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Hannah Akuffo, Adjunct Professor of Parasitology at Karolinska Institutet, will be broadcasted on Monday August 16, on Sommar i P1 (Summer on P1), one of the most popular shows on Swedish radio. Hi Hannah, what did the editorial team of ”Sommar i P1” say when they first contacted you? “Not quite unusually, I was on duty travel out of Sweden when the editorial team first tried to contact me in early February 2016. This time I was in Bonn as a member of the review panel for German-Africa Cooperation Projects in Infectiology for the German Research Foundation. Because of the intensity of the sessions I had turned off all my various modes whereby I could be contacted. Thus the various attempts by the Sommar i P1 editorial team to reach me did not bear fruit. The team thus resorted to ringing my husband, who finally managed to contact me and told me they wanted to be one of the speakers in Sommar in 2016.“  What was your response? ”’Why me? What do they know about me? Who would want to listen to me?’ I am too shy. I do not like to speak about myself to people I do not know very well. Then I pulled myself together and dug deep and convinced myself that for reasons unknown to me the Sommar i P1 team are giving me this honour, so mine is to say simply ’yes thank you’”. What will you be talking about on your Sommar? ”If I tell you too much, it will take away any chance of surprise! I will talk a bit about my background, how I ended up in Sweden, my deep interest in parasitic diseases, especially leishmaniasis, my current work, some somewhat funny things and some serious issues related to getting on here in Sweden.” How will you present yourself, the short version? ”As a Leishmaniac. For once a Leishmaniac, always a Leishmaniac.” Will you reveal anything that you never revealed before? ”Since I have never been a ’fika’ loving person, being more of ’my coffee on my desk’ type, most people I encounter outside my family and my close friends know very little about me. For most of my life I have found it more interesting to listen to others. However, I realize with age that I hear myself speaking more than before. So I guess I will reveal more of me and few of the the things that formed me.” Will you be talking about your research? ”I will say a thing or two about my research and my work at Sida which aims to assist universities in low-income countries to develop environments that are conducive for doing research, so they can better ask their own questions and have the skills and means to address their problems.” What has been the outcome of preparing the show? ”The whole process of developing the programme made me have to do quite a bit of introspection. It was sometimes hard, other times uplifting to find some answers about things which I have not quite understood in the same way previously. From a point when ’I thought how can I speak for such a long time’, I landed at the time where I had to ruthlessly cut many of my darling bits, almost leaving me in tears. Great therapy I say!” Anyone in particular that you are hoping for will be listening? ”The main person that I want to listen to me is that young black girl who may be at a point where her self esteem/confidence may have been knocked about for whatever reason, who may be doubting her abilities, for her to get hope and an urge to use the gifts given her, whatever they may be, to try to be the best version of herself that she can be. Of course I want as many young people and early career people from all parts of the world to be encouraged by my Sommar”. Text: Madeleine Svärd Huss More on Sommar i P1 at Sveriges Radio (in Swedish only) Read more about Hannah Akuffo on ki.se

Scientists at Karolinska Institutet in collaboration with Estonian Competence Centre on Health Technologies have developed a new gene expression analysis method to widen the usage of blood in biomarker discovery and analysis. Their paper is published in the journal Scientific Reports. Blood carries cells that provide biomarkers for a number of applications. Blood as a type of liquid biopsy is widely used in clinical research due to its ease of sampling and its rapid dynamics: the majority of the cells are erythrocytes that carry oxygen, causing 50–80 per cent enrichment of globin RNA molecules among all blood RNA. Technical bias This high prevalence of globin complicates blood related gene expression biomarker studies, causing technical bias and leaving biologically relevant molecules undetectable. According to the researchers the study reveals for the first time the detailed methodology – GlobinLockTM – how to overcome a limitation in blood sample analysis caused by erythrocytes, which complicates any downstream biomarker identification or tracking from blood. The published and patent pending assay minimizes the needs of reagents and sample material, which makes it an effective and robust tool. ”The globin reduction rate of GlobinLock is sufficient for any applications. It reduces the globin prevalence from 63 per cent before to five per cent which makes it an effective tool for biotechnology companies as an additive to their kits, said Dr Kaarel Krjutškov, the leading author of the study from both Karolinska Institutet and Estonian Competence Centre on Health Technologies. DNA strands The new method consists of a pair of short synthetic DNA strands that silence majority of globin RNA molecules by highly specific binding. The strands are introduced to purified RNA sample, and according to the researchers, being effective immediately after RNA denaturation and add only ten minutes of incubation time to the whole complementary DNA synthesis procedure.  The locking DNA molecules bind specifically at globin RNA poly-A site that is needed for further analysis. Therefore the globin RNAs are “locked” prior downstream manipulations and are unavailable to cause technical biases in blood RNA biomarker applications. “We show that globin locking is fully effective not only for human samples but also for widely used animal models, like mouse and rat, cow, dog and even zebrafish”, said professor Juha Kere in who’s laboratory the invention was created at Karolinska Institutet. The research and development from idea to patent pending method was financed by Swedish Foundation for Strategic Research, Strategic Research Program funding on Diabetes to Karolinska Institutet, Swedish Research Council, Orion Research Foundation, EU, Enterprise Estonia, and the Estonian Ministry of Education and Research. The GlobinLock technology is already applied in different ongoing research projects. Publication Globin mRNA reduction for wholeblood transcriptome sequencing Kaarel Krjutškov, Mariann Koel, Anne Mari Roost, Shintaro Katayama, Elisabet Einarsdottir, Eeva-Mari Jouhilahti, Cilla Söderhäll, Ülle Jaakma, Mario Plaas, Liselotte Vesterlund, Hannes Lohi, Andres Salumets and Juha Kere. Scientific Reports, published online 12 August, 2016, doi: 10.1038/srep31584.

