Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multi- forme (GBM) cell lines and primary culture models are reported. Dose–response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repop- ulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR func- tions. DP68-induced interstrand DNA cross-links were dem- onstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell–cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti- glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collec- tively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DN

One Arctic - One Health

One Health takes a multidisciplinary approach to health risks and risk mitigation for humans, animals, plants and the environment, with the understanding that human health welfare is dependent on ecosystem health. The U.S. and Canada started the One Health project under the Sustainable Development Working Group (SDWG) of the Arctic Council in 2015, Finland joined the project as a colead in 2017. This report is a summary of the Finnish activities and achievements in the One Arctic - One Health project during the Finnish Chairmanship of the Arctic Council. The main actions included the One Arctic - One Health conference in Oulu, establishment of the TremArctic network, and two published Systematic Review papers and two manuscripts. There were also joint sessions and presentations in scientific conferences, seminars and workshops, and joint meetings and collaboration with the other Arctic Council Working Groups, the University of the Arctic, other organisations, and scientific projects. The report concludes with some updated proposals for further work, based on previous works and reflecting progress over the past two years. The Finnish One Arctic - One Health team consisted of scientists from the University of Oulu, National Institute for Health and Welfare (THL), University of Helsinki and the Finnish Food Authority. This work was supported by the grant of the Ministry for Foreign Affairs of Finland.Yhteisen terveyden (One Health) perusajatus on, että ihmisten, eläinten, kasvien ja ympäristön terveys on toisistaan riippuvaista, ainakin niin, että sairaassa ympäristössä ei ihminenkään voi olla hyvinvoiva. Yhdysvaltain johtaessa puhetta Arktisessa neuvostossa, USA ja Kanada aloittivat kestävän kehityksen työryhmän (SDWG) alaisuudessa One Health -hankkeen, jonka johtoon Suomi liittyi toimiessaan Arktisen neuvoston puheenjohtajana 2017-2019. Tämä raportti on yhteenveto Suomen toimista ja saavutuksista puheenjohtajakaudellaan. Tärkeimmät toimet olivat One Arctic - One Health -konferenssi Oulussa, TremArctic-verkoston toiminnan aloittaminen, kaksi julkaistua laajaa systemaattista katsausta ja kaksi käsikirjoitusta. Lisäksi Suomen työryhmä osallistui tieteellisiin konferensseihin, seminaareihin ja työpajoihin, sekä yhteisiin kokouksiin ja muuhun yhteistyöhön Arktisen neuvoston muiden työryhmien kanssa. Raportti sisältää myös päivitettyjä jatkotoimenpide-ehdotuksia, jotka perustuvat aikaisempaan työhön ja viimeisten kahden vuoden aikana tapahtuneeseen kehitykseen. Suomen Yksi Arktis – yhteinen terveys -työryhmä koostui asiantuntijoista Oulun yliopistosta, Terveyden ja hyvinvoinnin laitoksesta, Helsingin yliopistosta ja Ruokavirastosta. Hanketta rahoitti Suomen ulkoministeriö.Grundprincipen till One Health -tänkandet är att människohälsa, djurhälsa, planthälsa och ekosystemhälsa är nära besläktade. I alla fall så att människans välfärd kräver frisk natur. Under det amerikanska ordförandeskapet i Arktiska rådet inledde USA och Kanada One Health -projektet i regi av arbetsgruppen för hållbar utveckling (Sustainable Development Working Group, SDWG). Finland gick med i ledningen av projektet under Finland ordförandeskap 2017-2019. Denna rapport är en sammanfattning av finska åtgärder och resultat under Finlands ordförandeskap. De mest viktiga handlingarna var arrangerandet av One Arctic - One Health – konferensen i Uleåborg, startandet av TremArctic-nätverket, publiceringen av två systematiska litteraturöversikter och produceringen av två vetenskapliga manuskript. I tillägg deltog den finska arbetsgruppen i vetenskapliga konferenser, seminar och verkstäder med gemensamma sessioner och presentationer. Vidare hade man gemensamma möter samt annat samarbete med andra arbetsgrupper under Arktiska rådet. Rapporten innehåller också uppdaterade förslag till för ytterligare åtgärder baserade på tidigare arbeten och utvecklingen under Finland ordförandeskap. Finlands One Arctic – One Health - arbetsgrupp bestod av forskare från Uleåborgs universitet, Institutet för hälsa och välfärd, Helsingfors universitet, samt Livsmedelsverket. Projektet fick finansiering från det finska utrikesministeriet

Redo ventral rectopexy : is it worthwhile?

