Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration

Peer reviewe

Preliminary report:osteoarthritis and rheumatoid arthritis synovial fluid increased osteoclastogenesis In vitro by monocyte differentiation pathway regulating cytokines

Abstract Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are common joint diseases associated with changes in local, as well as systemic bone structure and osteoclast function. We investigated how the different soluble inflammatory stimuli in these diseases can affect osteoclastogenesis and bone resorption in vitro. Methods: Human peripheral blood mononuclear cell-derived osteoclasts were cultured on bone slices with serum from treatment-naïve RA patients and healthy controls and with synovial fluid samples acquired from RA and OA patients. The concentrations of 29 different cytokines and related proteins, including RANKL and OPG, were analyzed in the fluids tested. Results: RA serum and synovial fluid increased both osteoclastogenesis and bone resorption. Osteoclastogenesis and activity increased more in the cultures containing OA than RA synovial fluid. The osteoclasts cultured in different culture media exhibited different phenotypes, especially the cells cultured with OA synovial fluid were generally larger and had more nuclei. A general increase in proinflammatory cytokines in RA synovial fluid and serum was found. Surprisingly, OA synovial fluid showed lower levels of osteoclastogenesis inhibiting cytokines, such as IL-4 and IL-10, than RA synovial fluid, which at least partly explains more pronounced osteoclastogenesis. No significant difference was found in RANKL or OPG levels. Conclusions: The proinflammatory stimulus in OA and RA drives the monocyte differentiation towards inflammatory osteoclastogenesis and altered osteoclast phenotype

1,25(OH)₂D₃ and its analogue calcipotriol inhibit the migration of human synovial and mesenchymal stromal cells in a wound healing model:a comparison with glucocorticoids

Abstract Vitamin D analogue calcipotriol is currently used in the local treatment of psoriasis. However, it also has antiproliferative and anti-inflammatory effects in the cells of the joint — suggesting a possible benefit in local treatment of arthritis. In this study, calcipotriol was studied in different in vitro methods to find out its effect on synovial and mesenchymal stromal cells. Primary human cell lines of osteoarthritis or rheumatoid arthritis patients (five mesenchymal stromal cells, MSC, and four synovial stromal cells, SSC) were cultured to study migration and proliferation of the cells in a wound healing model. The media was supplemented with calcipotriol, 1,25(OH)2D3, dexamethasone, betamethasone, methylprednisolone or control solution in 1–100 nM concentrations. To see possible toxic effects of calcipotriol, concentrations up to 10 µM in SSCs and MSCs were studied in apoptosis and necrosis assays in four cell lines. Calcipotriol and 1,25(OH)₂D₃, as well as the three glucocorticoids, reduced the migration of both SSCs and MSCs. In SSCs, the effect of calcipotriol and 1,25(OH)₂D₃ was at least as effective as with glucocorticoids, while with MSCs, the glucocorticoids were stronger inhibitors of migration. The antimigratory of calcipotriol and 1,25(OH)₂D₃ was consistently maintained in 10 µM and 1 µM. Calcipotriol was not toxic to MSCs and SSCs up to concentrations of 10 µM. Calcipotriol, as well as 1,25(OH)₂D₃, exerts antimigratory and antiproliferative effects on human SSCs and MSCs of the joint. These effects are not caused by apoptosis or necrosis. Both calcipotriol and 1,25(OH)₂D₃ have similar effects as glucocorticoids without apparent toxicity, suggesting that calcipotriol might be an eligible candidate to the local treatment of arthritis with a broad therapeutic window

Hyperpolarised NMR to aid molecular profiling of electronic cigarette aerosols

Abstract Signal amplification by reversible exchange (SABRE) hyperpolarisation is used to enhance the NMR signals of nicotine and acrolein in methanol-d₄ solutions of electronic cigarette aerosols. Consequently, detection of 74 μM nicotine is possible in just a single scan ¹H NMR spectrum. The first example of an aldehyde hyperpolarised using SABRE is demonstrated and we work towards novel real-world applications of SABRE-hyperpolarised NMR for chemical analysis