A new publication in the scientific journal Gut sheds light on the role that certain genes have in determining how people differ in their bowel habits. The study results from the collaboration of research groups at Karolinska Institutet and the University Medical Centre Groningen, Groningen, the Netherlands. How often people move the bowels is important for their well-being, as altered patterns are often observed, for instance, in common gastrointestinal conditions like irritable bowel syndrome (IBS), affecting millions worldwide.  By studying two population-based cohorts from Sweden (PopCol) and the Netherlands (LifeLines-Deep), researchers from the Department of Biosciences and Nutrition at Karolinska Institutet and the University Medical Center Groningen have tested the hypothesis that human genes may contribute to individuals’ differences in their evacuation rates (stool frequency). They used genome-wide association studies (GWAS) to look at the genetic make-up of people who kept daily records of their bowel movements, and identified genes that are associated with increased or decreased stool frequency. Among these, two important classes of genes were most abundant: cytochromes and ion channels. Cytochromes are enzymes that help detoxify our body from substances known as xenobiotics (chemicals found in foods and drugs), while sodium and other ion channels are important conductors of the electric pulses controlling, for instance, heart pumping and bowel contractions. - This is a good example of the potential for translational medicine that can be gained from the study of the general population; the genetic mechanisms we have started to unearth represent known druggable targets and may be exploited for future therapeutic options in common conditions like IBS, Senior co-author Mauro D’Amato comments. Publication A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency Jankipersadsing SA, Hadizadeh F, Bonder MJ, Tigchelaar EF, Deelen P, Fu J, Andreasson A, Agreus L, Walter S, Wijmenga C, Hysi P, D'Amato M, Zhernakova A. Gut. 2016 Jul 29. pii: gutjnl-2016-312398. doi: 10.1136/gutjnl-2016-312398.

Women with an inactive Wnt5a gene run a higher risk of aggressive breast cancer. In a transatlantic collaboration between Karolinska Institutet and Weill Cornell Medicine in New York scientists have discovered how Wnt5a prevents tumour development. The study is published in the periodical PLOS Genetics. Breast cancer is globally the most common form of cancer in women, with 7,800 women in Sweden alone having been diagnosed with the disease in 2013 and the number of new cases rising by an annual two per cent. Previous large studies have shown that women who have an inactive Wnt5a gene are at greater risk of developing aggressive breast cancer. Inhibits ability An active Wnt5a gene, on the other hand, inhibits the ability of cells to propagate and form tumours. The precise mechanism behind this phenomena has been unclear, but now the researchers have found an explanation. The building blocks of the human body are made up of proteins manufactured in our cells in protein factories called ribosomes. The creation of ribosomes – ribosomal biogenesis – is a highly complex process that consumes 60 to 80 per cent of a cell’s total energy. Tumour cells, which divide more often than normal cells, need more proteins and therefore more ribosomes in order to continue the mitotic process. Ribosomal biogenesis is controlled by the RNA-polymerase I (Pol I) enzyme complex, which is overactive and uncontrolled during cancer. “Our research group has discovered that an active Wnt5a gene regulates and inhibits Pol I activity and with it ribosomal biogenesis in breast cancer cells, which inhibits cell growth and division,” explains Theresa Vincent, research group leader at Karolinska Institutet’s Department of Physiology and Pharmacology and at Weill Cornell Medicine’s Department of Physiology and Biophysics. New treatment Their results show why drugs that mimic the activity of the Wnt5a gene could lead to a new treatment for aggressive breast cancer. “We also show that breast cancer patients with an active Wnt5a live longer than those without,” continues Dr Vincent. “With a better understanding of ribosome biology we will be able to design new types of drug able, hopefully, to combat aggressive breast cancer tumours and possibly other forms of cancer too.” The study was financed with grants from the Swedish Research Council, the Georg and Eva Klein Visiting Junior Scientist Award, the American-Scandinavian Foundation, the Swedish Cancer Society, the VINNMER Marie Curie International Qualification, Karolinska Institutet, the National Institutes of Health, Göran and Birgitta Grosskopf, Lund University, New York University Abu Dhabi and the Tri-Institutional Stem Cell Initiative, New York. Publication Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I Randall A. Dass, Aishe A. Sarshad, Brittany B. Carson, Jennifer M. Feenstra, Amanpreet Kaur, Ales Obrdlik, Matthew M. Parks, Varsha Prakash, Damon K. Love, Kristian Pietras, Rosa Serra, Scott C. Blanchard, Piergiorgio Percipalle, Anthony M. C. Brown, C. Theresa Vincent. Plos Genetics, published online 8 August 2016, doi:10.1371/journal.pgen.1006217.

Many types of cancer are caused by gene mutations in the signalling pathways that control cell growth, such as the hedgehog signalling pathway. A new study from the Karolinska Institutet, published in the journal Nature Communications, now surprisingly shows that in colon cancer hedgehog signalling has a protective function. Mutations that lead to the activation of hedgehog signalling are the cause of almost all cases of basal cell carcinoma (a common form of skin cancer) and certain types of brain tumours. Previous studies have indicated that hedgehog signalling is also important in other types of cancer, such as colon cancer – one of the commonest types of cancer in Sweden. Influencing cell growth The research team at the Department of Biosciences and Nutrition at Karolinska Institutet’s campus in Huddinge, led by Marco Gerling and Rune Toftgård, has been working alongside researchers in Holland looking at the possibility of influencing cell growth in colon cancer by altering hedgehog signalling. In view of the fact that tumours consist of different types of cells apart from the cancer cells themselves, the researchers used various databases to analyse gene expression in colon cancer. Although the team was not able to find any activation of the signalling pathway in the cancer cells, it was able to confirm earlier observations that it is only the hedgehog ligand, the protein needed to launch the signalling process that is produced by the cancer cells. In contrast, the hedgehog signalling pathway and expression of its target genes are specifically activated in the surrounding cells of the connective tissue. Mouse model To investigate the importance of the hedgehog signalling from cancer cells to connective tissue cells, the researchers used a mouse model in which the signalling pathway could be switched on specifically in the connective tissue cells. When mice were treated with substances that induce colon cancer, the mice with activated hedgehog signalling in the connective tissues developed significantly fewer tumours than those with a normal hedgehog function. When the team then did the opposite – inhibiting hedgehog signalling in different mouse models – the mice developed more tumours. The researchers were able to show that the connective tissue cells with activated hedgehog signalling change their gene expression and send a signal back to the tumour cells, inhibiting the development and growth of tumours. “The results show that non-cancerous cells in tumours have a great capacity to influence how tumours develop,” says Marco Gerling, one of the researchers. “In the long term we hope to be able to provide a detailed explanation of how the activation of hedgehog signalling in the cells surrounding the tumour can prevent the growth of tumours and to use this knowledge to develop new types of treatment that can restrain the development of cancer.”  The research was funded through support from organisations such as the Swedish Cancer Society, the Swedish Research Council, the German Research Foundation and the Ruth and Richard Julin Foundation. Publication Stromal hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth Marco Gerling, Nikè V.J.A. Büller, Leonard M. Kirn, Simon Joost, Oliver Frings, Benjamin Englert, Åsa Bergström, Raoul V. Kuiper, Leander Blaas, Mattheus C.B. Wielenga, Sven Almer, Anja A. Kühl, Erik Fredlund, Gijs R. van den Brink and Rune Toftgård. Nature Communications, published online 5 Augusti 2016, doi 10.1038/NCOMMS12321

