KI News

Researchers at Karolinska Institutet have identified cell surface markers specific for the very earliest stem cells in the human embryo. These cells are thought to possess great potential for replacing damaged tissue but until now have been difficult to distinguish from classical embryonic stem cells. The study is published in the prestigious journal Cell Stem Cell. During the first week of fertilisation, the embryo grows from a single cell into a blastocyst, a hollow cluster of a few hundred cells. The blastocyst then attaches itself to the wall of the uterus (implantation), and for a limited period from fertilisation to a few days after implantation the embryo contains pluripotent stem cells. These cells can develop into all the body’s cell types and are therefore of considerable interest to the field of regenerative and reparative medicine. Two stages for human pluripotent stem cells A few years ago, it was discovered that there are two stages for human pluripotent stem cells, corresponding to the pre-implanted and post-implanted embryonic cells. Although the classical stem cells used in regenerative medicine are isolated from the pre-implanted embryo, they have adopted a mature stage that is most likely more similar to a post-implantation embryo. A new type of pluripotent cell that genuinely corresponds to the more immature, pre-implantation stage has been identified and can now be cultivated in the laboratory. These immature stem cells are of great scientific interest since they are believed to have the potential to build certain cell types that are difficult to obtain from the classical stem cells, and they may also be easier to cultivate and manipulate in the laboratory. Fredrik Lanner’s research team at Karolinska Institutet and their colleagues in Peter Rugg-Gunn’s team at Cambridge’s Babraham Institute in the UK have now developed a tool for separating the two stem cell states. They have screened combinations of antibodies that bind to specific proteins on the surface of the immature and mature stem cells and that can be used for flow cytometry, a common laboratory technique for sorting cells. Benefits future stem cell research “We’ve not had cell surface markers for the different stem cell states before, which has made it hard to study them,” says Fredrik Lanner, Assistant Professor at Karolinska Institutet’s Department of Clinical Science, Intervention and Technology. “We now have a simple tool for identifying and sorting the cells, which benefits future stem cell research and basic research on early embryonic development.” Mature embryonic stem cells cultivated in the laboratory can, under the right conditions, be backed up in their development to the more immature stem cell type. The researchers tested their technique on such cultivated stem cells of both a mature and immature type, and on donated human embryos left over from IVF treatments. As expected, only the immature stem cell type was identified in such pre-implanted embryos, which indicates that the antibodies are highly specific. A highly critical time for the embryo “It is at the point of implantation that the stem cells go through this change and ‘mature’, which is also a highly critical time for the embryo,” says Dr Lanner. “These cells are therefore also of interest to infertility research.” The study was financed by several bodies, including the Swedish Research Council, the Ragnar Söderberg Foundation, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Centre for Innovative Medicine (CIMED) and the Ming Wai Lau Centre for Reparative Medicine. Publication Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States Amanda J. Collier, Sarita P. Panula, John Paul Schell, Peter Chovanec, Alvaro Plaza Reyes, Sophie Petropoulos, Anne E. Corcoran, Rachael Walker, Iyadh Douagi, Fredrik Lanner, Peter J. Rugg-Gunn Cell Stem Cell, online 23 March 2017, doi: 10.1016/j.stem.2017.02.014

Young men who are overweight or obese could run a higher risk of developing severe liver disease or liver cancer, suggests research from Karolinska Institutet published in the scientific journal Gut. It has been shown before that a high BMI is associated with an increased risk for future severe liver disease and liver cancer in adults. A high BMI also increases the risk for type 2 diabetes, which is, in turn, linked to a higher risk of severe liver disease. The risk seems to be present from an early age, according to a new observational study. Researchers led by Dr Hannes Hagström at Karolinska Institutet’s Department of Medicine, Huddinge, investigated the impact of BMI in adolescence on liver problems later in life. They used register data from more than 1.2 million Swedish men enlisted for military conscription between 1969 and 1996. They also linked data on severe liver disease, liver cancer and type 2 diabetes during follow-up from population-based registers. The researchers discovered that overweight men were nearly 50 percent more likely and obese men more than twice as likely to develop liver disease in later life than men of normal weight. Men with both obesity and type 2 diabetes were more than three times more likely to have liver problems when they were older compared with non-diabetic, normal weight men. Factors such as alcohol consumption and smoking were taken into account. This news article is an edited version of a press release from BMJ/Gut. Publication 'High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men' Hannes Hagström, Per Tynelius, Finn Rasmussen Gut, online 20 March 2017, doi:10.1136/gutjnl-2016-313622

