og kneleddet ble tappet for 15 ml gulaktig væske. Denne ble analysert med celletelling (leukocytter 5,7 · 109/l), men var mikroskopi- og dyrkingsnegativ. Revmatolog satte inn 2 ml Lederspan (et kortikosteroidpreparat) da vi antok at han nå hadde en postinfeksiøs reaktiv artritt. CRP-nivået falt da til 1 ved kontroll én uke senere. Senere fikk han på ny lett CRP-stigning til 17, og han ble behandlet med diklofenak 50 mg 1 · 3 i én uke. Ved avsluttende kontroll var CRP-verdien

Diskusjon

Ved feber og monoartritt overveies i første omgang septisk artritt, reaktiv artritt eller krystallartritt. Med polyartralgi i tillegg vil også systemsykdom som adult Stills sykdom eller virusinfeksjon med leddaffinitet være aktuelt. Hvis symptomene har oppstått ved reise til et tropisk område, øker de differensialdiagnostiske mulighetene. Det er avgjørende å punktere leddet for leddvæskeanalyser og ta blodkulturer.

Gonokokkartritt er en kjent, men forholdsvis sjelden årsak til septisk artritt. I Norge påvises årlig 1 – 2 tilfeller med gonokokker i leddvæske (Øyvind Nilsen, MSIS, Folkehelseinstituttet, personlig meddelelse). Gonokokker forårsaker vanligvis uretritt og cervisitt, men fra litteraturen er det kjent at mellom 0,5 – 3 % av personer med mukosal gonokokkinfeksjon utvikler disseminert gonokokkinfeksjon (1 – 3). Flertallet av disseminerte gonokokkinfeksjoner, 42 – 85 %, vil presentere seg med artritt (2). I Norge har det de siste ti årene vært påvist 12 tilfeller av gonokokker i leddvæske, av totalt 3 682 tilfeller av gonokokkinfeksjon, tilsvarende 0,3 % (Øyvind Nilsen, personlig meddelelse).

Ved disseminert gonokokksykdom foreligger hovedsakelig purulent artritt eller et syndrom med tenosynovitt, dermatitt og polyartralgi, eventuelt en kombinasjon av dette (4, 5).

Denne pasienten hadde åpenbart septisk artritt, med purulent leddvæske og oppvekst av bakterier. I tillegg hadde han klinisk tenosynovitt, dermatitt og polyartralgi. Hovedsymptomene var sterke smerter i høyre ankel, ledsaget av høy feber og generelle smerter i kroppen. I tillegg fant vi ved undersøkelse erytem på høyre legg, petekkialt utslett på høyre fot og hydrops i høyre kne. Han hadde også generelle smerter i skuldre, rygg og venstre hofte.

Invasiv gonokokksykdom er assosiert med komplementmangel og systemisk lupus erythematosus (SLE). Pasienten hadde ikke hatt dette. Prøve på antinukleære antistoffer (ANA) var negativ, og komplementtest var normal.

Diagnostikk, resistens og behandlingslengde

Direkte mikroskopi av leddvæske har en høy forekomst av falskt negative funn ved septiske artritter, og sensitivitetstall fra under 50 % til 78 % er oppgitt (6, 7).

Metoden brukes likevel ved alvorlige infeksjoner der funn ved mikroskopi vil kunne ha konsekvens for valg av behandling. For vår pasient sikret metoden at det raskt ble skiftet behandling til korrekt antibiotika. Flere mikrobiologiske laboratorier i Norge kan nå også hurtig påvise gonokokker med nukleinsyreamplifiseringstester (PCR).

Isolatet var resistent for ampicillin og ciprofloksacin. Av antibiotika som isolatet var følsomt for, var kun ceftriaxon og azitromycin registrert i Norge, mens spectinomycin måtte bestilles med en leveringstid på cirka tre uker.

I litteraturen er det angitt at 7 – 10 dager samlet behandlingstid vanligvis er nok for gonokokkartritt (8). Vi valgte å gi betydelig lengre behandling på grunn av vedvarende smerter, febrilia og høye inflammasjonsmarkører. Vi valgte derfor intravenøs ceftriaxon initialt mens vi dekket med peroral azitromycin så lenge han fikk adjuvant steroidbehandling.

Adjuvant steroidbehandling ble valgt da vi oppfattet vedvarende febrilia til å være immunologisk utløst og hans hydrops i høyre kne til å være reaktiv artritt (8).

