Update of the management of chronic psoriasis: new approaches and emerging treatment options

Psoriasis is a common, chronic inflammatory skin disease which is associated with a number of significant co-morbidities including: impairment of quality of life; cardiovascular disease; and a seronegative arthritis known as psoriatic arthritis. Our understanding of the pathogenesis of psoriasis has developed at a remarkable rate in recent years. These new insights have significantly changed our perception of the condition and have led to the development of several new treatment strategies. Biological agents have proved a major step forward in therapeutic options for psoriasis. The ability to clear, or almost clear, cutaneous disease has changed the outcomes and expectations of many patients with this disease. The impact on both physical and psychological health may be great. This review covers the clinical features and management of psoriasis with specific reference to new therapeutic options

X-ray observations of the galaxy cluster PKS 0745-191: To the virial radius, and beyond

We measure X-ray emission from the outskirts of the cluster of galaxies PKS 0745-191 with Suzaku, determining radial profiles of density, temperature, entropy, gas fraction, and mass. These measurements extend beyond the virial radius for the first time, providing new information about cluster assembly and the diffuse intracluster medium out to ~1.5 r_200, (r_200 ~ 1.7 Mpc ~ 15'). The temperature is found to decrease by roughly 70 per cent from 0.3-1 r_200. We also see a flattening of the entropy profile near the virial radius and consider the implications this has for the assumption of hydrostatic equilibrium when deriving mass estimates. We place these observations in the context of simulations and analytical models to develop a better understanding of non-gravitational physics in the outskirts of the cluster.Comment: 10 pages, 11 figures, accepted to MNRAS; expanded discussion of analysis and uncertainties, results qualitatively unchange

Inhibition of vascular endothelial growth factor‐A downregulates angiogenesis in psoriasis: A pilot study

BackgroundVascular Endothelial Growth Factor (VEGF)-A-mediated angiogenesis participates in the pathogenesis of psoriasis, thus inviting the hypothesis that anti-VEGF-A therapy could be beneficial in psoriasis. While anti-angiogenic agents are used in oncology and ophthalmology, these therapeutic strategies remain unexplored for the management of psoriasis.ObjectiveOur objective was to investigate ex vivo how VEGF-A blockade impacts blood vessels, epidermis and immune cells in organ-cultured plaque and non-lesional skin from patients with psoriasis.MethodsSkin biopsies from patients with psoriasis (n = 6; plaque and non-lesional skin) and healthy controls (n = 6) were incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or a human IgG1 isotype control for 72-h in serum-free organ culture. CD31/LYVE-1, Ki-67, and mast cell tryptase expression were assessed by quantitative immunohistomorphometry. VEGF-A levels in plasma, PBMCs and skin culture supernatants were measured.ResultsInhibition of VEGF-A blocked all free VEGF-A ex vivo, reduced blood vessel area and the number of blood vessel endothelial cells in plaques of psoriasis (*p < 0.05). The treatment effect correlated significantly with levels of VEGF-A in organ culture supernatants (r = 0.94; *p < 0.05) from plaque skin and with plasma levels of VEGF-A from patients with psoriasis (r = 0.943; *p = 0.017).ConclusionsThese ex vivo data are the first studies to objectively investigate the potential of VEGF-A inhibition as a novel adjuvant treatment strategy for psoriasis. Taken together, our data encourage further investigation by clinical trial to explore whether downregulating pathological angiogenesis has clinical utility, especially in patients with severe psoriasis or those with elevated levels of VEGF-A in plasma and/or skin

Analytical Method of Approximating the Motion of a Spinning Vehicle with Variable Mass and Inertia Properties Acted Upon by Several Disturbing Parameters

An analytical method has been developed which approximates the dispersion of a spinning symmetrical body in a vacuum, with time-varying mass and inertia characteristics, under the action of several external disturbances-initial pitching rate, thrust misalignment, and dynamic unbalance. The ratio of the roll inertia to the pitch or yaw inertia is assumed constant. Spin was found to be very effective in reducing the dispersion due to an initial pitch rate or thrust misalignment, but was completely Ineffective in reducing the dispersion of a dynamically unbalanced body

