Therapeutic goals and treatment response evaluation in moderate to severe psoriasis: an experts opinion document

Objective: To critically analyse and define therapeutic objectives, response to treatment evaluation and related decisions in psoriasis. Methods: Expert consensus meetings, a systematic and narrative reviews and a collaborative Delphi procedure were carried out. A steering committee from the Spanish Group of Psoriasis was established who based on the reviews generated a set of related statements. Subsequently, a group of 40 experts tested their agreement with the statements, through 3 Delphi rounds. Results: We found a great variability in clinical guidelines regarding to the definition of treatment goal and the response. In general, treatment failure was considered if a PASI50 is not achieved. The panel of experts agreed on (1) clearly differentiate between ideal and a realistic goals when establishing the therapeutic goal in moderate to severe psoriasis; (2) treatment goals should be in general established regardless of the type of drug for psoriasis; (3) treatment failure if PASI75 response is not reached; (4) an absolute PASI is in general preferred to the rate of PASI improvement from baseline; (5) disease characteristics, patients and physicians opinions/needs and treatment adherence influence treatment goals. Conclusions: A clear treatment decision making framework is vital to improve management of psoriasis.KEY MESSAGES Psoriasis characteristics, patients and physicians opinions/needs and treatment adherence influence treatment goals. Different disease indexes could be used to assess treatment response but absolute PASI is preferred In general psoriasis treatment failure should be considered if PASI75 response is not reachedThis project was promoted and funded by the Spanish Academy of Dermatology and Venereology (AEDV) with unrestricted grant from Leo Pharma

Photorefractive nonlinear propagation of single beams in undoped LiNbO3: Self-defocusing and beam break-up

Beam propagation in photorefractive LiNbO3 planar waveguides has been studied at different beam intensities and propagation lengths. Self-defocusing and beam break-up have been observed and explained using BPM simulations under a 2-centre band transport model

Optimising the Therapeutic Interval for Biologics in Patients with Psoriasis

In our clinical experience, more than half of patients do not present a complete response to biologic drugs, or drug loses its efficacy over time. Plasma determinations of drug and antidrug antibodies levels are an objective tool for optimisation in these patients; however, established therapeutic ranges are not suitable, so the objective of this study was to study these patients and optimise their healthcare. We have made a retrospective, observational study, using data of plasma levels of drugs and anti-drugs antibodies of infliximab, adalimumab or Etanercept, we summarise all data and make a study of sensitivity, specificity, positive and negative predictive value on current therapeutic ranges. We have found a statistically significant association between subtherapeutic levels and therapeutic failure in psoriasis treated with infliximab and adalimumab. New ranges were found with higher sensitivity than the established ones, we propose 2–10 g/mL therapeutic range for infliximab, 3–11 g/mL for adalimumab, and 1–7 g/mL for etanercept. In conclusion, levels of drug and anti-drug antibodies are a decisive tool for predicting therapeutic response. The current therapeutic ranges may have minimum values that are excessively high, owing to which lowering them significantly increases the sensitivity of the test in all cases, and negative predictive value in the case of etanercept. Further prospective studies are needed to prove the usefulness of these new ranges.9 página

Comparative theoretical analysis between parallel and perpendicular geometries for 2D particle patterning in photovoltaic ferroelectric substrates

This paper describes the dielectrophoretic potential created by the evanescent electric field acting on a particle near a photovoltaic crystal surface depending on the crystal cut. This electric field is obtained from the steady state solution of the Kukhtarev equations for the photovoltaic effect, where the diffusion term has been disregarded. First, the space charge field generated by a small, square, light spot where d < l (being d a side of the square and l the crystal thickness) is studied. The surface charge density generated in both geometries is calculated and compared as their relation determines the different properties of the dielectrophoretic potential for both cuts. The shape of the dielectrophoretic potential is obtained and compared for several distances to the sample. Afterwards other light patterns are studied by the superposition of square spots, and the resulting trapping profiles are analysed. Finally the surface charge densities and trapping profiles for different d/l relations are studied

Calculation of the spatial distribution of photovoltaic field by arbitrary 2D ilumination patterns en LiNbO3; application to photovoltaic particle trapping.

Patterns of evanescent photovoltaic field induced by illumination on a surface of lithium niobate (LN) have been calculated and compared with the experimental patterns of nano- and microparticles trapped by dielectrophoretic forces. A tool for this calculation has been developed. Calculo de distribución espacial de campo por efecto fotovoltaico con patrones arbitrarios de iluminación, en LiNbO

Calculation of dielectrophoretic potential generated under illumination patterns on x- and z-cut LiNbO3 : application to photovoltaic particle trapping

The dielectrophoretic potential generated near the surface of a z-cut LiNbO3 by photovoltaic charge transport has been calculated for first time. The procedure and results are compared with the ones corresponding to x-cut. Diferences in the position, sharpness and time evolution are reported, and their implication on particle trapping are discussed

1D and 2D neutral particle patterning by dielectrophoretic forces on z-cut Fe:LiNbO3 crystals