Younger siblings, single children and older siblings are at different risk of developing asthma and other common childhood diseases, according to a Swedish population study carried out by researchers at Karolinska Institutet and published in The Journal of Allergy and Clinical Immunology. Much research has been done indicating that younger siblings run a lower risk of developing asthma or allergies such as hay fever and atopic eczema. Similar sibship effects has been observed for other disorders too, such as type 1 diabetes and certain neuropsychiatric conditions like ADHD. The present study is an attempt by the researchers to obtain a more synthesised understanding of the issue. “Our study confirms a link between sibship and childhood disease,” says principal investigator Catarina Almqvist Malmros, professor at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics and paediatrician at Astrid Lindgren’s Children’s Hospital. Sibship data Professor Almqvist Malmros and her colleagues extracted sibship data from the Swedish Multigenerational Registry linked to the Medical Birth Registry on over 300,000 children born between 1996 and 2002. Just over 13% of the children had no siblings (single children), 43% were first-born and 44% had an older sibling. The researchers measured the prevalence of disease in the children in 2008 when they were between 6 and 12 years old. Information on specialist care and medication for asthma, type 1 diabetes, ADHD and respiratory infection was collected from the Swedish Prescribed Drug Register and the National Patient Register. “We found that single children had a higher risk of asthma, diabetes and ADHD than first-borns who had younger siblings, but showed no difference in the risk of developing respiratory infections,” says Dr Almqvist Malmros. Lower risk Younger siblings had a lower risk of asthma and respiratory infections than first-borns with siblings. The study provides no answers as to the cause of this correlation between sibship and childhood disease, but the researchers attribute it either to differences in exposure to bacteria and viruses, to the uterine environment during gestation, or to reduced health seeking behavior in parents who are used to viral infections in their second borns, more comfortable with the disease and less likely to seek evaluation or treatment. The research was financed by grants from the Swedish Research Council through SIMSAM (the Swedish Initiative for Research on Microdata in the Social and Medical Sciences), the Swedish Heart and Lung Foundation, the Åke Wiberg Foundation, Sällskapet Barnavård, grants provided from the Stockholm County Council (ALF project) and the Strategic Research Program in Epidemiology at Karolinska Institutet. Publication Sibship and risk of asthma in a total population - a disease comparative approach Catarina Almqvist, Henrik Olsson, Tove Fall, Cecilia Lundholm Journal of Allergy and Clinical Immunology, published online 17 June 2016, doi: 10.1016/j.jaci.2016.05.004

Researchers at Karolinska Institutet have elucidated a novel role for neutrophils in immune function, in that they are important in control of B cell immune responses. The study, which is published in the Journal of Experimental Medicine, may have an impact on how vaccinations are performed. In a person infected by bacteria or viruses the immune system becomes activated to protect against these microorganisms. Macrophages residing in tissues detect these intruders and alert the rest of the immune system. Greater functionality One of the first cell types to arrive at the infected site is the neutrophil, which are very effective in destroying bacteria. It has long been believed that this was the only role neutrophils had, but studies have shown that they may have greater functionality during inflammatory processes.  “Using an experimental model of neutrophil depletion we have demonstrated that on immune activation there is a cascade of immune activation that results in a significantly increased B cell response with heightened production of antibodies as an endpoint,” says Professor Bob Harris, Department of Clinical Neuroscience, the principal investigator of the study. The researchers demonstrate that T cells using the cytokine IL-17 are able to attract a large number of neutrophils into the inflamed lymph nodes. These are a meeting place for immune cells that communicate with each other before migrating to an inflamed tissue. In the lymph node these neutrophils help to activate B cells through producing BAFF, a protein that amplifies the B cell activation and plasma cell development, finally resulting in production of large quantities of antibodies. Understanding cell function The Applied Immunology and Immunotherapy research group led by Bob Harris is primarily interested in understanding myeloid cell function. For PhD student Roham Parsa it was his unexpected finding that he had managed to deplete neutrophils that led to the published study. Despite being initially neutropenic (lacking neutrophils in steady-state), on immune stimulation the few remaining neutrophils expanded rapidly and a state of emergency granulopoesis with an over-production of new neutrophils ensued. It was the dual phases of neutrophil depletion followed by neutrophil excess that leads to the heightened B cell response and antibody production, which is a novel finding.  “For diseases such as SLE we should be able to down-regulate antibody responses, and for viral infections in which heightened antibody responses would be of benefit then manipulation of neutrophil reactivity using the cascade we have defined should be beneficial. What we have also learnt from this study is that it is important to reflect on unexpected findings and to pursue new avenues if they address interesting research questions,” Bob Harris says. First author of the study has been Roham Parsa. The study has been supported by Vetenskapsrådet, Cancerfonden and Karolinska Institutet (KID). Publication BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis Parsa R, Lund H, Georgoudaki A-M, Zhang X-M, Ortlieb Guerreiro-Cacais A, Grommisch D, Warnecke A, Croxford AL, Jagodic M, Becher B,. Karlsson MCI, Harris RA. Journal of Experimental Medicine, published online July 18, 2016, doi: 10.1084/jem.20150577.