KI researcher Birgitta Henriques Normark has been appointed Wallenberg Clinical Scholar 2017. She is granted SEK 15 million to find out how new strains of Streptococcus pneumoniae bacteria form and become resistant to antibiotics. The programme Wallenberg Clinical Scholars is part of the SEK 1.7 billion that the Knut and Alice Wallenberg Foundation is investing to boost medical research and the life sciences over a ten-year period. Universities with medical faculties are invited to nominate researchers for these research grants. The Royal Swedish Academy of Sciences is responsible for the scientific evaluation. “Clinical researchers have a pressured situation, so I am extremely happy that the Knut and Alice Wallenberg Foundation’s Scholars program is providing some of our very best clinical researchers with the opportunity to concentrate on and expand their important research,” says the Secretary General of the Royal Swedish Academy of Sciences, Göran K. Hansson, in a press release. Colonizing the nose Birgitta Henriques Normark, head physician and professor at KI’s Department of Microbiology, Tumor and Cell Biology, leads the national surveillance of severe pneumococcal infections and the effects of the introduction of pneumococcal vaccines in Sweden. As a Wallenberg Clinical Scholar, she will identify strains of S. pneumoniae that are especially capable of spreading in the society and study mechanisms for their disease causing capability. Why do some of pneumococcal strains stay colonizing the nose, while others penetrate the blood-brain barrier and cause meningitis? How does S. pneumoniae pickup genes and spread antibiotic resistance? One important aim will be to find treatment that prevent pneumococci from colonizing the nose and to spread across the blood-brain barrier and cause meningitis. Rare types of pneumococci Up to 60 percent of all pre-school children carry S. pneumoniae bacteria in the nose. Pneumococci are often harmless, but are also common causes of ear infections, lung infections, sepsis or meningitis. Around two million people die from pneumococcal infections every year globally. To prevent severe pneumococcal infections, Swedish children are now being vaccinated against the most common types of S. pneumoniae. Vaccination has been successful in protecting vaccinated children, but has also led to the spread of more rare types of pneumococci, even in the elderly population. Some of these are resistant to antibiotics.

Karolinska Institutet’s Acting Vice-Chancellor Karin Dahlman-Wright has announced her decision that researcher Karl-Henrik Grinnemo did not act carelessly when making a grant application to the Swedish Research Council, overturning KI’s previous decision on he matter. Dr Grinnemo was reported in April 2014 for having made illicit use of data from the now dissolved ACTREM, a research group led by Paolo Macchiarini, who was a visiting professor at Karolinska Institutet at the time. The then Ethics Council at Karolinska Institutet issued its pronouncement on the case in 2015, which KI’s former vice-chancellor accepted and upon which he drew for his formal decision: that Dr Grinnemo was guilty of carelessness but not of scientific misconduct. After the former vice-chancellor’s resignation, the matter was passed by KI’s Acting Vice-Chancellor Karin Dahlman-Wright to the expert panel for scientific misconduct at the Central Ethical Review Board (CEPN) for an official pronouncement. In December 2016, the expert group accordingly issued its statement, in which it pointed out that many of those working at ACTREM made use of each other’s data in different research grant applications. While the expert group was highly sceptical about whether this grant application strategy could be considered consistent with accepted scientific practice, it did accept that it was probably the result of a systemic fault rather than personal misconduct. Karolinska Institutet’s decision of 21 March is consistent with the CEPN exert group’s pronouncement. “The way the application in question was handled is probably based on a systemic fault for which an individual researcher cannot be held accountable,” says Professor Dahlman-Wright commenting on the decision. “In the view of KI’s former vice-chancellor, the matter could have been one of plagiarism,” she continues. “With today’s decision, Dr Grinnemo is cleared of any such suspicion.”

On 21 March 2017 Nature Communications retracted the paper “Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats” by Sjöqvist S, et al, due to concerns regarding the integrity of the study. Nature Communications previously issued an Editorial expression of concern related to this article, following the publication of a report commissioned by Karolinska Institutet and prepared by the Expert group for misconduct in research at the Central Ethical Review Board. According to the group’s statement on 6 September 2016, Paolo Macchiarini, as the article’s lead author, is guilty of scientific misconduct for having been misleading in both the presentation and interpretation of their results. Some of the raw data on which the published results were based were also withheld, according to the Expert Group. Publikation:  ”Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats”, Sebastian Sjöqvist, Philipp Jungebluth, Mei Ling Lim, Johannes C. Haag, Ylva Gustafsson, Greg Lemon, Silvia Baiguera, Miguel Angel Burguillos, Costantino Del Gaudio, Alexander Sotnichenko, Karolina Kublickiene, Henrik Ullman, Heike Kielstein, Peter Damberg, Alessandra Bianco, Rainer Heuchel, Ying Zhao, Domenico Ribatti, Cristián Ibarra, Bertrand Joseph, Doris A. Taylor & Paolo Macchiarini, Nature Communications, 15 april 2014, doi:10.1038/ncomms4562.

