In depth analyses of peripheral blood immune cell populations in patients with psoriasis - effect of biological treatment and alternative medicine

Psoriasis er en kronisk immun-mediert sykdom i huden med systemisk betennelse og ledsagende komorbiditeter. Selv om alvorlighetsgraden av sykdommen kan variere over tid, lider de fleste pasienter med psoriasis av mild til moderat sykdom. I mange tilfeller vil lokal behandling være tilstrekkelig for å kontrollere symptomene, men på bekostning av flere bivirkninger. ω-3 flerumettede fettsyrer (PUFA) har vist lovende resultater i kliniske studier med mild til moderat psoriasis. Opptil en tredjedel av pasienter med psoriasis er rammet av psoriasisartritt (PsA). Målrettet behandling med biologiske terapier har forvandlet behandlingen av begge sykdommene. Til tross for suksessen med terapi for noen pasienter, fremhever imidlertid eksistensen av pasienter hvis symptomer ikke blir bedre med anvendt behandling, behovet for prediktive biomarkører for respons og mer målrettet behandlingstilnærming som bør forbedre pasientbehandlingen og gi betydelige økonomiske besparelser. I studie I undersøkte vi virkningen av fosfolipidbundet dokosaheksaensyre (DHA) og eikosapentaensyre (EPA) i silderognolje (HRO) på sirkulerende immuncelleaktivitet og plasmacytokinnivåer ved ikke-alvorlig plakkpsoriasis. Plasmakonsentrasjonene av cytokiner ble målt med Luminex-teknologi og sirkulatorisk immuncelleaktivitet ble analysert ved flerfarget flowcytometri. I studie II brukte vi flowcytometri for å utføre dyptgående fenotyping av perifere blodmononukleære celler (PBMC) og undersøke deres respektive aktivitet gjennom ekspresjon av celleoverflatemarkører i friske kontroller og pasienter med moderat til alvorlig plakkpsoriasis/PsA på stabil anti- tumornekrosefaktor (TNF) behandling. I studie III utførte vi immunanalyser av dendritiske cellepopulasjoner (DC) hos pasienter med moderat til alvorlig plakkpsoriasis/PsA, før og under behandling med anti-TNF-medisinene infliksimab (IFX), etanercept, anti-IL-17A secukinumab, og anti-IL12/IL-23 ustekinumab, for å identifisere immuncellepopulasjoner/undergrupper i forhold til klinisk respons. I alle studiene ble kliniske og standard laboratorieparametre inkorporert i analysene. I studie I var positivt klinisk utfall av ω-3 PUFA hos pasienter med psoriasis muligens relatert til de reduserte nivåene av CCL2 og økte nivåer av IFN-γ over tid. I tillegg støttet redusert aktivitet på grunn av lavere ekspresjon av CD38 på CD4+ and CD8+ T celler, og CD56bright NK celler T-celler den gunstige effekten av HRO-tilskudd. I studie II beholder pasienter med psoriasis eller/og PsA på stabil biologisk behandling med infliksimab (IFX) fortsatt spor av sykdommen og har fenotypiske egenskaper. Økningen i aktive mellomliggende CD14+CD16+ monocytter reflekterte den bevarte pågående systemiske betennelsen. Den gunstige effekten av IFX-behandling ble imidlertid reflektert i redusert cytotoksisitet av NK-celler i begge pasientgruppene og CD8+ T-celler hos pasienter med PsA. I studie III skilte utforskede frekvenser av DC-populasjoner og deres undergrupper seg hos pasienter sammenlignet med kontroller, så vel som pasienter med psoriasis sammenlignet med PsA, men endret seg stort sett ikke ved behandling. De vedvarende lave nivåene av pDC i perifertblod hos pasienter med PsA kan relateres til tilstedeværelsen av leddgikt og bør undersøkes videre. Vedvarende reduksjon av CD5+ DC2 hos secukinumab-behandlede pasienter kan sannsynligvis være relatert til tilstedeværelsen av PsA og lavere behandlingsrespons. Ytterligere studier av cytokiner og perifere mononukleære blodceller kan være av stor betydning i den videre stratifiseringen av pasienter for passende terapeutiske intervensjoner. Mer personlig behandling kan forbedre livskvaliteten og endre forløpet av komorbiditeter.Psoriasis is a chronic immune-mediated disease of the skin with systemic inflammation and accompanied comorbidities. Although the disease severity may vary over time, most patients with psoriasis suffer from mild to moderate disease. In many cases, local treatment will be sufficient to control the symptoms, but at the cost of several side effects. ω-3 poly-unsaturated fatty acids (PUFA) have shown promising results in clinical trials with mild-to-moderate psoriasis. Up to one-third of patients with psoriasis are affected with psoriatic arthritis (PsA). Targeted treatment with biologic therapies has transformed the management of both diseases. However, despite the success of therapy for some patients the existence of patients whose symptoms do not improve with applied treatment, highlight the needs for predictive biomarkers of response and more targeted treatment approach that should improve patient care and deliver substantial economic savings. The general aim of this dissertation was to explore the systemic immune response through clinical and biological investigation and to identify disease-specific immune profiles and indicators in patients with psoriasis of different disease severity, treated with alternative medicine and biological treatment. In study I, we explored the impact of phospholipid bound docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) contained in herring roe oil (HRO) on circulating immune cell activity and plasma cytokine levels in non-severe plaque psoriasis. The plasma concentrations of cytokines were measured by Luminex technology and circulatory immune cell activity was analyzed by multicolor flow cytometry. In study II, we employed flow cytometry to perform in-depth phenotyping of peripheral blood mononuclear cells (PBMCs) and examine their respective activity through the expression of cell surface markers in healthy controls and patients with moderate to severe plaque psoriasis/PsA on stable anti-tumor necrosis factor (TNF) treatment. In study III, we performed immune analyzes of dendritic cell (DC) populations in patients with moderate to severe plaque psoriasis/PsA, before and during therapy with the anti-TNF drugs infliximab (IFX), etanercept, the anti-IL-17A secukinumab, and the anti-IL12/IL-23 ustekinumab, to identify immune cell populations/subsets relative to clinical response. In all studies, clinical and standard laboratory parameters were incorporated in the analyses. In study I, positive clinical outcome of ω-3 PUFAs in patients with psoriasis was possibly related to the decreased levels of CCL2 and increased levels of IFN-γ over time. Additionally, reduced activity due to lower expression of CD38 on CD4+ and CD8+ T cells, and CD56bright NK cells supported the beneficial effect of HRO supplementation. In study II, patients with psoriasis or/and PsA on stable biological treatment with infliximab (IFX) still retain imprint from the disease and have phenotypic peculiarity. The increase in active intermediate CD14+CD16+ monocytes reflected the preserved ongoing systemic inflammation. However, the beneficial effect of IFX treatment was reflected in reduced cytotoxicity of NK cells in both patient groups and CD8+ T cells in patients with PsA. In study III, explored frequencies of DC populations and their subsets differed in patients compared to controls as well as patients with psoriasis compared to PsA, but mostly did not change upon treatment. However, the persisting low levels of pDC in peripheral blood in patients with PsA might relate to the presence of arthritis and should be further investigated. Sustained reduction of CD5+ DC2 subset in secukinumab-treated patients could probably be related to the presence of PsA and lower treatment rensponsiveness. Further studies of cytokines and peripheral blood mononuclear cells may be of great importance in the further stratification of patients for appropriate therapeutic interventions. More personalized treatment can improve quality of life and change the course of comorbidities.Doktorgradsavhandlin