It is known that people who have attempted suicide have ongoing inflammation in their blood and spinal fluid. Now, a collaborative study from research teams in Sweden, the US and Australia published in Translational Psychiatry shows that suicidal patients have a reduced activity of an enzyme that regulates inflammation and its byproducts. (English text: edited and translated by Van Andel Research Institute). The study is the result of a longstanding partnership between the research teams of Professor Sophie Erhardt, Karolinska Institutet, Professor Lena Brundin at Van Andel Research Institute in Grand Rapids, USA, and Professor Gilles Guillemin at Macquarie University in Australia. The overall aim of the research is to find ways to identify suicidal patients. Biological factors "Currently, there are no biomarkers for psychiatric illness, namely biological factors that can be measured and provide information about the patient's psychiatric health. If a simple blood test can identify individuals at risk of taking their lives, that would be a huge step forward", said Sophie Erhardt, a Professor at the Department of Physiology and Pharmacology at the Karolinska Institutet, who led the work along with Lena Brundin. The researchers analyzed certain metabolites, byproducts formed during infection and inflammation, in the blood and cerebrospinal fluid from patients who tried to take their own lives. Previously it has been shown that such patients have ongoing inflammation in the blood and cerebrospinal fluid. This new work has succeeded in showing that patients who have attempted suicide have reduced activity of an enzyme called ACMSD, which regulates inflammation and its byproducts. “We believe that people who have reduced activity of the enzyme are especially vulnerable to developing depression and suicidal tendencies when they suffer from various infections or inflammation. We also believe that inflammation is likely to easily become chronic in people with impaired activity of ACMSD,” said Brundin Important balance The substance that the enzyme ACMSD produces, picolinic acid, is greatly reduced in both plasma and in the spinal fluid of suicidal patients. Another product, called quinolinic acid, is increased. Quinolinic acid is inflammatory and binds to and activates glutamate receptors in the brain. Normally, ACMSD produces picolinic acid at the expense of quinolinic acid, thus maintaining an important balance. “We now want to find out if these changes are only seen in individuals with suicidal thoughts or if patients with severe depression also exhibit this. We also want to develop drugs that might activate the enzyme ACMSD and thus restore the balance between quinolinic and picolinic acid,” Erhardt said. The study was funded with the support of the Swedish Research Council, Region Skåne and Central ALF funds. Additional support came from National Institute of Mental Health (NIMH), the American Foundation for Suicide Prevention, Van Andel Research Institute, Rocky Mountain MIRECC, the Merit Review CSR & D and the Joint Institute for Food Safety and Applied Nutrition (University of Maryland), and the Australian Research Council. Several of the researchers have indicated that they have business interests, which are recognized in the article. Publication An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation Lena Brundin, Carl M. Sellgren, Chai K. Lim, Jamie Grit, Erik Palsson, Mikael Landen, Martin Samuelsson, Christina Lundgren, Patrik Brundin, Dietmar Fuchs, Teodor T. Postolache, Lil Träskman-Bendz, Gilles J. Guillemin, Sophie Erhardt. Translational Psychiatry, published online August 2, 2016, doi: 10.1038 / TP.2016.133.

The researcher Fredrik Piehl at the Department of Clinical Neuroscience at Karolinska Institutet has been rewarded a grant of approximately 8,5 million US dollar, from The Patient-Centered Outcomes Research Institute, PCORI, USA. Together with others researchers at the Department of Clinical Neuroscience and in collaboration with other clinical researchers in Sweden and in California, USA, Piehl will be studying the long-term efficacy of different disease-modifying treatments, DMT, for multiple sklerosis, MS. — There are several existing drugs registered for treatment of MS, but still lacking is knowledge on their long-term efficacy and quality of life,. the latter which by the patients is the single most important factor, says Fredrik Piehl. Moreover, during the latest years we have detected that rituximab, a drug approved for rheumatoid, in comparison to many other MS treatments seems to be a very effective, relatively safe and also very cost-effective treatment also for MS patients. The PCORI grant gives us the means to thorouoghly compare rituximab with other MS treatments thus gaining further evidence on recommended application. Some 6.000 patients are estimated to be part of the study and about 4.000 will have an annual follow-up during six to nine years. MS is a chronic disease and as of today there is no cure but there are a number of DMT:s that can palliate disease progression and symptoms. In this specific round of PCORI grant allocation, a total of 35 awards totalling 153 million US dollar was awarded within the areas of chronic pain MS and dpression. The Patient-Centered Outcomes Research Institute is an independent nonprofit, nongovernmental organization located in Washington, DC. Fredrik Piehl's profile page

Patients with OCD are 10 times more likely to commit suicide, contrary to what was previously thought. In a new study from Karolinska Institutet published in the journal Molecular Psychiatry, is also shown that the main predictor of suicide in OCD patients is a previous suicide attempt, which offers opportunities for prevention. Suicide is a major public health problem that leads to an estimated 800 000 deaths worldwide each year. People with mental health conditions are at higher risk to die by suicide, and about 90 percent of those who die by suicide are considered to suffer from a mental disorder. However, little attention has been paid to the risk of suicide among people suffering from obsessive-compulsive disorder (OCD), one of the most common psychiatric disorders. OCD has a lifetime prevalence of about two per cent in the general population, generally runs a chronic course, and is often associated with a significantly reduced quality of life. The risk of suicide in OCD has traditionally been considered low. In order to estimate the risk of suicide among people affected by OCD and identify risk and protective factors associated with suicidal behavior in this group, the researchers analyzed data from the Swedish national registers, spanning over 40 years. They identified 36 788 OCD patients in the Swedish National Patient Register between 1969 and 2013, of whom 545 had died by suicide and 4297 had attempted suicide. The risk of death by suicide was approximately ten times higher, and the risk of attempted suicide five times higher than that of the general population. After adjustment for other psychiatric disorders, the risk was reduced, but remained substantial. - Within the OCD cohort, a previous suicide attempt was the strongest predictor of death by suicide. Having a personality disorder or a substance use disorder also increased the risk. In contrast, being a woman, higher socioeconomic status, and having an anxiety disorder were protective factors, says Lorena Fernández de la Cruz, an Assistant Professor at the Department of Clinical Neuroscience. - The researchers concluded that patients with OCD are at significant risk of suicide, even in the absence of other psychiatric conditions, which clinicians should be aware of. Suicide risk must be closely monitored in these patients, especially in those who have previously attempted suicide. These results are a first step towards the design of preventive strategies aimed at preventing fatal consequences in patients with OCD.   Publication "Suicide in obsessive-compulsive disorder: a population-based study of 36,788 Swedish patients" L Fernández de la Cruz, M Rydell, B Runeson, D'Onofrio BM, G Brander, C Rück, Lichtenstein P, H Larsson, D Mataix-Cols. Molecular Psychiatry, published online 19 July 2016, doi: 10.1038 / mp.2016.115.   For more information contact Lorena Fernández de la Cruz Department of Clinical Neuroscience, Karonlinska Institutet Phone: 0768477999 Mail: lorena.fernandez.de.la.cruz@ki.se