Comment: A female patient, the last survivor of the three who had been given a synthetic trachea by Paolo Macchiarini, has died in an American hospital, SVT reports. “It’s terrible what this patient had to endure,” says Karin Dahlman-Wright, acting vice-chancellor of Karolinska Institutet. “I deeply regret the suffering caused to her and her family and we dearly wish it had been otherwise.” The woman had suffered a tracheal injury in her native Turkey in connection with an operation for hyperhidrosis, or sweaty hands. In 2012 she was admitted to Karolinska University Hospital, where the new trachea was surgically implanted. Following the failure of the operation, the woman spent many years in hospital in Sweden before being transferred to the USA. She passed away on 19 March.

Researchers from around the world will gather at Karolinska Institutet on Monday 20 March to discuss what nobody can see, but that used in the right way can be extremely important for health and healthcare. The topic under discussion will be “Big Data”, which can lead doctors in the right direction in prevention, diagnosis and treatment. “Big Data offers incredible possibilities in healthcare,” says professor Jonas Ludvigsson, paediatrician and organiser of the Big Data conference at Karolinska Institutet, which is being sponsored by the Journal of Internal Medicine. The idea is to bring together the world’s leading researchers in the field to discuss the next step into the future. But what is it really all about? To come a little closer to the highly abstract concept, we talk to professor Ludvigsson, where we catch him as he makes a brief stop on Banhusbron in Stockholm on his morning walk to work at Karolinska Institutet. Cars, trains, homes, offices and mobile phones; the swarms of people around Central Station, Norra Bantorget and Klara sjö make the area look like an anthill. And we leave digital footprints behind us everywhere. When we buy something with our credit card, surf the web and use the apps on our smartphones. This enormous amount of data can be compared to the anthill taking shape under Banhusbron: Big Data, our “digital DNA”, is formed, and can be identified using computers and algorithms. Our digital DNA can make us healthier “When I realised that the advertisements along side my Google searches on the web matched my interests, I was really astonished,” says professor Ludvigsson. But the fact is that our digital DNA can make us healthier. Big Data can be of enormous help in healthcare. How is what the world’s leading researchers in the use of Big Data in care and medicine will be discussing at their conference at KI. “Several speakers from Microsoft and Google will talk about their Big Data initiative to improve people’s health,” Jonas Ludvigsson continues. He gives an example: “Five years ago, I visited the Mayo Clinic in Minnesota and already then they were testing mainframe computers that could detect matches between journals and patients’ medical histories and produce suggestions like ‘Do you want to do a thyroid test on this patient?’ There was a yes and no box to check so it was always the doctor who made the decision. The point is that the computer’s question was based on the symptoms in combination with old patient records and diseases in the family,” says Jonas Ludvigsson. The make or break issue is personal integrity. “But when a child becomes ill, it would help if it were possible for the family to give their consent for us to merge their records and have the computer find links that it would take a long time to see otherwise. Sometimes parents are totally unaware that they were ill as children. Sometimes there are clues to children’s illnesses in events that took place when the child was a baby. Computer would help make decisions faster A computer would also help in the same way in emergency care. “There are large numbers of patient records to go through and here again a computer would help us make decisions faster based on a large amount of information,” Jonas Ludvigsson goes on. “If there’s one thing I’m hoping for personally from Big Data, it’s that we soon have systems that help us who work in healthcare make diagnoses and administer patients. That would probably also contribute to people throughout Sweden receiving the same (good) care and doctors following national guidelines to an even greater degree. I also think it would make healthcare cheaper.” Hits from Internet searches are also useful in epidemiology. “You can see where in a particular country people google influenza symptoms and track how the contagion breaks out and predict how it will spread more easily so that we can increase hospitals’ preparedness,” says Jonas Ludvigsson. People’s behaviour online would also help healthcare measures be taken earlier. “There are a number of mental illnesses where we would be able to see more quickly if patients were on the way to becoming manic or depressed solely on the basis of how they are using their mobile phone. Changes in their behaviour, for example if the patient begins making calls or texting in a way that he or she does not do during their healthy periods, would trigger an early alarm from the computer,” says Jonas Ludvigsson and interrupts himself: “But there again, integrity! It must always be based on consent and be totally voluntary.” Can you give an example of Big Data where you don’t need to give your consent and that would still make a difference in the future? “Just look at how meteorology has advanced. They handle incredibly more data than before and analyses of tomorrow’s and next week’s weather have become so much more detailed and accurate. I’m convinced that they could analyse what the weather is normally like before severe drought periods in for example Africa. Then we could take preventive action several months beforehand and even avoid an imminent famine and disaster.   