Karolinska Universitetssjukhuset

Stockholm, Sweden

Karolinska Universitetssjukhuset

Stockholm, Sweden
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Nosi U.,University of Toronto | Lanner F.,Karolinska Institutet | Lanner F.,Karolinska Universitetssjukhuset | Huang T.,University of Toronto | Cox B.,University of Toronto
Cell Reports | Year: 2017

The first cell fate choice of the preimplantation embryo generates the extraembryonic trophoblast and embryonic epiblast lineages. Embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) can be utilized to investigate molecular mechanisms of this first cell fate decision. It has been established that ESCs can be induced to acquire trophoblast lineage characteristics upon manipulation of lineage-determining transcription factors. Here, we have interrogated the potential of microRNAs (miRNAs) to drive trans-differentiation of ESCs into the trophoblast lineage. Analysis of gene expression data identified a network of TSC-enriched miRNAs that were predicted to target mRNAs enriched in ESCs. Ectopic expression of these miRNAs in ESCs resulted in a stable trophoblast phenotype, supported by gene expression changes and in vivo contribution potential. This process is highly miRNA-specific and dependent on Hdac2 inhibition. Our experimental evidence suggests that these miRNAs promote a mural trophectoderm (TE)-like cell fate with physiological properties that differentiate them from the polar TE. © 2017 The Author(s)

Agency: European Commission | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2007-2.2-01 | Award Amount: 8.06M | Year: 2008

European clinical research needs an integrated and distributed infrastructure able to provide efficient support to multinational clinical trials, taking advantage of the European population and competencies, unlocking latent expertise and patients scattered across the EU member states. ECRIN (European Clinical Research Infrastructures Network) is designed to bridge the fragmentation of clinical research in Europe through the connection of national networks of clinical research centres and clinical trial units. Participants are currently Austria, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, Switzerland, the United Kingdom, and the EORTC. It will provide integrated, one-stop shop services to investigators and sponsors in multinational studies (patient recruitment and investigation, data management, GMP manufacturing of biotherapy products, quality assurance, monitoring, ethics, regulatory affairs and adverse event reporting). With this objective, the preparation phase will consist of - WP2: selection of a legal status and of the governance structure - WP3: agreement on a financial plan leading to a long-term sustainability during the construction step and the operation phase - WP4: survey on needs in terms of GMP facilities for biopharmaceuticals and biotherapy, and their design. - WP5: education programme for multinational clinical studies - WP6: extension to other EU member states - WP7: capacity building to help national networks fulfil the sponsors tasks - WP8: update and upgrade of the quality assurance system - WP9: internal and external communication - WP10: accreditation of data centres - WP11: support to pilot projects Users will be investigators and sponsors in the academic and SME sector. Participants will be the national coordination of clinical research infrastructures, and national ministries and funding agencies in order to reach an agreement ensuring the long-term sustainability of the infrastructure.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-3.1-6 | Award Amount: 3.44M | Year: 2008

Research has shown that every year 30,000 European patients suffer preventable harm during treatment. It is estimated there were potentially 1,735 avoidable deaths in 2004. The financial cost of avoidable adverse events is reckoned at 167 million, 1% of hospitals total budget, due to longer hospital stays and additional treatment. Many of these adverse events relate to handoff in care. Poor continuity of clinical care (with multiple provider involvement), either at a patients referral to a hospital by a primary care specialist or at a patients discharge from the hospital, is a critical aspect of a patients care. Incomplete handoffs to a secondary/tertiary care unit or discharge from hospital can lead to adverse events for patients that may ultimately lead to either life threatening situations during treatment/surgery or avoidable treatment and / or re-hospitalizations after the patients discharge. Care transitions are especially important for vulnerable groups as the elder and the very young as for high-risk patients with multiple co-morbidities. The overall objective the HANDOVER project is optimize the continuum of clinical care at the primary care hospital interface by reducing unnecessary and avoidable treatment - medical errors and loss of life, by identifying and studying best practices and creating standardized approaches to handoff communication at the primary care hospital interface and measuring the effectiveness of these practices in terms of costs and impact. Handoffs take as many forms as there are handoff scenarios. The idea of developing a single approach for all handoffs is not likely to be possible due to the diversity and complexity of healthcare. HANDOVER will therefore aim at providing standardised basic elements in handoff processes, which can be tailored to meet local and/or institutional needs for flexibility.