Kirurgisk behandling: Tapping versus skylling

Generelt anbefales artroskopisk skylling ved septisk artritt. Ved gonokokkartritt er det anbefalt enten skylling eller gjentatte punksjoner. Vi valgte gjentatte punksjoner (8). Det forelå svært beskjeden mengde leddvæske, slik at risikoen for leddskade syntes lav.

Årlig antas det å forekomme minst 78 millioner nye gonorétilfeller globalt (9). Funn av Neisseria gonorrhoeae er i Norge meldepliktig til Meldingssystem for smittsomme sykdommer (MSIS). Folkehelsesinstituttet har i de senere årene rapportert om stadig økende forekomst (10) (fig 3).

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Figur 3  Oversikt over antall meldte gonorétilfeller, forekomst etter påvisningsmetode (10). Illustrasjonen er basert på Folkehelseinstituttets figur og gjengitt med tillatelse fra Øivind Nilsen

Man har også lenge sett en bekymringsfull økning i ciprofloksacinresistente isolat både i Norge og internasjonalt, noe som førte til at ciprofloksacin ble forlatt som empirisk behandling i norske retningslinjer fra 2013 (11, 12). Også cefalosporinresistens er økende globalt, og sykdommen blir stadig vanskeligere å behandle (13).

Vår pasient presenterte seg med atypisk klinisk bilde. Sykdommen er økende, og det er viktig at både helsearbeidere og personer i risikogruppene er oppmerksomme på sykdommen, også ved atypiske symptomer.



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Antitumor Effect of Programmed Death-1 (PD-1) Blockade in Humanized the NOG-MHC Double Knockout Mouse

Purpose: Humanized mouse models using NOD/Shi-scid-IL2rnull (NOG) and NOD/LtSz-scid IL2rnull (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xenograft versus host disease in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility class I- and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the antitumor effect of anti-programmed death-1 (PD-1) antibody.

Experimental Design: Humanized NOG-dKO mice, in which human PBMCs and human lymphoma cell line SCC-3, or glioblastoma cell line U87 were transplanted, were used as an immunotherapy model to investigate the effect of anti-PD-1 antibody. A biosimilar anti-PD-1 mAb generated in our laboratory was administered to humanized NOG-dKO mice transplanted with tumors.

Results: Within 4 weeks after transplantation, human CD45+ cells in antibody-treated mice constituted approximately 70% of spleen cells. The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of CTLs against SCC-3 cells and upregulation of natural killer cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte profiling showed that more exhausted marker (PD1+TIM3+LAG3+) positive T cells maintained in anti-PD-1 antibody–treated tumor. A greater number of CD8+ and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody.

Conclusions: These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment. Clin Cancer Res; 23(1); 149–58. ©2016 AACR.



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Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma

Purpose: Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC.

Experimental Design: PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression.

Results: Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy.

Conclusions: PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2–CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC. Clin Cancer Res; 23(1); 137–48. ©2016 AACR.



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Correction: Niclosamide Inhibits Androgen Receptor Variants Expression and Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer



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Correction: p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses



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Phase I Trial: SABR and Ipilimumab--Response



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Phase I Trial: SABR and Ipilimumab--Letter



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Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer

Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential.

Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum.

Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66–0.75) or pAUC (range, 0.007–0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86–0.89; all P <0.05).

Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311–9. ©2016 AACR.



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Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell-like Phenotype via Dysregulation of PITX2

Purpose: We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.

Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.

Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain- and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell–like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell–associated phenotype, at least partially, by inactivation of the Akt/GSK-3β/β-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.

Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298–310. ©2016 AACR.



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The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature

Purpose: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.

Experimental Design: Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.

Results: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%–99%] and 74% (95% CI, 58%–86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98–16.6, P < 0.05).

Conclusions: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289–97. ©2016 AACR.



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Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

Purpose: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.

Experimental Design: Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.

Results: TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (P = 0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).

Conclusions: Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of MEC. Clin Cancer Res; 23(1); 283–8. ©2016 AACR.



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Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome

Purpose: The majority of gastrointestinal stromal tumors (GIST) are driven by KIT, PDGFRA, or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs.

Experimental Design: Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathologic features.

Results: Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7 of 11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs.

Conclusions: NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a nongastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition. Clin Cancer Res; 23(1); 273–82. ©2016 AACR.



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Integrated Epigenomics Analysis Reveals a DNA Methylation Panel for Endometrial Cancer Detection Using Cervical Scrapings

Purpose: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer.

Experimental Design: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation–specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination.

Results: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%–96.0% and specificity of 78.7%–96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4–989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients.