Text: PeKå Englund Foto: Gustav Mårtensson   A few of the important names at the Big Data conference at KI on 20 March: Victor Mayer-Schönberger, Professor of Internet Governance and Regulation at the University of Oxford and author of “Big Data: a revolution that will transform how we live, work, and think”. Victor Mayer-Schönberger will be talking about a future with Big Data. Andrew Morris, Scotland’s Chief Scientist, will speak about how Scotland has used Big Data to improve health there. Anders Hviid from Copenhagen has written more than 30 articles in medical journals such as NEJM, The Lancet, JAMA and BMJ and has among other things studied the long-term effects of vaccinations. He will be speaking about how Big Data can support studies of drugs and the risk of side-effects.   Wikipedia on Big Data: “Big data is a term for data sets that are so large or complex that traditional data processing application softwares are inadequate to deal with them. Big data contains resources for very large databases (VLDBs), data warehouses and data mining. The term Big Data became generally adopted in 2009. No corresponding term has become established in Swedish.“

Researchers at Karolinska Institutet have found that parenthood is associated with a longer life than childlessness. The study is published in the Journal of Epidemiology & Community Health. At the age of 60, the impact on projected life expectancy of having a child/children was almost two extra years for men, and 1.5 extra years for women. The study included all men (704,481) and women (725,290) with a birth date between 1911 and 1925 and living in Sweden, using national registry data. The study also gathered registry data on marital status and the number and sex of any children they had. The association was not affected by the sex of the child/children, as has been suggested by previous research. The association seemed to be stronger among those who weren’t married – at least among the men. Since it’s an observational study, no firm conclusions about cause and effect can be drawn. First author is Karin Modig, Assistant professor at the institute of environmental medicine, Karolinska Institutet. This news article is an edited version of a press release from the Journal of Epidemiology & Community Health. Publication “Payback time? Influence of having children on mortality in old age” K Modig, M Talbäck, J Torssander, A Ahlbom. Journal of Epidemiology & Community Health, online 14 March 2017, doi: 10.1136/jech-2016-207857

There were both tears and laughter when Hans Rosling’s family, colleagues from around the world and many others who wanted to pay their respects gathered for a memorial at Karolinska Institutet on 14 March. Close friend Hans Wigzell led the ceremony in Aula Medica that turned into a spectrum of professor Rosling’s contributions to global health.  Since Hans Rosling’s death on 7 February, a whole world has expressed its sorrow and shared its appreciation of Hans Rosling, professor of international health at Karolinska Institutet. During the course of Tuesday’s memorial,, guests from around the world and, via large-screen TV, also Bill and Melinda Gates, sent greetings to honour their friend. Hans Wigzell, professor and former Vice-Chancellor of Karolinska Institutet, explained before the ceremony how he wished to honour Hans Rosling: “I want the memorial to give an understanding of how Hans Rosling became the man he was. How his father worked as a coffee roaster in Uppsala and told Hans about poor coffee growers and exotic countries. And his mother who contracted tuberculosis and had to hand over caring for Hans to her parents. It was cured with the help of new medications and she returned to Hans a few years later,” Hans Wigzell said. Doctoral students and family among the speakers Some of Hans Rosling’s former doctoral students attended the memorial, along with colleagues, friends and family members. Speakers included the co-founders of Gapminder, Hans Rosling’s son Ola Rosling and daughter-in law Anna Rosling Rönnlund, associate professor of international health Johan von Schreeb, professor of parasitology Hannah Akuffo, director of the National Nutrition Programme in the Democratic Republic of Congo Jean Pierre Banea Mayambu and assistant professor of global health Helena Nordenstedt. As a representative of his own country and countries in eastern and central Africa, Jean Pierre Banea Mayambu thanked Hans Rosling for discovering the paralytic disease konzo and its connection to high consumption