Brauer-Krisch E.,European Synchrotron Radiation Facility | Serduc R.,European Synchrotron Radiation Facility | Siegbahn E.A.,Karolinska Universitetssjukhuset | Le Duc G.,European Synchrotron Radiation Facility | And 4 more authors.
Mutation Research - Reviews in Mutation Research | Year: 2010

Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600 keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow (∼25-100 μm wide) microplanar beams separated by wider (100-400 μm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100 mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to ∼2 yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68-0.95 mm, centre-to-centre distances 1.2-4 mm), which may differ to some extent from those of microscopic beams, have been followed up to ∼7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented. © 2010 Elsevier B.V. All rights reserved.

Gustavsson A.,I3 Innovus | Bjorkman J.,Grunenthal | Ljungcrantz C.,I3 Innovus | Rhodin A.,Grunenthal | And 3 more authors.
Pain | Year: 2012

Slow-release strong opioids (SRSO) are indicated in patients with severe chronic pain. Side effects, lack of efficacy and risk of dependency limit their use in clinical practice. The aim of this study was to explore prescription patterns of SRSO in Swedish real-world data on patients with a diagnosis related to chronic pain (DRCP). Patient-level data were extracted from the national prescriptions register and a regional register with diagnosis codes. The prescription sequences, switches, co-medications, and strengths over time were analyzed for cancer and noncancer patients. Of 840,000 patients with a DRCP, 16,257 initiated treatment with an SRSO in 2007 to 2008. They were 71 years old on average; 60% were female and 34% had cancer. The most common first prescription was oxycodone (54%) followed by fentanyl (19%), buprenorphine (14%), and morphine (13%). 63% refilled their prescription within 6 months, and 12% switched to another SRSO, most commonly fentanyl. After 3 years, 51% of cancer and 27% of noncancer patients still being in contact with health care remained on any SRSO. Of noncancer patients, 35% had a psychiatric co-medication (SSRI or benzodiazepine). In conclusion, fewer patients remain on SRSO in the long-term in clinical practice than reported in previous clinical trials. Oxycodone is the most common first SRSO prescription and one-third of patients get a prescription indicating psychiatric comorbidity. Our interpretation of these findings are that there is need for better treatment options for these patients, and that more effort is needed to improve treatment guidelines and to ascertain that these guidelines are followed. © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Rosenborg S.,Karolinska universitetssjukhuset | Elinder C.-G.,Stockholms lans landsting
Lakartidningen | Year: 2013

Kidney function should be regarded when dosing and prescribing. We assessed the prescribing information available in the Summary of Product Characteristics (SmPC) for the 253 drug substances on the Stockholm County Formulary for the year 2010 (a.k.a. "The Wise List"). More than half of the 253 drug substances (58%) were excreted by the kidneys by more than 20%. 61% of them had some remark or regarding renal function. Different eGFR methods were recommended for different drugs and clar definitions of the GFR limit for dose adjustment were often lacking. Future recommendations in the SmPCs should be improved on dose adjustment in renal impairment, e.g. clarifying which eGFR method to use and at what GFR the dose should be adjusted.

Elvander C.,Karolinska Universitetssjukhuset | Ekeus C.,Karolinska Institutet | Gemzell-Danielsson K.,Karolinska University Hospital | Cnattingius S.,Karolinska Universitetssjukhuset
Acta Obstetricia et Gynecologica Scandinavica | Year: 2013

Objective To explain the increasing rates of vacuum extraction in Sweden. Design Population-based register study. Setting Nationwide study in Sweden. Population A total of 589 108 primiparous women with singleton, term live births in 1992-2010. Methods Odds ratios with 95% confidence intervals were estimated for potential risk factors for vacuum extraction and emergency cesarean. To explain the increase in vacuum extraction over time, we successively adjusted for maternal and infant characteristics in four different models. Main outcome measures Vacuum extraction. Results Rates of vacuum extraction increased from 11.5% in 1992 to 14.8% in 2010. The risk of vacuum extraction increased with maternal age and gestational length, but decreased with increasing maternal height. The increased use of vacuum extraction over time was partly explained by increasing maternal age and increased use of epidural anesthesia. Among women with and without epidural analgesia, the increase in vacuum extraction over time was confined to vacuum extraction due to signs of fetal distress. Conclusions Depending on risk factors, the odds of being delivered by vacuum extraction can vary immensely from one woman to another. Increasing maternal age explains a substantial fraction of the increase in vacuum extraction use since 1992. Whether the increase in vacuum extractions due to fetal distress reflects a true increase in fetal distress during labor remains to be explained. © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.

