Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKε-mediated IRF activation

Viruses are detected by different classes of pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-like helicases. Engagement of PRRs leads to activation of interferon (IFN)-regulatory factor 3 (IRF3) and IRF7 through and TBK1 and consequently IFN-β induction. Vaccinia virus (VACV) encodes proteins that manipulate host signalling, sometimes by targeting uncharacterised proteins. Here, we describe a novel VACV protein, K7, which can inhibit PRR-induced IFN-β induction by preventing TBK1/IKKε-mediated IRF activation. We identified DEAD box protein 3 (DDX3) as a host target of K7. Expression of DDX3 enhanced Ifnb promoter induction by TBK1/IKKε, whereas knockdown of DDX3 inhibited this, and virus- or dsRNA-induced IRF3 activation. Further, dominant-negative DDX3 inhibited virus-, dsRNA- and cytosolic DNA-stimulated Ccl5 promoter induction, which is also TBK1/IKKε dependent. Both K7 binding and enhancement of Ifnb induction mapped to the N-terminus of DDX3. Furthermore, virus infection induced an association between DDX3 and IKKε. Therefore, this study shows for the first time the involvement of a DEAD box helicase in TBK1/IKKε-mediated IRF activation and Ifnb promoter induction

Efficiency of Polish metallurgical industry based on data envelopment analysis

The main purpose of this paper is to compare the technical efficiency of 12 sectors manufacturing basic metals and metal products in Poland. This article presents the use of Data Envelopment Analysis models, to determine overall technical efficiency, pure technical efficiency and scale efficiency of metallurgical branches in Poland. The average technical efficiency of metallurgical industry in Poland was quite high. The analysis gives a possibility to create a ranking of sectors. Three branches were found to be fully efficient: manufacture of basic iron and steel and of ferroalloys, manufacture of basic precious and other non - ferrous metals and manufacture of tubes, pipes, hollow profiles and related fittings, of steel. The results point out the reasons of the inefficiency and provide improving directions for the inefficient sectors.Web of Science55224824

Multi-Criteria Decision Analysis (MCDA) Models in Health Technology Assessment of Orphan Drugs—a Systematic Literature Review. Next Steps in Methodology Development?

Background: Multi-criteria decision analysis (MCDA) is a decision-making tool that can take into account multidimensional factors and enables comparison of (medical) technologies by combining individual criteria into one overall appraisal. The MCDA approach has slowly gained traction within Health Technology Assessment (HTA) and its elements are gradually being incorporated into HTA across Europe. Several groups of scientists have proposed MCDA approaches targeted toward orphan drugs and rare diseases by including criteria specific to rare diseases. The goal of this article is to provide an overview of the current state of knowledge and latest developments in the field of MCDA in HTA for orphan drugs, to review existing models, their design characteristics, as well as to identify opportunities for further model improvement.Methods: A systematic literature search was conducted in January 2018 using four databases: MEDLINE (Pubmed), EBSCO HOST, EMBASE, and Web of science to find publications related to use of MCDA in the rare disease field (keywords: MCDA/orphan drug/rare disease and synonyms). Identified MCDA models were analyzed, e.g., structure, criteria, scoring, and weighting methodology.Results: Two hundred and eleven publications were identified, of which 29 were included after removal of duplicates. 9 authors developed own MCDA models, 7 of which based on literature reviews intended to identify the most important and relevant decision criteria in the model. In 13 publications (8 models) weights were assigned to criteria based on stakeholder input. The most commonly chosen criteria for creation of the MCDA models were: comparative effectiveness/efficacy, the need for intervention, and disease severity. Some models have overlapping criteria, especially in the treatment cost and effectiveness areas.Conclusions: A range of MCDA models for HTA have been developed, each with a slightly different approach, focus, and complexity, including several that specifically target rare diseases and orphan drug appraisal. Models have slowly progressed over the years based on pilots, stakeholder input, sharing experiences and scientific publications. However, full consensus on model structure, criteria selection and weighting is still lacking. A simplification of the MCDA model approach may increase its acceptance. A multi-stakeholder discussion on fundamental design and implementation strategies for MCDA models would be beneficial to this end

Reakcje anafilaktyczne jako przyczyna hospitalizacji — doświadczenia ośrodka akademickiego

