Search

Väitekirja elektrooniline versioon ei sisalda publikatsioone, Osteoartriit (OA) on kõige levinum liigesehaigus, millel ei ole tänaseni patogeneetilist ravi. Tõhusate ravimeetodite arendamise peamised väljakutsed on OA heterogeensus ja ebaselge patoloogia. OA-d, mida tavapäraselt tuntakse kui „vananemishaigust“, peetakse järjest enam krooniliseks põletikuliseks haiguseks. Käesoleva doktoritöö eesmärk oli hinnata sünoviaalvedelikuga seotud põletikulist mehhanismi, mis on OA patoloogias üks põhilisi põletikukohti. Seda silmas pidades piirdub sünoviaalvedeliku analüüs sageli tema molekulaarse koostise uurimisega, kuid funktsionaalse ulatuse hindamiseks on vaja laiemat tausta. Seetõttu püüti molekulaarse signaali dekodeerimisega uurida sünoviaalvedeliku laiemat kaasatust haiguse patogeneesis. Viidi läbi mitmetasandiline analüüs, kasutades OA-st mõjutatud sünoviaalmembraani ja osteofüütide biopsiaid ning sünoviaalvedeliku proove. Lisaks tehti rakupõhiseid analüüse, kasutades inimese monotsüütide rakuliine (THP1 ja U37) ning inimese vereloome tüvirakke. Bioloogiliste testide tulemuste toetamiseks viidi läbi proteoomi analüüs ja sünoviaalvedeliku immuno-fenotüüpimine. Sünoviaalmembraani rakkude geeniekspressiooni uuring näitas püsivat põletikku OA liigestes. Suurem põletik haiguse varases staadiumis annab vältimatu tõuke kõhrkoe kiiremaks lagunemiseks haiguse hilisemates staadiumites. Kõigi OA staadiumide sünoviaalvedeliku proovid, inkubeerides neid THP1 ja U937 rakkudega, suutsid rakkudes esile kutsuda põletikku. Samas katses näidati, et OA sünoviaalvedelik võib indutseerida immuunrakkude eristumist ja toimida nišina, pakkudes olulist mikrokeskkonda, mis toetab immuunrakkude funktsionaalset aktiivsust ning põhjustab põletiku süvenemist ja kestmist. Sünoviaalvedeliku proteoomianalüüs paljastas mitmeid suures koguses esinevaid valke, mis võivad, nagu täheldati, indutseerida immuunrakkude eristumist. Lõpuks viidi läbi osteofüütide RNA-seq analüüs, et uurida selles toimuvaid molekulaarseid ja rakulisi protsesse, eriti OA patoloogia kontekstis. Geeniekspressiooni mustri funktsionaalne analüüs näitas progresseeruvat aktiivset luu ümberkujunemist ja nuumrakkude tihedat seotust selles protsessis. See teadmine on OA patoloogias uus ja peaks olema arvesse võetud sobivate ravimeetodite kavandamisel., Osteoarthritis (OA) is the most common joint disease, which has no cure to date. The major challenges in developing effective therapies are, heterogenous nature and obscure pathology of OA. Conventionally known as ‘aging disease’, OA is increasingly accepted as a complex disease with an implication of chronic-low-grade inflammation. More illumination is needed on the involved inflammatory mechanism. The present thesis was aimed to evaluate inflammatory mechanism revolving around the synovium-synovial fluid (SF) axis, which are the main inflammation sites in OA pathology. In this regard, particularly SF analysis is limited to understand a molecular make-up of the fluid and there is a wider scope to assess its functional involvement. Therefore, the attempt was to investigate a ‘performance-based involvement’ of SF by decoding the molecular signalling. A multilevel analysis was done using OA affected synovium biopsies, SF and osteophyte samples. Also, cell-based assays were performed using human monocyte cell lines (THP1 and U937) and human hematopoietic stem cells. Proteome analysis and SF immunophenotyping was performed to support the outcomes from the biological assays. Synovium gene expression study showed a persistent nature of inflammation in OA joints. Higher inflammation in early stage provides a necessary impetus for accelerated cartilage-loss at later stages. SF samples of all OA stages, when incubated with THP1 and U937 cells, was able to induce inflammation in the cells. In the same experimental design, we showed that OA SF can induce immune cell differentiation and act as a niche by providing an essential microenvironment, which enable immune cells to be functionally active and for contributing to aggravate and maintain inflammation. Proteome analysis of SF revealed many proteins in abundance, which can induce immune cell differentiation as was observed. Finally, RNA-seq analysis of osteophytes was performed to investigate molecular and cellular events in it, especially in the context of OA pathology. Functional analysis of the gene expression patten, revealed an on-going active bone remodelling and close involvement of mast cells in the process, which is a new dimension of OA pathology and should prove worthy for taking into consideration for designing appropriate therapies., https://www.ester.ee/record=b5518321

Background MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated the safety and tolerability, efficacy, and pharmacokinetics of MHAA4549A in outpatients with acute, uncomplicated influenza A infection. Methods This was a phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg of MHAA4549A or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred within ≤72 hours of symptom onset; the study duration was 14 weeks. The primary end point was the nature and frequency of adverse events (AEs). Secondary end points included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. Results Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. The frequency of AEs between the MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose-proportional. No hospitalizations or deaths occurred. Between the MHAA4549A and placebo groups, no statistically significant differences occurred in the median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. Conclusions While MHAA4549A was safe and well tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection., D/C/F/TAF is the reference for combination therapy based on protease inhibitors but has not been compared with regimens containing integrase inhibitors as initial ART. We could not demonstrate D/C/F/TAF noninferiority relative to DTG/ABC/3TC, although both regimens were similarly well tolerated.

Background: Diabetes mellitus (DM) is increasing in its potential in developing countries. Rise in diabetic patients calling emergency medical services (EMS) is expected. It calls for thorough assessment of patients with DM utilizing EMS. In the present study, was to assess magnitude of DM among patients utilizing EMS and its clinico-social parameters.Methods: It was hospital record based observational study of patients calling EMS delivered by a tertiary care hospital in Pune, Maharashtra, India during 1st January 2013 to 31st December 2014. Patients with incomplete records were excluded. A person with medical background was trained to extract required information from hospital records. Patients with previously diagnosed DM were considered those who were on diet, oral hypoglycemic agents or taking insulin therapy and newly diagnosed patients with DM were considered those with the value of glycemia on admission >200 mg/dl in first 24 hours. Data analysis was done using SPSS 15.0 software.Results: 45.8% (894/1951) were Patients with DM out of that 78.19% (699/894) were known to have DM while 28.81% (195/1951) were new cases of DM. 5.1% (100/1951) patients had uncontrolled DM. DM was significantly more in >60 years age group and in urban residents (p