Background Minimally invasive ventral mesh rectopexy (VMR) is a widely used surgical treatment for posterior pelvic organ prolapse; however, evidence of the utility of revisional surgery is lacking. Our aim was to assess the technical details, safety and outcomes of redo minimally invasive VMR for patients with external rectal prolapse (ERP) recurrence or relapsed symptoms of internal rectal prolapse (IRP). Methods This is a retrospective cohort study of patients with recurrent ERP or symptomatic IRP who underwent redo minimally invasive VMR between 2011 and 2016. The study was conducted at three hospitals in Finland. Data collected retrospectively included patient demographics, in addition to perioperative and short-term postoperative findings. At follow-up, all living patients were sent a questionnaire concerning postoperative disease-related symptoms and quality of life. Results A total of 43 redo minimally invasive VMR were performed during the study period. The indication for reoperation was recurrent ERP in 22 patients and relapsed symptoms of IRP in 21 patients. In most operations (62.8%), the previously used mesh was left in situ and a new one was placed. Ten (23.3%) patients experienced complications, including 2 (4.7%) mesh-related complications. The recurrence rate was 4.5% for ERP. Three patients out of 43 were reoperated on for various reasons. One patient required postoperative laparoscopic hematoma evacuation. Patients operated on for recurrent ERP seemed to benefit more from the reoperation. Conclusions Minimally invasive redo VMR appears to be a safe and effective procedure for treating posterior pelvic floor dysfunction with acceptable recurrence and reoperation rates.Peer reviewe

Laparoscopic ventral rectopexy in male patients with external rectal prolapse is associated with a high reoperation rate

Background Laparoscopic ventral rectopexy has been used to treat male patients with external rectal prolapse, but evidence to support this approach is scarce. The aim of this study was to evaluate the results of this new abdominal rectopexy surgical technique in men. Methods This was a retrospective multicenter study. Adult male patients who were operated on for external rectal prolapse using ventral rectopexy in five tertiary hospitals in Finland between 2006 and 2014 were included in the study. Patient demographics, detailed operative, postoperative and short-term follow-up data were collected from patient registers in participating hospitals. A questionnaire and informed consent form was sent to all patients. The questionnaire included scores for anal incontinence, obstructed defecation syndrome, urinary symptoms and sexual dysfunction. The main outcome measure was the incidence of recurrent rectal prolapse. Surgical morbidity, the need for surgical repair due to recurrent symptoms and functional outcomes were secondary outcome measures. Results A total of 52 adult male patients with symptoms caused by external rectal prolapse underwent ventral rectopexy. The questionnaire response rate was 64.4 %. Baseline clinical characteristics and perioperative results were similar in the responder and non-responder groups. A total of 9 (17.3 %) patients faced complications. There were two (3.8 %) serious surgical complications during the 30-day period after surgery that necessitated reoperation. None of the complications were mesh related. Recurrence of the prolapse was noticed in nine patients (17 %), and postoperative mucosal anal prolapse symptoms persisted in 11 patients (21 %). As a result, the reoperation rate was high. Altogether, 17 patients (33 %) underwent reoperation during the follow-up period due to postoperative complications or recurrent rectal or mucosal prolapse. According to the postoperative questionnaire data, patients under 40 had good functional results in terms of anal continence, defecation, urinary functions and sexual activity. Conclusions Laparoscopic ventral rectopexy is a safe surgical procedure in male patients with external prolapse. However, a high overall reoperation rate was noticed due to recurrent rectal and residual mucosal prolapse. This suggests that the ventral rectopexy technique should be modified or combined with other abdominal or perineal methods when treating male rectal prolapse patients.Peer reviewe

The Barents area changes – How will Finland adapt? (Barentsin alue muuttuu – miten Suomi sopeutuu?)

The cumulative impacts of environmental, climatic and societal changes and their consequences will affect the development of the Arctic region in the coming decades. Adaptation to these changes will require measures of all the actors in the region. Finland, part of the Euro-Arctic region, will adapt to these changes in a variety of ways. The Barents area is unique in the Arctic in being a multicultural, relatively densely populated area with well-developed industries and infrastructure. This report examines adaptation to changes and their consequences in the Barents area in terms of governance and Finland’s capacities to adapt. The aim has been to produce comprehensive information from the Finnish perspective for local and national decision-makers about long-term changes in the region, their expected impacts and adaptation options, and to support decision-making that will advance adaptation. The report includes recommendations. This report is based on the contribution of Finnish experts to an Arctic Council and Arctic Monitoring and Assessment Programme (AMAP) project titled ”Adaptation Actions for a Changing Arctic” (AACA). The project has prepared a pilot report by Nordic and Russian experts on the Barents area in English on changes, their impacts and adaptation options. The report will be published in 2017 (AMAP 2017)

Therapist-guided, Internet-delivered cognitive behaviour therapy for adolescents with body dysmorphic disorder: A feasibility trial with long-term follow-up