Conclusions: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings. Clin Cancer Res; 23(1); 263–72. ©2016 AACR.



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A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases

Purpose: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases.

Experimental Design: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation.

Results: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis.

Conclusions: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250–62. ©2016 AACR.



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The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model

Purpose: Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions, including direct tumor lysis and stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T-cell responses in oncolytic adenoviral therapy.

Experimental Design: An immunocompetent and viral replication–permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by T-cell deletion, immunohistochemical staining, and CTL assay.

Results: Deletion of T cells with an anti-CD3 antibody completely demolished the antitumor efficacy of oncolytic Ad. Intratumoral injection of Ad induced strong virus- and tumor-specific T-cell responses, as well as antiviral antibody response. Both antiviral and antitumor T-cell responses contributed to the efficacy of oncolytic Ad. Deletion of T cells increased viral replication and extended the persistence of infectious virus within tumors but almost abrogated the antitumor efficacy. Preexisting antiviral immunity promoted the clearance of injected oncolytic Ad from tumors but had no effect on antitumor efficacy. Strikingly, the repeated treatment with oncolytic Ad has strong therapeutic effect on relapsed tumors or tumors insensitive to the primary viral therapy.

Conclusions: These results demonstrate that T cell–mediated immune responses outweigh the direct oncolysis in mediating antitumor efficacy of oncolytic Ad. Our data have a high impact on redesigning the regimen of oncolytic Ad for cancer treatment. Clin Cancer Res; 23(1); 239–49. ©2016 AACR.



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Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker

Purpose: Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma.

Experimental Design: From 2011 to 2015, blood samples were prospectively collected from all consecutive patients with pancreatic adenocarcinoma treated in our center. Identification of ctDNA was done with next-generation sequencing targeted on referenced mutations in pancreatic adenocarcinoma and with picoliter droplet digital PCR.

Results: A total of 135 patients with resectable (n = 31; 23%), locally advanced (n = 36; 27%), or metastatic (n = 68; 50%) pancreatic adenocarcinoma were included. In patients with advanced pancreatic adenocarcinoma (n = 104), 48% (n = 50) had ctDNA detectable with a median mutation allelic frequency (MAF) of 6.1%. The presence of ctDNA was strongly correlated with poor overall survival (OS; 6.5 vs. 19.0 months; P < 0.001) in univariate and multivariate analyses (HR = 1.96; P = 0.007). To evaluate the impact of ctDNA level, patients were grouped according to MAF tertiles: OS were 18.9, 7.8, and 4.9 months (P < 0.001). Among patients who had curative intent resection (n = 31), 6 had ctDNA detectable after surgery, with an MAF of 4.4%. The presence of ctDNA was associated with a shorter disease-free survival (4.6 vs.17.6 months; P = 0.03) and shorter OS (19.3 vs. 32.2 months; P = 0.027).

Conclusions: ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. Clin Cancer Res; 23(1); 116–23. ©2016 AACR.



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Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.

Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs.

Results: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells.

Conclusions: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214–24. ©2016 AACR.



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BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression

Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population.

Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data, we performed unsupervised clustering using non-negative matrix factorization to identify gene expression–based subgroups and characterized pathway activation.

Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers.

Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting. Clin Cancer Res; 23(1); 104–15. ©2016 AACR.



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Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas

Purpose: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS.

Experimental Design: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed.

Results: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples.

Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124–36. ©2016 AACR.



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The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care

Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models.

Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies.

Results: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma.

Conclusions: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225–38. ©2016 AACR.



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Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC.

Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response.

Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I–III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status.

Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. Clin Cancer Res; 23(1); 159–70. ©2016 AACR.



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A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma

LKB1 is a commonly mutated tumor suppressor in non–small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene. In silico screening of drug sensitivity data identified putative LKB1-selective drug candidates, revealing novel associations not apparent from analysis of LKB1 mutations alone. Among the candidates, MEK inhibitors showed robust association with signature expression in both training and testing datasets independent of RAS/RAF mutations. This susceptibility phenotype is directly altered by RNA interference–mediated LKB1 knockdown or by LKB1 re-expression into mutant cell lines and is readily observed in vivo using a xenograft model. MEK sensitivity is dependent on LKB1-induced changes in AKT and FOXO3 activation, consistent with genomic and proteomic analyses of LKB1-deficient lung adenocarcinomas. Our findings implicate the MEK pathway as a potential therapeutic target for LKB1-deficient cancers and define a practical NanoString biomarker to identify functional LKB1 loss. Cancer Res; 77(1); 153–63. ©2016 AACR.

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