Impaired Langerhans cell migration in psoriasis

We have examined whether psoriasis is associated with systemic effects on epidermal Langerhans cell (LC) function and, specifically, the migration of LCs from the skin. Compared with normal skin, the frequency and morphology of epidermal LCs in uninvolved skin from patients with psoriasis was normal. However, mobilization of these cells in response to stimuli that normally induce migration (chemical allergen, tumor necrosis factor α [TNF-α], and interleukin-1β [IL-1β]) was largely absent, despite the fact that treatment with TNF-α and IL-1β was associated with comparable inflammatory reactions in patients and controls. The failure of LC migration from uninvolved skin was not attributable to altered expression of receptors for IL-1β or TNF-α that are required for mobilization, nor was there an association with induced cutaneous cytokine expression. Although a role for altered dynamics of LC migration/turnover has not been formally excluded, these data reveal a very consistent decrement of LC function in psoriasis that may play a decisive role in disease pathogenesis

Who stands in the way of women? Open vs. closed lists and candidate gender in Estonia

The literature on women's descriptive representation has looked at the debate on open and closed lists as a choice between electoral systems. This article instead focuses on whether voters or the parties are biased against female candidates. Using data from six Estonian elections, the article finds that voters are not consistently biased against female candidates and open lists do not necessarily decrease women's representation. However, unknown and non-incumbent female candidates fare significantly worse than similar men. The analysis also shows that parties do not place women in electable positions on closed lists, and closed lists do not improve women's representation

The RCSB Protein Data Bank: views of structural biology for basic and applied research and education.

The RCSB Protein Data Bank (RCSB PDB, http://www.rcsb.org) provides access to 3D structures of biological macromolecules and is one of the leading resources in biology and biomedicine worldwide. Our efforts over the past 2 years focused on enabling a deeper understanding of structural biology and providing new structural views of biology that support both basic and applied research and education. Herein, we describe recently introduced data annotations including integration with external biological resources, such as gene and drug databases, new visualization tools and improved support for the mobile web. We also describe access to data files, web services and open access software components to enable software developers to more effectively mine the PDB archive and related annotations. Our efforts are aimed at expanding the role of 3D structure in understanding biology and medicine

Lack of Durable Cross-Neutralizing Antibodies Against Zika Virus from Dengue Virus Infection

Cross-reactive antibodies elicited by dengue virus (DENV) infection might affect Zika virus infection and confound serologic tests. Recent data demonstrate neutralization of Zika virus by monoclonal antibodies or human serum collected early after DENV infection. Whether this finding is true in late DENV convalescence (>6 months after infection) is unknown. We studied late convalescent serum samples from persons with prior DENV or Zika virus exposure. Despite extensive cross-reactivity in IgG binding, Zika virus neutralization was not observed among primary DENV infections. We observed low-frequency (23%) Zika virus cross-neutralization in repeat DENV infections. DENV-immune persons who had Zika virus as a secondary infection had distinct populations of antibodies that neutralized DENVs and Zika virus, as shown by DENV-reactive antibody depletion experiments. These data suggest that most DENV infections do not induce durable, high-level Zika virus cross-neutralizing antibodies. Zika virus–specific antibody populations develop after Zika virus infection irrespective of prior DENV immunity

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.</p

Computer-assisted estimates of lesion sizes and shrinkage in denervated areas from receptor autoradiograms using a digitizing tablet

Area measurements taken from receptor autoradiograms were employed to estimate the size of striatal kainate lesions and the amount of shrinkage in deafferented projection areas. There was no significant difference in the size of substantia nigra (SN) on the denervated side as compared to the intact side one week and one month after unilateral striatal lesions. Although there was no change in the size of globus pallidus (GP) on the lesioned side one week after the lesion, there was a 17% shrinkage one month after the lesion. At 3-4 months after the lesion, the amount of shrinkage was 19% in SN and 16% in GP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24901/1/0000328.pd