Gastric bypass surgery is used to help obese patients lose weight, but a study from Karolinska Institutet published in The Annals of Surgery shows that people with a history of depression run a high risk of severe post-operative depression. Gastric bypass, or bariatric surgery, is used around the world to help seriously obese patients lose weight, reducing their chances of diabetes and improving the quality of their lives. However, there has also been some debate on whether it can have adverse psychiatric consequences. In the present study, the researchers examined the frequency of hospitalisation for depression, self-harm and suicide after gastric bypass surgery using data from the Swedish National Patient Register, the Swedish Prescribed Drug Register and the Cause of Death Registry. “Our results show that people with a previous diagnosis of depression up to two years prior to surgery were 52 times more likely to become so depressed that they required inpatient psychiatric care in the two years following surgery,” says Ylva Trolle Lagerros, Associate Professor at the Department of Medicine, Solna. “People without a depression diagnosis, but who had been prescribed antidepressants at least once ran an eight times higher risk of such severe depression.” Patients with a self-harm diagnosis prior to surgery were 36 times more likely to repeat their self-harming behaviour afterwards. This risk was highest in the under-25 group and declined with age. Amongst women the risk of suicide was 4.5 times higher than Swedish women of the same age. To conduct their study, the team studied registry data for everyone – 22,539 people in total – who had undergone bariatric surgery in Sweden between the years of 2008 and 2012. The average age was 41.3 years and 75.3 per cent were women. The number of patients who had been diagnosed with self-harm or depression or who had been prescribed antidepressants up to two years before surgery was noted, and the risk of hospitalisation for depression or self-harm during the two years following surgery was then calculated. As regards suicide, the risk for bariatric surgery patients was compared with that for the Swedish population of the same sex and age over the two years following surgery. “Our results show that we need more awareness of the psychiatric risks facing this patient group,” says Dr Trolle Lagerros. “These are alarming figures and they therefore should be offered extra post-operative psychiatric support. But it would be wrong to say that this patient group should be denied the possibility of receiving surgery for their obesity.” Publication “Suicide, self-harm and depression after gastric bypass surgery: a nationwide cohort study” Ylva Trolle Lagerros, Lena Brandt, Jakob Hedberg, Magnus Sundbom och Robert Bodén. Annals of Surgery, published online 14 June 2016 doi: 10.1097/SLA.0000000000001884

Scientists from Karolinska Institutet, Sweden, have discovered how the brain controls our breathing in response to changing oxygen and carbon dioxide levels in the blood. (Text: courtesy of eLife Press) The control of breathing is essential for life. Without an adequate response to increased carbon dioxide levels, people can suffer from breathing disturbances, sickness, and panic. In worst-case scenarios, it can lead to premature death, as in sudden infant death syndrome. There has been some debate over how the brain controls breathing. Now, a new study in mice, to be published in the journal eLife, shows that when exposed to decreased oxygen or increased carbon dioxide levels, the brain releases a small molecule called Prostaglandin E2 (PGE2) to help protect itself and regulate breathing. To discover this mechanism, the researchers grew a section of a mouse’s brainstem (the central trunk of the brain) in a type of dish. The slice contained an arrangement of nerve and supporting cells that allowed it to ‘breathe’ for three weeks. During this time, the team monitored the cells and their behaviour in response to changes in the environment. “Our novel brainstem culture first revealed that cells responsible for breathing operate in a small-world network. Groups of these cells work very closely with each other, with each group interconnected by a few additional cells that appear to work as hubs. This networking activity and the rhythmic respiratory motor output it generated were preserved for the full three weeks, suggesting that our brainstem can be used for long-term studies of respiratory neural network activity,” explains David Forsberg, PhD student and first author of the study. “Secondly, we saw that exposure to different substances made the brainstem breathe faster or slower. Perhaps most interesting was its response to carbon dioxide, which triggered a release of PGE2. Here, PGE2 acted as a signaling molecule that increased breathing activity in the carbon dioxide-sensitive brainstem region, leading to slower and deeper breaths, or ‘sighs’.” These new insights have important implications for babies, who experience significantly reduced levels of oxygen during birth. At this stage, PGE2 protects the brain and prepares the brainstem to generate deep sigh-like breath intakes, resulting in the first breaths of air following birth. The study also reveals a novel pathway linking the inflammatory and respiratory systems. PGE2 is released during inflammation and fever, which can dysregulate breathing patterns and interfere with normal responses to carbon dioxide. This can in turn cause disturbed and even dangerous halts in breathing. “Our findings go some way to explaining how and why our breathing responses to imbalanced oxygen and carbon dioxide levels are impaired during infectious episodes. It also helps further our understanding of why infection can inhibit breathing so severely in new-born babies,” says Eric Herlenius, Professor at Karolinska Institutet’s Department of Women’s and Children’s Health, and senior author of the paper. “We now want to find out how breaths form and develop during episodes of inflammation. This could be useful for researching potential new ways to save babies’ lives when they are unable to catch their breaths.” Reference  The paper ‘CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture’ can be freely accessed online at http://dx.doi.org/10.7554/eLife.14170. Contents, including text, figures, and data, are free to reuse under a CC BY 4.0 license.  Media contacts Emily Packer, eLife  e.packer@elifesciences.org  01223 855373  Eric Herlenius, Karolinska Institutet Eric.Herlenius@ki.se +46-(0)8-5177 5004 | 070-78 78987

In the journal Cell Reports researchers at Karolinska Institutet together with international colleagues present new data on the pediatric tumor neuroblastoma. Neuroblastoma is a nerve cell cancer that affects young children and originates in the peripheral nervous system along the spine and in the adrenal glands. - In some high-risk tumors the MYCN gene is activated and can be amplified up to 100 copies in a single cell, said Marie Arsenian-Henriksson, professor at Karolinska Institutet and the principal investigator of the study, in a comment to the publication. The research team has found that the cortisol receptor, a hormone receptor located in the cell nucleus, is down regulated by a certain microRNA cluster, miR 17-92, which in its turn is activated by the MYCN protein. They have then studied the effects of combining reduced MYCN protein levels  followed by activation of the cortisol receptor, and found that this treatment results in neuronal maturation  and decreased tumor growth in mice. The results may have implications for the treatment of neuroblastoma patients. One possibility is that dexamethasone or steroid hormones could be used for the therapy of patients who have high levels of the cortisol receptor. - Our study also shows that cells from high-risk patients with high levels of MYCN respond with maturation when treated with a combination of MYCN inhibitors  and dexamethasone. The MYCN inhibitors both reduce MYCN levels as well as increase the cortisol receptor thus enabling the cells to respond to dexamethasone and to differentiate into nerve cells, says Marie Arsenian-Henriksson. -We hope that this new combination therapy soon will be used in clinical trials in neuroblastoma patients, concludes Diogo Ribeiro.

