Experimental models of focal neuroinflammation - Efficacy assessment of pharmaceuticals of multiple sclerosis using PET imaging

Neuroinflammation (NI) is a key player in neurodegenerative diseases, such as multiple sclerosis (MS). Magnetic resonance imaging is the gold standard imaging method for diagnosis of MS, however, better diagnostic tools are needed for the follow-up of disease progression, earlier diagnosis, and assessment of patients’ response to therapy. Positron emission tomography (PET) is a sensitive and selective functional imaging method for investigating mechanisms of diseases at a molecular level. NI can be visualised in PET by targeting the 18 kDa translocator protein (TSPO), which is upregulated during NI on the mitochondria of glial cells. This study aimed to evaluate the properties of [18F]GE-180, a 2nd generation TSPO PET radiotracer, in a unilateral model of acute NI and evaluate the efficacy of immunomodulatory drugs, anti-VLA-4 and dimethyl fumarate (DMF), in two different focal rat models of experimental autoimmune encephalomyelitis (EAE), the fDTH-EAE and fMOG-EAE models. The applied methods were in vivo PET imaging, digital autoradiography, and immunohistochemical (IHC) staining. Study I indicated improved binding potential of [18F]GE-180 over the 1st generation tracer [11C]PK11195 and showed that the unilateral model of acute NI is suitable for the evaluation of novel PET tracers of NI. Study II indicated that anti- VLA-4 had no short-term treatment effects in the fDHT-EAE-rat model. However, discontinuation of the treatment caused a rebound that could be detected with [18F]GE-180. Study III showed, that short-term, but not long-term, DMF treatment decreases uptake of [18F]GE-180 in the fDTH-EAE rat model, and no rebound effect was detected after halting the treatment for 10 weeks. Nevertheless, the efficacy of DMF was detected using IHC for CD4+ and CD8+ cells. No DMF treatment effect was observed in the fMOG-EAE model. In conclusion, focal animal models of NI are applicable for evaluating novel PET tracers. Furthermore, efficacy assessment of immunomodulatory drugs can be evaluated using TSPO PET when the tracer is binding to the same biomarker that the drug is affectingPesäkkeisen aivotulehduksen kokeelliset mallit – multippeliskleroosin lääkkeiden vaikuttavuuden arviointi käyttäen PETkuvantamista Keskushermoston tulehdus on tila, joka ilmenee useissa hermorappeumasairauksissa, kuten pesäkekovettumataudissa (MS-tauti). MS-taudin kuvantamisdiagnostiikan ensisijainen menetelmä on magneettikuvaus, mutta uusia diagnostisia menetelmiä tarvitaan taudin mahdollisimman varhaiseksi toteamiseksi, etenemisen seuraamiseksi, ja uusien lääkehoitojen tehon arvioimiseksi. Positroniemissiotomografia (PET) on kajoamaton kuvantamismenetelmä, jonka avulla on mahdollista seurata aivojen tulehdusreaktiota hyödyntämällä tulehduksen aikana yliilmentyvään translokaatioproteiiniin (TSPO) sitoutuvia PET-merkkiaineita. Tämän tutkimuksen tavoitteena oli verrata TSPO-molekyyliin sitoutuvan toisen sukupolven PET-merkkiaineen ([18F]GE-180) sekä jo käytössä olevan merkkiaineen ([11C]PK11195) ominaisuuksia akuutin tulehduksen rottamallissa. Lisäksi tavoitteena oli arvioida immuunivastetta muokkaavien lääkkeiden, anti-VLA-4:n ja dimetyylifumaraatin, tehokkuutta lyhyt- ja pitkäaikaishoidossa fDTH-EAE- ja fMOG-EAE-malleissa, joissa rotille aiheutetaan pesäkkeinen autoimmuunienkefalomyeliitti. Tulehdusreaktiossa tapahtuvia muutoksia seurattiin hyödyntäen in vivo [18F]GE-180-PET-kuvantamista, autoradiografiaa, sekä kudosvärjäyksiä. Ensimmäisessä osatyössä [18F]GE-180-merkkiaineen havaittiin soveltuvan [11C]PK11195-merkkiainetta paremmin aivotulehduksen kuvantamiseen eläinmalleissa: aivojen tulehdusalue oli merkittävästi suurempi ja merkkiaineen sitoutumiskyky ja spesifisyys parempi. Toisessa osatyössä anti-VLA-4-lääkehoidon vaikutusta ei ollut mahdollista seurata [18F]GE-180-PET-kuvantamisella fDTHEAE-mallin kroonisen tulehduksen vaiheessa. Hoidon lopettamisen jälkeen ilmenevä voimakas tulehduksen uudelleenaktivoituminen oli kuitenkin mahdollista havaita PET-kuvauksella. Kolmannessa osatyössä dimetyylifumaraatin havaittiin hillitsevän tulehdusta fDTH-EAE-mallissa lyhytaikaishoidossa yhden viikon hoidon jälkeen, mutta ei enää myöhemmissä aikapisteissä, eikä fMOG-EAE-mallissa. Tämä väitöskirjatutkimus osoitti, että pesäkkeisen tulehduksen rottamalleja voidaan hyödyntää uusien tulehdusta kuvantavien PET-merkkiaineiden, sekä immuunivastetta muokkaavien lääkkeiden tehokkuuden arvioinnissa

Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium.

BACKGROUND The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. METHODS For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. FINDINGS Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. INTERPRETATION COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. FUNDING Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization

Impact of ion valency on the assembly of vimentin studied by quantitative small angle X-ray scattering

The assembly kinetics of intermediate filament (IF) proteins from tetrameric complexes to single filaments and networks depends on the protein concentration, temperature and the ionic composition of their environment. We systematically investigate how changes in the concentration of monovalent potassium and divalent magnesium ions affect the internal organization of the resulting filaments. Small angle X-ray scattering (SAXS) is very sensitive to changes in the filament cross-section such as diameter or compactness. Our measurements reveal that filaments formed in the presence of magnesium chloride differ distinctly from filaments formed in the presence of potassium chloride. The principle multi-step assembly mechanism from tetramers via unit-length filaments (ULF) to elongated filaments is not changed by the valency of ions. However, the observed differences indicate that the magnesium ions free the head domains of tetramers from unproductive interactions to allow assembly but at the same time mediate strong inter-tetrameric interactions that impede longitudinal annealing of unit-length filaments considerably, thus slowing down filament growth

Seroprevalence of antibodies to tick-borne encephalitis virus and Anaplasma phagocytophilum in healthy adults from western Norway

The aim of this study was to assess the seroprevalence of antibodies to tick-borne encephalitis virus (TBEV) and Anaplasma phagocytophilum in a healthy adult population from Sogn and Fjordane county in western Norway. Sera from 1, 213 blood donors were analysed for IgG-antibodies to TBEV, and a random subgroup of 301 donors for IgG to A. phagocytophilum. In the TBEV ELISA, five (0.4%) sera were positive. These were all interpreted as “false” positives, as four had received vaccines against flaviviruses, and the remaining was negative for neutralizing antibodies to TBEV. Antibodies to A. phagocytophilum were detected by indirect immunofluorescence in 49 (16.2%) subjects (titer range 80-1280). The results indicate that TBE currently is not endemic in this part of western Norway. However, there is serological evidence of the existence of human granulocytic anaplasmosis in the population

Rotavirus detection in bulk stool and rectal swab specimens in children with acute gastroenteritis in Norway

Background Bulk stool specimens are traditionally used for rotavirus detection but may be challenging to obtain from young children. Immediate and easy sampling may however be required in different situations, such as outbreak investigation. Objectives We assessed the diagnostic performance of rectal swabs compared to bulk stools for the detection of rotavirus by Enzyme Immunoassay (EIA) and multiplex semi-nested reverse transcription PCR (semi-nested RT-PCR) in children recruited through active hospital-based surveillance of acute gastroenteritis in Norway. Study design We obtained 265 paired bulk stool and rectal swab specimens from children under 5 years of age hospitalized with acute gastroenteritis (AGE). Both types of specimens were analyzed for rotavirus by EIA and semi-nested RT-PCR. In addition, VP6-spesific real-time PCR was used to evaluate the detection performance in the two specimen types. Results Concordant results were obtained in 257 (97%) paired specimens by EIA and in 248 (94%) pairs by semi-nested RT-PCR. Results of VP6-specific real-time PCR obtained from 100 pairs of specimens showed concordance in 91% of the pairs. Sensitivity and specificity for rectal swab specimens were 95% and 100% by EIA; 95% and 92% by semi-nested RT-PCR, respectively. Conclusion Both EIA and semi-nested RT-PCR showed a high accuracy, and rectal swab specimens are appropriate for rotavirus diagnosis and may be used as an alternate specimen type when collection of bulk stool is not feasible