Content adaptive wavelet based method for joint denoising of depth and luminance images

In this paper we present a new method for joint denoising of depth and luminance images produced by time-of-flight camera. Here we assume that the sequence does not contain outlier points which can be present in the depth images. Our method first performs estimation of noise and signal covariance matrices and then performs vector denoising. Luminance image is segmented into similar contexts usina k-means algorithm, which are used for calculation of covariance matrices. Denoising results are compared with the ground truth images obtained by averaging of the multiple frames of the still scene

Composite localized modes in discretized spin-orbit-coupled Bose-Einstein condensates

We introduce a discrete model for binary spin-orbit-coupled (SOC) Bose-Einstein condensates (BEC) trapped in a deep one-dimensional optical lattice. Two different types of the couplings are considered, with spatial derivatives acting inside each species, or between the species. The discrete system with inter-site couplings dominated by the SOC, while the usual hopping is negligible, \textit{emulates} condensates composed of extremely heavy atoms, as well as those with opposite signs of the effective atomic masses in the two components.\ Stable localized composite states of miscible and immiscible types are constructed. The effect of the SOC on the immiscibility-miscibility transition in the localized complexes, which emulates the phase transition between insulating and conducting states in semiconductors, is studied.Comment: Journal of Physics B , in pres

Comment on "Spatial optical solitons in highly nonlocal media" and related papers

In a recent paper [A. Alberucci, C. Jisha, N. Smyth, and G. Assanto, Phys. Rev. A 91, 013841 (2015)], Alberucci et al. have studied the propagation of bright spatial solitary waves in highly nonlocal media. We find that the main results in that and related papers, concerning soliton shape and dynamics, based on the accessible soliton (AS) approximation, are incorrect; the correct results have already been published by others. These and other inconsistencies in the paper follow from the problems in applying the AS approximation in earlier papers by the group that propagated to the later papers. The accessible soliton theory cannot describe accurately the features and dynamics of solitons in highly nonlocal media.Comment: 2 page

Leptin immunoexpression and innervation in rat interscapular brown adipose tissue of cold-acclimated rats: the effects of L-arginine and L-NAME.