of cassava root. “We will always remember Hans Rosling in our hearts,” said Jean Pierre Banea Mayambu. Johan von Schreeb, associate professor at Karolinska Institutet and who heads the Centre for Research on Health Care in Disasters, observed that Hans Rosling’s life was six months shorter than today’s global life expectancy of 69 years. He went on to speak about Hans Rosling’s view of development – like a shift to people burying their elders instead of being forced to bury their children. “It’s part of life to need to bury one’s parents, but it can never be normal to have to bury one’s children. Poverty is the opposite of development, it locks people in misery. Hans Rosling fought against poverty his entire life,” said Johan von Schreeb. Put everything aside when necessary Abela Agnarson, PhD in international health, is director of public health outcomes at pharmaceutical manufacturer and medical engineering company Johnson & Johnson. At the memorial she said that Hans Rosling was her mentor for ten years. With great sadness and loss in her voice she spoke about what Hans Rosling had meant to her and many other people. Not least when he managed to persuade Tanzania’s president to rescind an order to deport a group of inhabitants who did not have valid passports or visas – which, among others, would have hit Abela Agnarson’s relatives in Tanzania. “When you needed Hans he was the angel we were all hoping for. When I knocked on his door and told him about the order, he let everything he was doing at the time go. He contacted churches, every government he could find a way in to, CNN, the BBC and the United Nations. The next afternoon Tanzania’s president rescinded the order with immediate effect. From that day on we have five cows in my village in Tanzania that bear Hans Rosling’s name. Hans, you will always be in my compass in life,” Abela Agnarson said. Around the turn of the century the seed was planted for what was to be the Gapminder organisation. It was here that Hans Rosling’s eldest son Ola Rosling and his wife Anna Rosling Rönnlund helped Hans Rosling devise the bubble graph that was to become the Trendalyzer software, which makes large amounts of data intelligible. Ola Rosling and Anna Rosling Rönnlund spoke about how thy are continuing the mission of combating ignorance by spreading a fact-based picture of the world that everyone can understand. They urged doctors, schools, researchers and the rest of the world to study their tools on Gapminder’s website and continue to spread knowledge in the spirit of Hans Rosling. Created the chimpanzee test “Let the revolution continue through Gapminder,” urged financier and philanthropist Sven Hagströmer, who spoke about what a great impression Hans Rosling had made on him when he first heard him on the Sommar radio programme on P1.  “All my family listened with great fascination to what this man had to say, both once and twice,” Sven Hagströmer continued. Naturally, everyone at the memorial had to take the test that Hans Rosling often used to test his audience’s knowledge – the chimpanzee test. A chimpanzee always manages to answer correctly with a 50 per cent chance, which means that it is possible to measure if the audience will score better than chimpanzees would. Judging from this audience, many have learned from Hans Rosling; the results were well above the chimpanzees’ level. Text: Stina Moritz   How some of the speakers remember Hans Rosling: “I will remember Hans Rosling as a remarkable person who tool personal responsibility for things that we might think lay far outside his responsibility, for example his personal consideration for relatives of Swedish soldiers killed in Afghanistan. He was a man of his word and no promise was sacred and lasting until it had been honoured, for example his promise to Frelimo’s leader Mondlane in Uppsala in 1967 that when he had qualified as a doctor he would come to Mozambique and work as a doctor in the countryside there. I will also remember him as an extremely serious teacher for the world but at the same time a person who was very fond of childishly dramatic jokes.” Hans Wigzell, professor at the Department of Microbiology, Tumour and Cell Biology, former Vice-Chancellor of Karolinska Institutet “What was so typical of Hans was that when push came to shove he dropped everything, did what was needed and put the important things first. When things were not so serious he was instead rather difficult to get hold of because he was doing his own thing and had a lot of stuff going on. Many people are loyal and diligent when it comes to the everyday and fail miserably when it really matters. But not Hans Rosling. He was not so loyal and diligent in everyday matters but he never failed when it really mattered. When our son became ill, Hans put aside almost everything else and devoted himself totally to our son. I will remember his enormous heart.”Anna Rosling Rönnlund, Hans Rosling’s daughter-in-law and co-founder of the Gapminder foundation. “I characterise our relationship as Hans accelerating through life in a gleaming Ferrari, while I move forward in a reliable Volkswagen. He made me go outside my comfort zone, fore example by questioning Bill Gates. I thank God that Hans was in my life as my colleague and my friend.” Hannah Akuffo, programme manager for research cooperation at Sida and professor of parasitology at Karolinska Institutet