Introduction: In recent years, more and more often the increase in incidence of allergies is observed. According to the WHO, they are getting the fourth position amongst the most frequent diseases after cancers, cardiovascular diseases and AIDS. Anaphylaxis is a severe, life-threatening, systemic or generalised immediate hypersensitivity reaction. The analysis of the causes and the clinical picture of anaphylaxis in patients treated at single academic hospital centre was the purpose of the study. Material and methods: The study was based on retrospective analysis of case records of the patients hospitalised at the Chair and Department of Allergology, Clinical Immunology and Internal Diseases, the Jan Biziel University Hospital in Bydgoszcz in the years 2005−2010. 132 patients, in whom anaphylactic reaction appeared, were analysed. The examined population included 70 men and 62 women at 16−95 years of age. Results: The conducted examinations allowed to obtain information about the causes and the course of anaphylactic reactions. The problem of hypersensitivity to substances of various origin (biological or synthetic) can concern everyone irrespective of sex and age. Nevertheless, the phenomenon of anaphylaxis more often occurred in the examined men than women. Most cases of anaphylactic reactions were reported in the 26−50 age range. Based on the presented results, no regularity was observed in anaphylaxis clinical picture and its causative factor. Conclusions: It is difficult to forecast the course of the reaction based on the causative factor, for anaphylactic reaction is characterised by a great individual changeability and intensity of the first symptoms.Wstęp: Z roku na rok coraz częściej obserwuje się wzrost zachorowań na choroby alergiczne. Według Światowej Organizacji Zdrowia zajmują one 4 pozycję wśród najczęstszych schorzeń po nowotworach, chorobach układu krążenia i AIDS. Anafilaksja to ciężka, zagrażająca życiu, systemowa lub uogólniona, natychmiastowa reakcja nadwrażliwości. Celem pracy jest analiza przyczyn i obrazu klinicznego reakcji anafilaktycznych u pacjentów hospitalizowanych w ośrodku akademickim. Materiał i metody: Badanie przeprowadzono na podstawie retrospektywnej analizy historii chorób pacjentów hospitalizowanych w Katedrze i Klinice Alergologii, Immunologii Klinicznej i Chorób Wewnętrznych Szpitala Uniwersyteckiego im. Jana Biziela w Bydgoszczy w latach 2005−2010. Przeanalizowano 132 historie chorób pacjentów, u których wystąpiła reakcja anafilaktyczna. Badana populacja obejmowała 70 mężczyzn i 62 kobiety w przedziale wiekowym 16−95 lat. Wyniki: Przeprowadzone badania pozwoliły uzyskać informacje o przyczynach i przebiegu reakcji anafilaktycznych. Problem nadwrażliwości na substancje różnego pochodzenia (biologiczne czy syntetyczne) mogą dotyczyć każdego człowieka niezależnie od płci i wieku. Zjawisko anafilaksji w analizowanych historiach chorób częściej występowało jednak u mężczyzn niż u kobiet. Przedział wiekowy, w którym stwierdzono najwięcej przypadków reakcji anafilaktycznych, to 26.– 50. rok życia. Na podstawie przedstawionych wyników zaobserwowano brak prawidłowości pomiędzy obrazem klinicznym anafilaksji a czynnikiem ją wywołującym. Wnioski: Istnieją poważne trudności w przewidywaniu przebiegu reakcji na podstawie czynnika sprawczego, tym bardziej że cechuje ją duża indywidualna zmienność w pojawianiu się pierwszych symptomów i stopnia ich nasilenia

Dislocation of the mandible in a 47 year old patient

Dislocation of mandible is relatively uncommon disorder of temporomandibular joints. Disorder can occur during extreme dilation of mouth such as yawing, during dental treatments or endoscopic examination. 47- year old patient was admitted to the Department of Maxillo-facial Surgery in case of bilateral mandible dislocation. In this case the reposition in general anaesthesia was performed but ended up with failure

Planthoppers and leafhoppers (Hemiptera: Fulgoromorpha et Cicadomorpha) of the Eastern Beskidy Mountains

The results on studies of the fauna of Fulgoromorpha and Cicadomorpha conducted in 2013 and 2014, in the south-western part of the Eastern Beskidy Mts. are presented. A list of 64 species is given (38 are new to this zoogeographical region). Most of the species reported (69%) belong to the family Cicadellidae. Insects are analyzed in terms of their chorology, trophic relationships, humidity preferences and frequency of occurrence