Retention of metals in periprosthetic tissues of patients with metal-on-metal total hip arthroplasty is reflected in the synovial fluid to blood cobalt transfer ratio in the presence of a pseudotumour

Abstract Background: Modern metal-on-metal (MOM) arthroplasties were performed for over a decade before alarming reports of adverse metal reactions dramatically reduced their use. Failures are seen more often with high-wearing implants, but also well-positioned components with more favourable wear patterns can cause problems. There are no specific clinical indicators that could help us to predict the prognosis of these implants. For this reason, we still need more information on the effect of underlying factors that contribute to this process. Methods: In this prospective cohort study, we investigated how cup orientation and type of pseudotumour determined by the Hart classification effect the distribution of metals in blood, synovial fluid and tissues surrounding the metal-on-metal hip prosthesis in revision surgery patients. One thousand two hundred twenty-nine metal-on-metal hip patients were screened and of those, 60 patients that had a revision surgery due to adverse metal reaction were included. Whole blood, synovial fluid and synovial/pseudotumour tissue samples were analysed for metal ion concentrations (Co, Cr, Mo and Ti). Results: The lowest metal concentrations were found when both cup anteversion and inclination were optimal, and the highest when both were suboptimal. Suboptimal anteversion alone raised Cr-ion concentrations more than suboptimal inclination. The concentrations of metals in blood, synovial fluid or synovial soft tissue were the same in patients with and without a pseudotumour, but the relative transfer percentage of cobalt from synovial fluid to blood was higher in patients with a pseudotumour. Conclusions: The implant orientation alone does not explain the metal concentrations found in tissues or distribution of metals between different tissues. The accumulation of metals in periprosthetic soft tissues increase the total metal load, and in the presence of a pseudotumour this is reflected in the transfer ratio of Co from synovial fluid to the blood. The total metal load of the pseudotumour tissue should be defined in future studies to determine if this will provide new insights for clinical practice

A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes

Abstract Background: Pathogenic variants in the CEP78 gene can present as atypical Usher syndrome or as retinitis pigmentosa. Here, we present a review of all reported cases of CEP78 variants in the literature to date and present a novel variant of CEP78, c.1261_1262delinsA, in a consanguineous northern Finnish family with two individuals. Materials and methods: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on CEP78 was published in the year 2007, and the publications from the years 2007–2021 were included. Results: A large gene panel identified a homozygous CEP78 c.1261_1262delinsA variant in two affected siblings. In addition to the classical signs of retinitis pigmentosa, both siblings had large round atrophic spots in the mid periphery, and hyperautofluorescence of the macula. Patient 1 had age-related hearing impairment; patient 2 had normal hearing. In total, 20 articles have been published about CEP78. Eight of these papers report patient data with the affected individuals typically having retinal dystrophy combined with sensorineural hearing impairment, classified as atypical Usher syndrome. Conclusions: Here, we present a comprehensive review of CEP78 and expand the knowledge of pathogenic CEP78 variants and the phenotypic variety

Increased n-6 polyunsaturated fatty acids indicate pro- and anti-inflammatory lipid modifications in synovial membranes with rheumatoid arthritis

Abstract Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools

In utero deposition of trace elements and metals in tissues

Abstract Introduction: All animals, including humans, are exposed to heavy metals which are known to accumulate in different tissues, especially in bone. During pregnancy, the maternal bone turnover is increased and the metals in the mother’s body can be mobilized into the bloodstream. Heavy metals in maternal blood are known to pass through the placenta to the fetal blood and finally, deposited to bone tissue. However, there are no studies on the concentration of metals in the fetal solid tissues and until now, the rate of metal transfer from mother to fetus is not exactly known. Materials and methods: Samples of the blood, liver, placenta, and three different bones were collected from 17 pregnant ewes and their 27 fetuses. The animals had no known exposure to heavy metals. The concentrations of Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Sn, Sr, Te, Ti, Tl, V, and Zn were analyzed using ICP-MS. Results and discussion: The concentration of Sb, Sn, Te, and Tl were under the detection limit in all the samples. The other metals were found in all maternal and fetal tissues, suggesting that all detectable metals cross the placenta. Blood concentrations were low compared to solid tissue concentrations. The concentrations of essential elements varied between maternal and fetal tissues, which could be explained by biological differences. The differences in concentrations of non-essential elements between the ewe and fetuses were smaller. The most significant differences were between maternal and fetal concentrations of Ba and Sr, which is at least partly explained by the mineralization degree of the bone. Conclusion: Heavy metals accumulate in fetal solid tissues in sheep that are not directly exposed to heavy metals. Because of the differences in anatomy between human and sheep placenta, the accumulation in the tissue of human fetuses should be extrapolated cautiously. However, there might be some clinical relevance for fertile aged women who are exposed to heavy metals, such as women who work in the metal industry or who have undergone joint replacement surgery