Colombo N.,Instituto Europeo Of Oncologia | Mangili G.,Ospedale San Raffaele | Mammoliti S.,Azienda Ospedaliera San Martino | Kalling M.,Gynekologisk Onkologklinik Universitetssjukhuset | And 4 more authors.
Gynecologic Oncology | Year: 2012

Objective: The recombinant fusion protein, aflibercept binds and neutralizes vascular endothelial growth factor (VEGF) A, B and placental growth factor (PlGF). Aflibercept inhibits ascites formation and reduces tumor burden in an ovarian cancer model. This open-label, single-arm, multicenter phase II study assessed the efficacy and safety of aflibercept in patients with advanced chemo-resistant epithelial ovarian cancer and symptomatic malignant ascites. Methods: Patients who required ≥ 3 previous paracenteses at 1-4 paracenteses per month received intravenous aflibercept 4 mg/kg every 2 weeks. The primary endpoint was repeat paracentesis response rate (RPRR), with response defined as at least a two-fold increase in time to repeat paracentesis compared with the baseline interval. Results: Ten out of 16 enrolled patients achieved a response; the RPRR was 62.5% (95% CI 35.4%-84.8%). Aflibercept was considered effective based on a hypothesis that the RPRR was ≥ 60%. Median time to repeat paracentesis was 76.0 (95% CI 64.0-178.0) days, which was 4.5 times longer than the baseline interval (16.8 days). Median progression-free survival was 59.5 (95% CI 41.0-83.0) days. Twelve patients experienced adverse events considered related to aflibercept treatment including hypertension (7 patients), headache, anorexia, and dysphonia (3 patients each). Two patients experienced Grade 3/4 treatment-related adverse events (Grade 3 hypertension and weight loss in one patient, Grade 3 intestinal perforation in one patient). Conclusion: Aflibercept 4 mg/kg every 2 weeks was effective at controlling malignant ascites, reducing the interval between repeat paracenteses. The safety profile was consistent with that reported for anti-VEGF agents. © 2012 Elsevier Inc. All rights reserved.

Cardiovascular calcification is a common phenomena in patients with end-stage renal disease. The etiology of vascular calcification is multifactorial in the toxic uremic mileu and include not only hyperphosphatemia but also adynamic bone disease, inflammation, dyslipidemia and oxidativ stress. Recent studies indicate that also subclinical deficiency of vitamin K may promote the vascular calcification process via less activation of the vitamin K dependent protein matrix Gla protein (MGP). As vitamin K inhibitors (such as warfarin) not only inactivate coagulation factors but also the carboxylation of MGP evidence suggests that they may also promote the vascular calcification process in susceptible indviduals. As retrospective studies indicate that warfarin is rather associated with increased risk for stroke the relative roles of warfarin versus novel oral anticoagulants need further studies in this calcification prone patient group.

Acute-on-chronic liver failure (ACLF) is a condition that may develop in up to one third of patients with chronic liver disease who exhibit clinical signs of acute decompensation, i.e. ascites, gastrointestinal bleeding, hepatic encephalopathy or bacterial infection. ACLF implies the combination of acute hepatic decompensation with organ failure in kidney, brain, liver, lungs, circulation and/or coagulation. The prognosis worsens with the number of failing organs, renal involvement, advanced age and elevated leukocyte blood count. ACLF is caused by a systemic inflammation. Cultures from blood, urine and ascites should be drawn, and rapid antibiotic treatment is essential to prevent ACLF development. Renal function must be monitored and renal failure treated promptly. Acute alcoholic hepatitis may be considered a specific case of ACLF, which may be treated with corticosteroids in cases having high score in prognostic indices (GAHS, MELD or ABIC), and after bacterial infections have been ruled out or treated. © 2016, Swedish Medical Association. All rights reserved.

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