The aim of the present study was to explore the effect of nitric oxide on leptin immunoexpression and innervation in interscapular brown adipose tissue (IBAT) of room- and cold- acclimated rats. Animals acclimated both to room-temperature (22 +/- 1 degrees C) and cold (4 +/- 1 degrees C) were treated with L-arginine, a substrate for nitric oxide synthases (NOSs), or N?-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOSs, for 45 days. Leptin expression and localization in brown adipocytes was studied by immunohistochemistry, and innervation stained by the Bodian method. Strong leptin immunopositivity was observed in brown adipocytes cytoplasm of all room-acclimated groups, but nuclear leptin positivity was found only in L-NAME treated rats. In cold-acclimated control and L-NAME treated rats leptin immunopositivity was absent, while L-arginine treatment reversed the cold-induced suppression of leptin expression. Comparing to control, L-arginine, and even more L-NAME, at 22 +/- 1 degrees C induced greater innervation. In conclusion, L-arginine treatment changes leptin expression pattern on cold in rat IBAT

Quality Assurance of TPS: comparison of dose calculation for stereotactic patients in Eclipse and iPlan RT Dose

BackgroundQuality assurance (QA) in the radiation therapy planning process is essential to ensure accurate dose delivery to the patient and to minimize the possibility of accidental exposure. In recent years, several reports have been developed addressing issues related to the commissioning and quality assurance (QA) of RTPSs.AimTo evaluate the differences between dose distributions obtained with different dose calculation algorithms implemented in TPSs for stereotactic irradiation.Materials and MethodsBrainLab's iPlan v. 3.0.2 RT Dose calculates by pencil beam algorithm, while Eclipse v.7.5.18 (Varian Medical Systems) calculates by different types of pencil beam/AAA algorithms (selectable).ResultsThe largest difference was found in the lung patient, where a difference of 10.3% in the number of monitor units and 8.3% in dose to the isocentre occurred (with calculation by AAA algorithm of Eclipse in relation to iPlan PB algorithm). The average difference in all other cases (AAA compared to iPlan) was 2.2% for MUs and 1.5% for dose to the isocentre. The average difference in all other cases (PB compared to iPlan) was 1.9% for MUs and 3.2% for dose to the isocentre. When data were transferred from iPlan through DICOM RT to Eclipse, for all patients an isocentre shift was observed.ConclusionThe dose distribution calculated by three different photon calculation algorithms results in clinically significant dose differences in isodose distribution, especially in the area of high inhomogeneities

Uticaj termičkog tretmana na higijenski kvalitet mleka

In the conducted study, the influence of the pasteurization and sterilization regime on the hygienic quality of raw and thermally treated milk was analyzed. Tests were conducted in the dairy "MEGGLE Srbija, doo" in Kragujevac. The following methods of thermal treatment were applied: short-term HTST pasteurization of raw milk at 75ºC, high HTST pasteurization of raw milk at 95ºC and flow-through UHT sterilization at 139ºC of previously pasteurized milk at 75ºC. The efficiency of thermal treatments on the hygienic quality of milk was determined by the following microbiological analyzes: by determining the total number of bacteria by the indirect method by Koch and by the internal analysis method applied in the dairy "MEGGLE Srbija, doo". Based on the tests carried out, a significant reduction in the number of bacteria after the pasteurization process of milk samples and their complete inhibition after the sterilization process was determined.U sprovedenom ispitivanju analiziran je uticaj režima pasterizacije i sterilizacije na higijenski kvalitetet sirovog i termički tretiranog mleka. Ispitivanja su obavljena u mlekari „MEGGLE Srbija, d.o.o.“ u Kragujevcu. Primenjene su sledeće metode termičke obrade: kratkotrajna HTST pasterizacija sirovog mleka na 75ºC, visoka HTST pasterizacija sirovog mleka na 95ºC i protočna UHT sterilizacija na 139ºC prethodno pasterizovanog mleka na 75ºC. Efikasnost termičkih tretmana na higijenski kvalitet mleka utvrđivana je sledećim mikrobiološkim analizama: određivanjem ukupnog broja bakterija indirektnom metodom po Koch-u i metodom interne analize koja se primenjuje u mlekari „MEGGLE Srbija, d.o.o.“. Na osnovu obavljenih ispitivanja ustanovljena je značajna redukcija broja bakterija nakon procesa pasterizacije uzoraka mleka i njihova potpuna inhibicija nakon procesa sterilizacije