Body dysmorphic disorder (BDD) is a prevalent and impairing psychiatric condition that typically debuts in adolescence and is associated with risky behaviours. The disorder can be effectively treated with cognitive behaviour therapy (CBT). However, CBT for BDD is seldom available primarily due to a shortage of trained therapists. Internet-delivered CBT (ICBT) can be a way to increase treatment availability. The aim of this feasibility trial was to evaluate the feasibility, safety, and preliminary efficacy of a CBT protocol for adolescents with BDD, adapted to be delivered over the Internet with minimal therapist support. A total of 20 participants (12–17-year-olds) meeting criteria for BDD were recruited nationally to a specialist outpatient clinic in Stockholm, Sweden. One participant withdrew consent and their data could not be analysed. Nineteen participants were offered 12 modules of therapist-guided ICBT for BDD and were followed up to 12 months post-treatment. Preliminary efficacy was measured at the a priori primary endpoint (3-month follow-up) and at the 12-month follow-up with the clinician-rated Yale-Brown Obsessive Compulsive Scale Modified for BDD for Adolescents. The treatment was rated as both credible and satisfactory and was associated with a large and statistically significant reduction in BDD symptom severity (d = 2.94). The proportion of participants classified as responders at the primary endpoint was 73.7%, and the proportion of full or partial remitters was 63.2%. The average therapist support time was 8 min per participant per week. Treatment gains continued to accrue up to the 12-month follow-up. Two participants attempted suicide and another two reported non-suicidal self-injuries during the study period. ICBT with minimal therapist support is a feasible, potentially efficacious, and durable treatment for adolescents with BDD. Risky behaviours typical of this patient group should be carefully monitored during treatment

Appendicolith appendicitis is clinically complicated acute appendicitis – is it histopathologically different from uncomplicated acute appendicitis

Purpose: Acute appendicitis may present as uncomplicated and complicated and these disease forms differ both epidemiologically and clinically. Complicated acute appendicitis has traditionally been defined as an appendicitis complicated by perforation or a periappendicular abscess, and an appendicolith represents a predisposing factor of complicated disease. There are histopathological differences between uncomplicated acute appendicitis and the previously established traditional forms of complicated acute appendicitis, but to our knowledge, the histopathological differences between uncomplicated acute appendicitis and complicated acute appendicitis presenting with an appendicolith have not yet been reported. The study purpose was to assess these differences with two prospective patient cohorts: (1) computed tomography (CT) confirmed uncomplicated acute appendicitis patients enrolled in the surgical treatment arm of the randomized APPAC trial comparing appendectomy with antibiotics for the treatment of uncomplicated acute appendicitis and (2) patients with CT-verified acute appendicitis presenting with an appendicolith excluded from the APPAC trial.Methods: The following histopathological parameters were assessed: appendiceal diameter, depth of inflammation, micro-abscesses, density of eosinophils, and neutrophils in appendiceal wall and surface epithelium degeneration.Results: Using multivariable logistic regression models adjusted for age, gender, and symptom duration, statistically significant differences were detected in the depth of inflammation = 150/mm(2) (adjusted OR 0.97 (95%CI: 0.95-0.99, p=0.013), adjusted OR 3.04 (95%CI: 1.82-5.09, pConclusions: These results corroborate the known clinical association of an appendicolith to complicated acute appendicitis.</div

Vertical distribution of zooplankton in a shallow peatland pond: the limiting role of dissolved oxygen

We investigated the diel vertical distribution patterns of microcrustacean zooplankton (Cladocera, Copepoda) in a shallow pond (max. depth: 70 cm) of the Öreg-turján peatland (Ócsa, Central Hungary) during three 24-h periods in July (19–20th), August (17–18th) and September (11–12th) 2011. Environmental variables showed remarkable vertical stratification. Oxygen concentration was close to zero in the entire water column from night until sunrise, while the lower strata (from 20 cm below the surface) were close to anoxic during all three diel cycles. It proved to be the main determinant of the vertical distribution of microcrustaceans. Accordingly, the highest proportion of individuals was present in the surface layer. Chlorophyll-a concentration and phytoplankton biomass were inversely distributed compared to zooplankton. Microcrustaceans (mainly Daphnia curvirostris) migrated to the middle layer only in August, which could be explained by a trade-off between food resources, dissolved oxygen (DO) and competition with littoral zooplankters. The diurnal density patterns of microcrustaceans suggested horizontal migration into the aquatic macrophytes during night, which could be a strategy to avoid Chaoborus predation. Our results show that strong vertical gradients of abiotic and biotic factors occur even in such shallow waterbodies. Among them, DO can maintain constant vertical aggregation of zooplankters by limiting their occurrence to the surface layers