Early changes in osteochondral tissues in a rabbit model of post-traumatic osteoarthritis

Abstract Concurrent osteoarthritic (OA) manifestations in bone and cartilage are poorly known. To shed light on this issue, this study aims to investigate changes in subchondral bone and articular cartilage at two time points after anterior cruciate ligament transection (ACLT) in a rabbit model. 2 (N = 16) and 8 (N = 10) weeks after ACLT, the subchondral bone structure, cartilage thickness, Osteoarthritis Research Society International (OARSI) score, fixed charged density (FCD), and collagen orientation angle were analyzed. OA related changes were evaluated by comparing the ACLT to the contralateral (C-L) and control knees. Already 2 weeks after ACLT, higher trabecular number in the medial femoral condyle and femoral groove, greater OARSI score in the femoral condyles, and thinner trabeculae in the lateral tibial plateau and femoral groove were observed in ACLT compared to C-L knees. Only minor changes of cartilage collagen orientation in the femoral condyles and femoral groove and smaller FCD in the femoral condyles, medial tibial plateau, femoral groove and patella were observed. 8 weeks post-ACLT, the surgical knees had thinner subchondral plate and trabeculae, and smaller trabecular bone volume fraction in most of the knee locations. OARSI score was greater in the femoral condyle and lateral tibial plateau cartilage. FCD loss was progressive only in the femoral condyle, femoral groove, and patellar cartilage, and minor changes of cartilage collagen orientation angle were present in the femoral condyles, femoral groove, and lateral tibial plateau. We conclude that ACLT induces progressive subchondral bone loss, during which proteoglycan loss occurs followed by their partly recovery, as indicated by FCD results

Yrittäjyysilmasto Pohjois-Pohjanmaalla:SoloENTRE ja Yrittävä kulttuuri -hankkeen tuloksia