1D and 2D patterning of uncharged micro- and nanoparticles via dielectrophoretic forces on photovoltaic z-cut Fe:LiNbO3 have been investigated for the first time. The technique has been successfully applied with dielectric micro-particles of CaCO3 (diameter d = 1-3 μm) and metal nanoparticles of Al (d = 70 nm). At difference with previous experiments in x- and y-cut, the obtained patterns locally reproduce the light distribution with high fidelity. A simple model is provided to analyse the trapping process. The results show the remarkably good capabilities of this geometry for high quality 2D light-induced dielectrophoretic patterning overcoming the important limitations presented by previous configurations

Photovoltaic LiNbO3particles: Applications to Biomedicine/Biophotonics

Recently, a novel method to trap and pattern ensembles of nanoparticles has been proposed and tested. It relies on the photovoltaic (PV) properties of certain ferroelectric crystals such as LiNbO3 [1,2]. These crystals, when suitably doped, develop very high electric fields in response to illumination with light of suitable wavelength. The PV effect lies in the asymmetrical excitation of electrons giving rise to PV currents and associated space-charge fields (photorefractive effect). The field generated in the bulk of the sample propagates to the surrounding medium as evanescent fields. When dielectric or metal nanoparticles are deposited on the surface of the sample the evanescent fields give rise to either electrophoretic or dielectrophoretic forces, depending on the charge state of the particles, that induce the trapping and patterning effects [3,4]. The purpose of this work has been to explore the effects of such PV fields in the biology and biomedical areas. A first work was able to show the necrotic effects induced by such fields on He-La tumour cells grown on the surface of an illuminated iron-doped LiNbO3 crystal [5]. In principle, it is conceived that LiNbO3 nanoparticles may be advantageously used for such biomedical purposes considering the possibility of such nanoparticles being incorporated into the cells. Previous experiments using microparticles have been performed [5] with similar results to those achieved with the substrate. Therefore, the purpose of this work has been to fabricate and characterize the LiNbO3 nanoparticles and assess their necrotic effects when they are incorporated on a culture of tumour cells. Two different preparation methods have been used: 1) mechanical grinding from crystals, and 2) bottom-up sol-gel chemical synthesis from metal-ethoxide precursors. This later method leads to a more uniform size distribution of smaller particles (down to around 50 nm). Fig. 1(a) and 1(b) shows SEM images of the nanoparticles obtained with both method. An ad hoc software taking into account the physical properties of the crystal, particullarly donor and aceptor concentrations has been developped in order to estimate the electric field generated in noparticles. In a first stage simulations of the electric current of nanoparticles, in a conductive media, due to the PV effect have been carried out by MonteCarlo simulations using the Kutharev 1-centre transport model equations [6] . Special attention has been paid to the dependence on particle size and [Fe2+]/[Fe3+]. First results on cubic particles shows large dispersion for small sizes due to the random number of donors and its effective concentration (Fig 2). The necrotic (toxicity) effect of nanoparticles incorporated into a tumour cell culture subjected to 30 min. illumination with a blue LED is shown in Fig.3. For each type of nanoparticle the percent of cell survival in dark and illumination conditions has been plot as a function of the particle dilution factor. Fig. 1a corresponds to mechanical grinding particles whereas 1b and 1c refer to chemically synthesized particles with two oxidation states. The light effect is larger with mechanical grinding nanoparticles, but dark toxicity is also higher. For chemically synthesized nanoparticles dark toxicity is low but only in oxidized samples, where the PV effect is known to be larger, the light effect is appreciable. These preliminary results demonstrate that Fe:LiNbO· nanoparticles have a biological damaging effect on cells, although there are many points that should be clarified and much space for PV nanoparticles optimization. In particular, it appears necessary to determine the fraction of nanoparticles that become incorporated into the cells and the possible existence of threshold size effects. This work has been supported by MINECO under grant MAT2011-28379-C03

Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B) ⁄ ) mice maintained on mixed genetic background (C57Bl ⁄ 6J · 129Sv ⁄ J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B) ⁄ ) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1a wereobserved only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with agingassociated obesity, but not in PTP1B) ⁄ ) animals. Leanness in 16- month-old PTP1B) ⁄ ) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16- month-old control mice; however, studies with the hyperinsulinemic– euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were upregulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt ⁄ Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependentT2DMThis work was supported by grants from Ministerio de Ciencia e Innovación (Spain) SAF2009-08114 and (to A.M.V.), BFU2008- 04901-C03-02 and 03 (to M.R and J.M.C., respectively), BFU2008-01283 (to M.V), Comunidad de Madrid S2010/BMD- 2423 and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (Instituto Salud Carlos III). CBMSO is recipient of institutional aid from Ramón Areces Foundation. We also acknowledge grants NIH-R01 DK080756, ADA 7-07-RA-80, and NIH U24-DK093000 (to J.K.K.) and UMass Mouse Phenotyping Center supported by UMass Diabetes and Endocrinology Research Center Grant (DK32520) and EFSD/Amylin Programme 2011 grant (to A.M.V.)

Bimekizumab efficacy and safety through two years in patients with moderate psoriasis: Analysis of pooled data from five phase 3/3b clinical trials

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