Scientists at Karolinska Institutet in Sweden have developed a new technique that enables them to isolate single neurons from tissues and analyse the gene expression within. The study, which is published in Nature Communications, demonstrates how the method can be used by neurologists to distinguish between closely related neurons that may show differential vulnerability to disease. The method can also be of value to other areas, such as cancer research, pathology and biomarker identification. “Similar analyses used to require hundreds, if not thousands of cells,” says Eva Hedlund at the Department of Neuroscience, who led the study with Qiaolin Deng from the Department of Cell and Molecular Biology at Karolinska Institutet. “Our methodological development allows us to effectively analyse a small number of cells, even single neurons, from human and mouse tissues.” The ability to identify gene expression in different cell populations is a valuable tool for researchers in their efforts to understand disease mechanisms and biological processes. Two hurdles they commonly face is a lack of tissue material, especially from patients with different diseases, and small cell populations. In many cases, there are no unique genetic markers that can be used to identify the cells. Methods that enable identification and analysis of a small number of cells in scarce tissues are therefore warranted. The teams at KI have now combined two existing methods to develop a new method they call LCM-seq. First they use laser capture microscopy (LCM) to dissect specific cells from tissue samples and then deep RNA sequencing to study all the active genes within these. “One great advantage of the technique is that the tissue does not need to be broken up,” says Dr Qiaolin. “Thanks to that, the positional information remains intact in each isolated cell. Given that we don’t have to purify RNA molecules from the cells and can use off-the-shelf reagents, LCM-seq is simpler, cheaper and has much higher reproducibility and sensitivity than previous methods.” The researchers also show that LCM-seq can be used to learn more about populations of very similar nerve cells. They studied motor neurons isolated from different parts of the spinal cord that are susceptible to degeneration in the incurable disease ALS, and examined dopamine cells from different parts of the midbrain that are destroyed in Parkinson’s disease. “We show that we can identify specific differences between dopamine cells that are liable to atrophy in Parkinson’s disease and those that are resistant,” says Dr Hedlund. “Since very few cells are needed for LCM-seq, the technique could be of considerable use in other areas, such as cancer biology, pathology and biomarker identification.” The study was financed by grants from several bodies, including the EU’s Joint Programme for Neurodegenerative Disease, the Ragnar Söderberg Foundation, the Swedish Research Council, Karolinska Institutet, the Åhlén Foundation, the Parkinson Foundation, Neuro Sweden, the Swedish Society for Medical Research, the Jeansson Foundations and the Swedish Foundation for Strategic Research. Publication: 'Laser capture microscopy coupled with Smart-seq2 (LCM-seq) for precise spatial transcriptomic profiling', Susanne Nichterwitz, Geng Chen, Julio Aguila Benitez, Marlene Yilmaz, Helena Storvall, Ming Cao, Rickard Sandberg, Qiaolin Deng, Eva Hedlund, Nature Communications, published online xx xxxx 2016, doi: 10.1038/ncomms12139 For further questions, please contact: Eva Hedlund, Associate professor Department of Neuroscience Telephone: +46 (0)8-524 878 84 or +46 (0)76-1130911 E-mail: eva.hedlund@ki.se Profile page: http://ki.se/en/people/evahed   Qiaolin Deng, Assistant professor Department of Cell and Molecular Biology Telephone: +46 (0)76-2612920 E-mail: qiaolin.deng@ki.se Profile page: http://ki.se/en/people/qiaode

New methods to examine the brain and spinal fluid heighten the chance of early diagnosis of Alzheimer's disease.  Results from a large European study, led by researchers at the Karolinska Institutet, are now published in the medical journal BRAIN. These findings may have important implications for early detection of the disease, the choice of drug treatment and the inclusion of patients in clinical trials. Despite many years of intensive research, no effective treatment currently exists for Alzheimer's disease, which is the most common form of dementia. It has become increasingly clear that, if the disease is to be treated successfully, it must be detected early, perhaps even before symptoms are evident. Thus, there is a great need for reliable diagnostic methods so that treatment to slow or prevent the disease can begin as early as possible. A characteristic, pathological sign of Alzheimer's disease is the formation of insoluble amyloid plaques that accumulate in the brain. The presence of these plaques can be measured in the brain using positron emission tomography (PET camera) to visualize radioactive tracer molecules that bind to the amyloid plaques. Amyloid levels can also be measured in spinal fluid. While amyloid accumulates in the brain in Alzheimer's disease, research has shown that levels of amyloid in the spinal fluid is instead reduced.  In the current study, researchers compared the amyloid-PET measurements in the brain with amyloid-β42 in the spinal fluid to see how well they align. The investigations were performed at seven European memory clinics on 230 patients who were examined for memory disorders. Patients received various diagnoses, such as mild cognitive impairment (MCI), Alzheimer's disease and various types of dementia. A small group of healthy individuals were control subjects. PET studies on the patients’ brains were evaluated both locally at the seven different hospitals and centrally at the Karolinska Institutet. The researchers also used a new method, called the centiloid method, in order to standardize the measured amyloid values on a unified scale so they can be compared. Levels of amyloid42 were measured from the samples of cerebrospinal fluid at each local hospital. All samples were also analyzed centrally at Sahlgrenska Hospital in Gothenburg, where the levels of amyloid42, as well as a second amyloid protein amyloid40, were measured. The researchers found that the best fit was achieved when the amyloid level in the brain was compared with the ratio between the levels of amyloid42 and amyloid40 in the spinal fluid. Given this finding, the research team hypothesized that the forms of β-amyloid found in the brain and spinal fluid are not completely identical. “Interestingly, there was also a difference between the values measured in the brain and spinal fluid in a smaller group of patients. This may justify that, in some unclear cases, the diagnosis should include an amyloid PET scan to complement the cerebrospinal fluid sample. These findings are also important because it is increasingly common to perform amyloid-PET studies upon the inclusion of patients in new drug studies”, said the study's coordinator Agneta Nordberg at the Department of Neurobiology, Care Sciences and Society, Center for Alzheimer's Research, Karolinska Institutet. Doctoral student Antoine Leuzy, at the same institution, is the study's first author. The study was part of BIOMARKAPD, the EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The portion of the research conducted in Sweden has been funded with the support of the Swedish Research Council, Karolinska Institute, the Swedish Brain Power, Swedish Foundation for Strategic Research (SFF), the Swedish Brain Foundation and the Alzheimer Foundation. Publication: "Pittsburgh Compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European Memory Clinic study", Antoine Leuzy, Konstantinos Chiotis, G. Steen Hasselbalch, Juha O. Rinne, Alexandre de Mendonca, Markus Otto, Alberto Lleó, Miguel Castelo Branco, Isabel Santana, Jarkko Johansson, Sarah Anderl-Straub, Christine A. F. von Arnim, Ambros Beer, Rafael Blesa, Juan Fortea, Sanna-Kaisa Herukka, Erik Portelius, Joseph Pannee, Henrik Zetterberg, Kaj Blennow and Nordberg, Brain, published online 8 July 2106, doi: 10.1093 / brain / aww160 For more information, please contact: Agneta Nordberg, Professor, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer's Research Phone: 08-58585467 or 070-5107685 E-mail: Agneta.K.Nordberg@ki.se Profile Page: http://ki.se/people/agnnor