Abstract The objectives of the SoloENTRE and entrepreneurial culture -project were based on the provincial program and the provincial entrepreneurship education strategy. The project, in cooperation with micro-entrepreneurs, business service organizations and research actors, built a new set of micro-entrepreneurship services to support growth, job creation and export. The measures will support the sustainable growth and renewal of micro-entrepreneurs. The project was financed by the Council of Oulu Region the European Regional Development Fund (ERDF), through the Finnish Structural Funds programme. The project examined the current state of the entrepreneurial climate by providing information on attitudes towards entrepreneurship and media-mediated images of entrepreneurship. The attitudes of young people, teachers, and entrepreneurs in Northern Ostrobothnia concerning entrepreneurship were examined through surveys and interviews. Media-related attitudes about entrepreneurship were examined by analysing newspaper communication. The project contributed to the entrepreneurial climate through positive communication and events together with the media and business organizations. To strengthen the entrepreneurial culture, the project created materials that encourages entrepreneurship for various virtual platforms. The project participated in a nationwide network collaboration promoting an entrepreneurial culture. The project developed services that support digitalization, community, and future work models for those who are planning or already working as entrepreneurs. In the project, business service operators created services for the self-employed. The project also developed and produced a new type of web-based maturity model for educational institutions for self-assessment and goal-oriented development of experimental cultural development and the implementation of entrepreneurship education. The core group model of MicroENTRE micro-enterprises created in Northern Ostrobothnia is a peer network of micro-entrepreneurs, which has already expanded to several provinces. There is a significant need for the sharing and peer review of the expertise of business service operators. The SoloENTRE and entrepreneurial culture -project developed network cooperation between business service providers. Through the activities, the expertise and competence of the participants was strengthened through the sharing of knowledge and experiences and peer support.Tiivistelmä SoloENTRE ja Yrittävä kulttuuri -hankkeen tavoitteet pohjautuivat maakuntaohjelmaan ja maakunnalliseen yrittäjyyskasvatusstrategiaan. Hankkeessa rakennettiin yhteistyössä yksin- ja mikroyrittäjien, yrityspalveluorganisaatioiden ja tutkimustoimijoiden kanssa uudenlainen mikroyrittäjyyden palvelukokonaisuus, jolla tuetaan yritysten kasvua, työllistämistä ja vientiä. Toimenpiteet tukevat erityisesti yksin- ja mikroyrittäjien kestävää kasvua ja uudistumista. Hankkeen päärahoittajana oli Pohjois-Pohjanmaan liitto, Euroopan Aluekehitysrahasto (EAKR) Suomen rakennerahasto-ohjelman kautta. Hankkeessa selvitettiin yrittäjyyden ilmapiirin nykytilaa tuottamalla tietoa asenteista yrittäjyyteen ja median välittämistä yrittäjyyden mielikuvista. Pohjois-Pohjanmaan nuorten, opetushenkilöstön ja yrittäjien asenteita yrittäjyyttä kohtaan selvitettiin kyselyjen ja haastattelujen kautta, lisäksi median välittämää viestiä yrittäjyydestä tutkittiin painettujen lehtien viestintää analysoimalla. Hanke vaikutti yrittäjyysilmastoon positiivisella viestinnällä ja tapahtumilla yhdessä median ja yrittäjäjärjestöjen kanssa. Yrittävää kulttuuria vahvistettiin myös tallentamalla virtuaalisille alustoille yrittäjyyteen kannustavaa aineistoa. Hanke osallistui yrittävää kulttuuria edistävään valtakunnalliseen verkostoyhteistyöhön. Hankkeessa kehitettiin digitalisaation, yhteisöllisyyden ja tulevaisuuden työnteon muodot tukevia palveluita yrittäjyyttä suunnitteleville tai jo yrittäjinä toimiville. Hankkeessa yrityspalvelutoimijat kartoittivat yritysten palvelutarpeet ja tuottivat palvelutarjontaansa erityisesti yksinyrittäjille suunnattuja palveluita. Hanke kehitti ja tuotti lisäksi yksin- ja mikroyrityksille sekä yrityspalveluorganisaatioiden käyttöön yrityksen kasvun hallinnan ja digitalisoinnin valmiuksien arvioinnin ja kehittämisen avoimet sähköiset palvelut yhdessä kohderyhmien kanssa. Hanke kehitti ja tuotti uudenlaisen verkkopohjaisen kypsyysmallin myös oppilaitoksille yrittävän kulttuurin kehittymisen ja yrittäjyyskasvatuksen toteutumisen itsearviointiin ja päämäärätietoiseen kehittämiseen. Palvelu mahdollistaa yrittäjyyskasvatuksen tavoitteellisen seurannan ja tarvittavien toimenpiteiden suuntaamisen saatujen tulosten pohjalta. Pohjois-Pohjanmaalla luotu MicroENTRE:n mikroyritysten ydinryhmämalli on mikroyrittäjien vertaisverkosto, joka on laajentunut jo useaan maakuntaan ja sille on jatkuva tarve. Toiminnan aikana on huomioitu tarve vahvistaa yrityspalvelutoimijoiden asiantuntijuuden jakamista ja vertaistoimintaa. SoloENTRE ja Yrittävä kulttuuri -hankkeessa kehitettiin yrityspalvelutoimijoiden verkostoyhteistyötä. Toiminnan kautta osallistujien asiantuntijuus ja osaaminen vahvistui tiedon ja kokemusten jakamisen sekä vertaistuen kautta