Karolinska Institutet

About: Karolinska Institutet is a education organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Population & Cancer. The organization has 46212 authors who have published 121142 publications receiving 6008130 citations.

MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?

Abstract: MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

A new classification of thoracolumbar injuries : The importance of injury morphology, the integrity of the posterior ligamentous complex, and neurologic status

Abstract: Study design A new proposed classification system for thoracolumbar (TL) spine injuries, including injury severity assessment, designed to assist in clinical management. Objective To devise a practical, yet comprehensive, classification system for TL injuries that assists in clinical decision-making in terms of the need for operative versus nonoperative care and surgical treatment approach in unstable injury patterns. Summary of background data The most appropriate classification of traumatic TL spine injuries remains controversial. Systems currently in use can be cumbersome and difficult to apply. None of the published classification schemata is constructed to aid with decisions in clinical management. Methods Clinical spine trauma specialists from a variety of institutions around the world were canvassed with respect to information they deemed pivotal in the communication of TL spine trauma and the clinical decision-making process. Traditional injury patterns were reviewed and reconsidered in light of these essential characteristics. An initial validation process to determine the reliability and validity of an earlier version of this system was also undertaken. Results A new classification system called the Thoracolumbar Injury Classification and Severity Score (TLICS) was devised based on three injury characteristics: 1) morphology of injury determined by radiographic appearance, 2) integrity of the posterior ligamentous complex, and 3) neurologic status of the patient. A composite injury severity score was calculated from these characteristics stratifying patients into surgical and nonsurgical treatment groups. Finally, a methodology was developed to determine the optimum operative approach for surgical injury patterns. Conclusions Although there will always be limitations to any cataloging system, the TLICS reflects accepted features cited in the literature important in predicting spinal stability, future deformity, and progressive neurologic compromise. This classification system is intended to be easy to apply and to facilitate clinical decision-making as a practical alternative to cumbersome classification systems already in use. The TLICS may improve communication between spine trauma physicians and the education of residents and fellows. Further studies are underway to determine the reliability and validity of this tool.

Adenosine receptors as drug targets — what are the challenges?

Abstract: Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.