KI's pedagogical prize 2016 is awarded Dulceaydee Norlander Gigliotti, Associate Professor and Director of Studies at Comparative Medicine. She is awarded for having modernised and made the education in laboratory animal science more efficient. “It's a great joy receiving this prize, especially now that I retire after 32 years at KI. The prize is also important for comparative medicine”, says Dude Gigliotti. It has been five years since Dude Gigliotti started developing the new education in laboratory animal science. There are currently several different courses on different levels on offer for technicians and researchers. A web-based training course in laboratory animal science is of special relevance as it was created in order to meet a new EU directive. “When we launched the online training course 'Laboratory Animal Science for Researchers – Rodents and Lagomorphs' in January 2013, the universities of Lund, Gothenburg and Umeå were also offered to use KI's innovative online training course”, she says. Today there is a national consortium in laboratory animal science. In addition to the universities who joined in from the start, Uppsala and Stockholm University as well as the Swedish University of Agricultural Sciences are also part of the consortium. More than 2,000 users of laboratory animals have been trained since 2013. KI's web-based and species specific laboratory animal training courses are the first of their kind in the EU and have not only garnered great attention internationally but also had a positive impact with Swedish animal welfare bodies. The pedagogical prize is awarded by the Board of Higher Education. The chair of the prize committee is Annika Östman Wernerson, Dean of Higher Education. “We have many fantastically skilled and committed teachers at KI and it is important that we acknowledge and highlight those that in a very special way have contributed to increasing the quality of our training courses and programmes. The pedagogical prize winners inspire all other employees and make for important role models.” Congratulations to you Dude!   Text: Maja Lundbäck Photo: Stefan Zimmerman

Scientists at Karolinska Institutet and the Royal Institute of Technology (KTH) have devised a new high-resolution method for studying which genes are active in a tissue. The method can be used on all types of tissue and is valuable to both preclinical research and cancer diagnostics. The results are published in the journal Science. Disease changes the expression of RNA molecules and proteins in tissues. Microscopic studies of tissue samples are routinely carried out in laboratories and hospitals in the interests of furthering knowledge and diagnostics, but to date only the location of a small number of RNA molecules has been possible to establish simultaneously. A collaboration between professors Jonas Frisén (KI) and Joakim Lundeberg (KTH) at SciLifeLab has resulted in a novel method that allows analysis of the quantity of all RNA molecules and provides spatial information from the microscope. “By placing tissue sections on a glass slide on which we have placed DNA strands with built in address labels we have been able to label the RNA molecules formed by active genes,” says Professor Frisén. “When we analyse the presence of RNA molecules in the sample, the address labels show where in the section the molecules were and we can get high-resolution information on where different genes are active.” The results are also valuable for more precise diagnostics. Current practice is to take a tissue sample, grind it down and analyse the mix of cells, but the risk is that a few cancer cells become so diluted by the signals from all the other cells in the sample and are therefore overlooked. “With our method, we can pick up the tumour signal as it is not diluted,” he continues. “Because different parts of the tissue sample have their specific address labels we can identify a small number of tumour cells.” The method can be used on all types of tissue and diseases. It can also provide information about disease heterogeneity in cancer diagnostics, as is demonstrated in the study for breast cancer. What do you hope your method will lead to? “It makes it possible to study which genes are active in tissues with greater resolution and precision than ever before, which is valuable to both basic research and diagnostics,” says Professor Frisén. The study was financed with grants from the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Society, Karolinska Institutet, the Tobias Foundation, the Torsten Söderberg Foundation, the Ragnar Söderberg Foundation, StratRegen (the strategic research area in stem cell research and regenerative medicine at KI), the Åke Wiberg Foundation and the Jeanssons Foundations. Publication Visualization and analysis of gene expression in tissue sections by spatial transcriptomics Patrik L. Ståhl, Fredrik Salmén, Sanja Vickovic, Anna Lundmark, José Fernández Navarro, Jens Magnusson, Stefania Giacomello, Michaela Asp, Jakub O. Westholm, Mikael Huss, Annelie Mollbrink, Sten Linnarsson, Simone Codeluppi, Åke Borg, Fredrik Pontén, Paul Igor Costea, Pelin Sahlén, Jan Mulder, Olaf Bergmann, Joakim Lundeberg, Jonas Frisén. Science, published online 1 July 2016, doi: 10.1126/science.aaf2403.

