Neue Entwicklungen in der systemischen Psoriasistherapie

The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T‐cell‐mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T‐lymphocytes, the inhibition of antigen presentation and thus the regulation of T‐cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II‐ and phase III‐studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.     

Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart

We have identified the mouse and rat homologs of human interleukin-22 receptor alpha 2 (IL-22R alpha 2) and compared the localization, structure, and expression of the encoding murine and human genes. The mouse IL-22R alpha 2-encoding gene is located on chromosome 10A3 between, like in human, the genes for interferon-gamma R1 and IL-20R1. It spans a region of approximately 10 kb therefore being three times shorter than the human gene. Although the overall gene structure in both species is similar, the mouse gene lacks a counterpart to the third coding exon of the human gene known to be alternatively spliced. Like in human, mouse and rat IL-22R alpha 2 exist only as soluble receptors as deduced from the lack of transmembrane and intracellular domains encoding sequences. Quantitative expression analyses showed, analogically to the human system, a limited tissue distribution of mouse IL-22R alpha 2 mRNA. Differential modulation of IL-22R alpha 2 mRNA expression was observed upon systemic inflammation in mice in spleen, thymus, and lymph node.     

Frequency and Predictors of Non-compliance to Dietary Recommendations Among Hypertensive Patients

Compliance to dietary recommendations among hypertensive people is a major health care issue. Non-compliance can nullify the effects of even the most scientific and optimum treatment plan. The main aim of this study was to determine the frequency and predictors of non-adherence in our region. We also investigated the possible factors based on patient opinions that could increase compliance. A sample of 400 adult patients, diagnosed with hypertension for at least 3 years, who visited Civil Hospital during the time period April–June 2013 were included in this cross sectional study. Patient data and opinions were collected by two trained interviewers using a pre-coded questionnaire. Compliance was assessed based on patients self report. More than three quarters (n = 310, 77.5 %) of the hypertensive patients were non-compliant. More than one social gathering in a week, peer-influence, no friends to follow the recommended diet plan and lack of believe regarding diet as an effective measure to control blood pressure were found to be the significant predictors of non-compliance (P values <0.0001). Counseling was thought to be the most effective way by the patients to increase adherence. Non-compliance to dietary recommendations is a major problem prevalent especially in Pakistan. There is an urgent need for doctors and nurses to counsel their patients effectively to prevent future morbidities and mortalities because of non-compliance.     

Emergence of novel coronavirus and progress toward treatment and vaccine

In late December 2019, a group of patients was observed with pneumonia‐like symptoms that were linked with a wet market in Wuhan, China. The patients were found to have a novel coronavirus genetically related to a bat coronavirus that was termed SARS‐CoV‐2. The virus gradually spread worldwide and was declared a pandemic by WHO. Scientists have started trials on potential preventive and treatment options. Currently, there is no specific approved treatment for SARS‐CoV‐2, and various clinical trials are underway to explore better treatments. Some previously approved antiviral and other drugs have shown some in vitro activity. Here we summarize the fight against this novel coronavirus with particular focus on the different treatment options and clinical trials exploring treatment as well as work done toward development of vaccines.     

Dissociated glucocorticoid receptor ligands: compounds with an improved therapeutic index

Glucocorticoids are well known for their potent anti-inflammatory and immunosuppressive actions. However, due to their potential to induce serious undesired effects, there is a great need for compounds with a better therapeutic index. Recent discoveries have demonstrated that the positive and negative regulation of gene expression via the glucocorticoid receptor is mediated by different mechanisms. This regulation is predominantly responsible for either anti-inflammatory effects or certain side effects, depending on whether it is negative or positive. Compounds that preferentially induce transrepression rather than transactivation should be superior to classical glucocorticoids. Indeed, proof of concept has been recently achieved with such selective glucocorticoid receptor agonists.     

A novel E1A-E1B mutant adenovirus induces glioma regression in vivo

Malignant gliomas are the most frequently occurring primary brain tumors and are resistant to conventional therapy. Conditionally replicating adenoviruses are a novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses have been reported recently and E1A mutant replication-competent adenoviruses are in advanced preclinical testing. Here we constructed a novel replication-selective adenovirus (CB1) incorporating a double deletion of a 24 bp Rb-binding region in the E1a gene, and a 903 bp deleted region in the E1b gene that abrogates the expression of a p53-binding E1B-55 kDa protein. CB1 exerted a potent anticancer effect in vitro in U-251 MG, U-373 MG, and D-54 MG human glioma cell lines, as assessed by qualitative and quantitative viability assays. Replication analyses demonstrated that CB1 replicates in vitro in human glioma cells. Importantly, CB1 acquired a highly attenuated replicative phenotype in both serum-starved and proliferating normal human astrocytes. In vivo experiments using intracranially implanted D-54 MG glioma xenografts in nude mice showed that a single dose of CB1 (1.5 x 10(8) PFU/tumor) significantly improved survival. Immunohistochemical analyses of expressed adenoviral proteins confirmed adenoviral replication within the tumors. The CB1 oncolytic adenovirus induces a potent antiglioma effect and could ultimately demonstrate clinical relevance and therapeutic utility.     

Techniques: species' finest blend--humanized mouse models in inflammatory skin disease research

Differences between humans and mice often hamper the transfer of promising results from the bench to the clinic. For ethical reasons, research that involves patients is limited, and so there is an urgent need for models that mimic the human situation as closely as possible. In recent years, there has been considerable progress in generating humanized mouse models, and their application to drug discovery has proved fruitful. So, how can mice be humanized, and how can humanized mice be employed in immunology research and drug discovery? In this article, we answer these questions, focusing on T-cell-mediated skin diseases as an example.     

Selectin and selectin ligand binding: a bittersweet attraction

Inhibition of leukocyte migration into target organs has long been an attractive, though challenging, basis for anti-inflammatory strategies. However, to date, the manipulation of leukocyte rolling along blood vessels has not yielded successful new therapies. An important study may now open new avenues in this exciting field of anti-inflammatory therapies by introducing a putative inhibitor of poly-N-acetyllactosamine biosynthesis that affects selectin ligand activity and shows efficacy in a rodent skin inflammation model.