Colorectal cancer-derived microvesicles modulate differentiation of human monocytes to macrophages

BACKGROUND: Tumour-derived microvesicles (TMVs) are important players in tumour progression, modulating biological activity of immune cells e.g. lymphocytes, monocytes and macrophages. This phenomenon is particularly interesting in the progression of colon cancer, as macrophages in this type of tumour are relevant for the recovery processes. In the present study, the role of colon cancer cell-derived microvesicles in monocyte differentiation and activity profile (polarization) was investigated. METHODS: Monocyte-derived macrophages (MDM) were differentiated in vitro in the presence of TMVs obtained from colon cancer: Caco-2, SW620, LoVo or SW480 cell lines and analysed according to their morphology and biological functions, as defined by cytokine secretion, reactive oxygen intermediate (ROI) production and cytotoxic activity against respective colon cancer cells. RESULTS: Monocytes differentiated with TMVs exhibited morphological and phenotypical characteristics of macrophages. An early contact (beginning with the first day of the in vitro culture) of monocytes with TMVs resulted in increased IL-10 secretion and only slightly elevated TNF release. Early, or prolonged contact resulted in low ROI production and low cytotoxicity against tumour cells. On the other hand, late contact of MDM with TMVs, stimulated MDM to significant TNF and IL-12 secretion, ROI production and enhanced cytotoxicity against tumour cells in vitro. In addition, differences in MDM response to TMVs from different cell lines were observed (according to cytokine secretion, ROI production and cytotoxicity against tumour cells in vitro). Biological activity, STATs phosphorylation and microRNA profiling of MDMs indicated differences in their polarization/activation status which may suggest mixed polarization type M1/M2 with the predominance of proinflammatory cells after late contact with TMVs. CONCLUSIONS: Macrophage activity (polarization status) may be regulated by contact with not only tumour cells but also with TMVs. Their final polarization status depends on the contact time, and probably on the vesicle “cargo”, as signified by the distinct impact of TMVs which enabled the switching of MDM maturation to regulatory macrophages

Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores

Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.</p

Uterine leiomyomas: correlation between histologic composition and stiffness via magnetic resonance elastography — a Pilot Study

Objectives: To evaluate magnetic resonance elastography as a tool for characterizing uterine leimyomas.Material and methods: At total of 12 women with symptomatic leiomyomas diagnosed in physical and ultrasound examinationswere enrolled in this pilot study. Before surgery, all patients underwent magnetic resonance elastography ofthe uterus using a 1.5 T MR whole-body scanner (Optima, GE Healthcare, Milwaukee, WI, USA). Surgical specimens wereforwarded for histological examination. The findings were allocated into 3 categories depending on the percentage contentof connective tissue: below 15%, from 15 to 30% and more than 30%. The median stiffness of leiomyomas for each of thegroup was calculated. The U-Mann Whitney test was used for statistical analysis.Results: The stiffness of the leiomyomas ranged between 3.7–6.9 kPa (median value 4.9 kPa). The concentration of extracellularcomponents in the leiomyomas did not exceed 40%. An increasing trend of the stiffness with the growing percentageof extracellular component was observed. Stiffness of the leiomyomas obtained by MRE varies depending on microscopiccomposition.Conclusions: The value of stiffness shows a trend of increasing with the percentage of extracellular component of theleiomyoma. Further studies are required to assess the usefulness of MRE in diagnostics of uterine leiomyomas

Dislocation of mandible in 48 year old patient - the continuation of a therapy

Dislocation of a temporomandible joint (TMJ) is a rare disfunction, which has multiform background divided into imbalance in the function of neuromascular component or structural deficit. A 48-year-old woman was admitted to the Department of Maxillo-Facial Surgery of the Medical University of Lublin due to continuation of a treatment of TMJ dislocation. Previous hospitalization was performed a few months earlier. Reposition in general anaesthesia was used as a treatment, however it ended up with defeat. Current hospitalization with open surgery reposition was scheduled. Bilateral condylectomy was prosecuted. After surgery correct movability and proper anterior-posterior placement of mandible were achieved