Previous studies have shown that neurological diseases such as Alzheimer’s and Parkinson’s can be induced in healthy laboratory animals, causing concern that dementia diseases can be transmitted between individuals, possibly via blood transfusions. However, in a new study published in The Annals of Internal Medicine, a team from Karolinska Institutet shows that the diseases are not transmitted. Studies published in recent years have shown that a number of neurological conditions can be induced in healthy laboratory animals through the injection of diseased brain tissue from human sufferers. To determine whether dementia diseases can be transmitted between people via blood transfusion, researchers at Karolinska Institutet conducted a study based on a unique Swedish-Danish transfusion database. Their results demonstrate that dementia diseases are not transmitted in this way. “The results are unusually clear for such a complicated subject as this,” says principal investigator Gustaf Edgren, docent at the Department of Medical Epidemiology and Biostatistics. “We’ve been working with this question for a long time now and have found no indication that these diseases can be transmitted via transfusions.” Blood donors and patients The study was a collaboration with researchers at Statens Serum Institut in Copenhagen and was carried out using data on a total of 1.7 million blood donors and 2.1 million patients given blood transfusions in Sweden and Denmark. The researchers were able to identify over 40,000 patients who had been given blood from donors diagnosed with one of the studied dementia diseases within 20 years of having given blood. The patients were then followed up for a maximum of 44 years through the linking of a number of registries, including the Swedish and Danish patient registries. A total of 1.4 million patients who had not received blood from donors with a subsequent diagnosis were used as controls. The two groups were compared through statistical analysis taking account of sex, age, place of residence, blood group, number of transfusions and time since first transfusion. The same risk It turned out that the patients in the two groups had exactly the same risk of contracting these dementia diseases. “Blood transfusions are extremely safe in the Western world today, but even so we are working continuously and proactively on identifying any overlooked risks. The Swedish-Danish database that we have built up and used in many similar studies clearly demonstrates the value of our vast health registries. This kind of study would have simply been extremely difficult anywhere else in the world,” says Dr Edgren. The study was financed by the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Society for Medical Research and the Danish Council for Independent Research. Publication Transmission of Neurodegenerative Disorders Through Blood Transfusion A Cohort Study Gustaf Edgren, Henrik Hjalgrim, Klaus Rostgaard, Paul Lambert, Agneta Wikman, Rut Norda, Kjell-Einar Titlestad, Christian Erikstrup, Henrik Ullum, Mads Melbye, Michael P. Busch, Olof Nyrén Annals of Internal Medicine, published online 27 June 2016, doi:10.7326/M15-2421.

Structures on the surface of pneumococci determine the ability of these bacteria to enter the brain and cause severe infections, according to a paper published in The Journal of Clinical Investigation by researchers at Karolinska Institutet. Their findings suggest that certain pneumococci that are small in size, and which have a special protein on their surface, can more easily pass through the blood-brain barrier and cause meningitis that may be lethal. Pneumococci are known for causing infections in the respiratory tract such as sinusitis, otitis and pneumonia. They are also a common cause of severe diseases such as blood poisoning (septicemia) and meningitis. But how pneumococci enter the brain through the blood-brain barrier – the protective network of capillaries that prevents drugs and potentially harmful cells (e.g. immune cells, bacteria and viruses) from passing from the blood to the brain – is unclear. Structures on surface The current study, which was led by professor Birgitta Henriques-Normark, demonstrates that structures on the surface of the bacteria, so-called pili, affect how they can pass through the blood -brain barrier and infect the brain tissue. The researchers examined more closely one of the pilus proteins, RrgA, which they have shown is important for how pneumococci can bind to cells in the lung in previous studies. They now discovered that RrgA facilitates the passage of pneumococci through the blood-brain barrier. Pneumococci have a round ovoid form, and when they proliferate in the blood stream they usually appear in pairs or in short chains. However, the researchers have now found that a small proportion of pneumococci with pili in the blood, less than five per cent, can be found as individual spherical cocci. And it is these single cocci that promote penetration of the bacteria through the blood-brain barrier. Moreover, the researchers found that pneumococci with pili that infected brains were spherical, single cocci that did not express the protein DivIVA, which is involved in cell division and responsible for the oval-shaped form of pneumococci. ”Our data suggests that pneumococci that have the pilus protein RrgA, and that present as single cocci and are small in size, more easily pass from the blood into the brain, where they can cause potentially life-threatening meningitis,” says principal investigator Professor Henriques-Normark at the Department of Microbiology, Tumor and Cell Biology. Serious consequences Meningitis is an acute, suppurative infection of the brain membranes and the spaces in between them. Meningitis is most common in children and adults over the age of 60, and can trigger symptoms such as fever, headaches, stiff neck, insomnia, vomiting, spasms and coma. The disease can have serious long-term consequences and is often fatal. The study was financed with grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Foundation for Strategic Research (SSF), the ALF agreement with Stockholm County Council and the EU, the Marie Curie project LAPASO. Publication Pneumococcal meningitis is promoted by single cocci expressing pilus-adhesin RrgA  Federico Iovino, Disa Hammarlöf, Genevieve Garriss, Sarah Brovall, Priyanka Nannapaneni and Birgitta Henriques-Normark  Journal of Clinical Investigation, published online 27 June 2016. 

Signs with the Karolinska Institutet logo are being updated on the Solna campus. The famous gold-lettered sign on the brick wall to the entrance on Solnavägen 1 has already been replaced. The new sign – also in gold – includes the Karolinska Institutet seal as well as the name. Two new signs will also be erected along what in a few years time will become the “Akademiska stråket” thoroughfare. The facelift is part of Karolinska Institutet’s signage programme and is intended to protect KI’s brand and unify its design profile. “Admittedly, the gold logo signs are not part of our regular brand profile manual,” says Maria Deckeman, Brand Manager and the person in charge of the signage programme. “But we’ve decided to keep the gold colour to uphold tradition, while discreetly updating the signs with the seal’s current look and design. These gold signs will only mark the main entrances to the Solna campus.” The old entrance sign that has been removed will be stored by the Facilities Office, possibly mounted indoors as an artwork or decoration.  About the seal Right from from the founding more than 200 years ago, Karolinska Institutet has used the seal with the symbols of a snake bowl, the rod of Asclepius and a cockerel as its hallmark. Over the years, the seal gradually changed to suit the requirements of current times, but always retaining its specific character.  Learn more about the symbolism of the seal