Researchers at Karolinska Institutet collaborating in the large-scale Karolinska Schizophrenia Project are taking an integrative approach to unravel the disease mechanisms of schizophrenia. In the very first results now presented in the prestigious scientific journal Molecular Psychiatry, the researchers show that patients with schizophrenia have lower levels of the vital neurotransmitter GABA as well as changes in the brain’s immune cells. Schizophrenia is one of the most disabling psychiatric diseases and affects approximately one per cent of the population. It commonly onsets in late adolescence and is often a life-long condition with symptoms such as delusions, hallucinations, and anxiety. The disease mechanisms are largely unknown, which has hampered the development of new drugs. The drugs currently available are designed to alleviate the symptoms, but are only partly successful, as only 20 per cent of the patients become symptom-free. Comprehensive picture of disease mechanisms The Karolinska Schizophrenia Project (KaSP) brings together researchers from a number of different scientific disciplines to build up a comprehensive picture of the disease mechanisms and to discover new targets for drug therapy. Patients with an acute first-episode psychosis are recruited and undergo extensive tests and investigations. Cognitive function, genetic variation, biochemical anomalies as well as brain structure and function are analysed using the latest techniques and then compared with healthy peers. The first results from the project are now presented in two studies published in the journal Molecular Psychiatry. One of the studies shows that patients with newly debuted schizophrenia have lower levels of the neurotransmitter GABA in their cerebrospinal fluid than healthy people and that the lower the concentration of GABA the more serious their symptoms are. Important for most brain functions GABA is involved in most brain functions and along with glutamate it accounts for almost 90 per cent of all signal transmission. While glutamate stimulates brain activity, GABA inhibits it, and the two neurotransmitters interact with each other. “Over the years, animal studies have suggested a link between decreased levels of GABA and schizophrenia,” says Professor Göran Engberg at Karolinska Institutet’s Department of Physiology and Pharmacology. “Our results are important because they clinically substantiate this hypothesis.” The other study used the imaging technique of positron emission tomography (PET) to show that patients with untreated schizophrenia have lower levels of TSPO (translocator protein), which is expressed on immune cells such as microglia and astrocytes. “Our interpretation of the results is an altered function of immune cells in the brain in early-stage schizophrenia,” says Senior lecturer Simon Cervenka at Karolinska Institutet’s Department of Clinical Neuroscience. Follow-up studies are underway The results of the two studies provide new clues to the pathological mechanisms of schizophrenia, but it is unclear if the changes are the cause or the result of the disease. Follow-up studies are now underway to examine what causes the anomalies and how these biological processes can be influenced to change the progression of the disease. KaSP is a collaboration between clinical and preclinical research groups at Karolinska Institutet and four psychiatric clinics under Stockholm County Council. The study led by Göran Engberg was supported by grants from the Swedish Research Council, the Swedish Brain Foundation, Åhlén-stiftelsen, the Swedish Society of Medicine, Petrus och Augusta Hedlunds Stiftelse, Torsten Söderbergs Stiftelse, the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science, Söderström Königska fonden, Professor Bror Gadelius Minne, Knut och Alice Wallenbergs stiftelse, Stockholm County Council and KID-funding from Karolinska Institutet. The study led by Simon Cervenka was supported by grants from The Swedish Research Council, Stockholm County Council, the Swedish Society of Medicine, PRIMA Barn- och Vuxenpsykiatri AB, Torsten Söderbergs Stiftelse, Söderström Königska fonden, the European Union’s Seventh Framework Programme, and Centre for Psychiatry Research at Karolinska Institutet. One of the co-authors is employed by AstraZeneca, a couple of them have received grant support from AstraZeneca and served as one-off speakers for Roche and/or Otsuka Pharmaceuticals, and one has participated in workshops organized by Otsuka Pharmaceuticals.  Publications 'CSF GABA is reduced in first-episode psychosis and associates to symptom severity'. Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, Karolinska Schizophrenia Project (KaSP) Consortium, Cervenka S, Collste K, Victorsson P, Sellgren CM, Flyckt L, Erhardt S, Engberg G. Molecular Psychiatry, online 14 March 2017. doi:10.1038/MP.2017.25. 'Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28'. Collste K, Plavén-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, Amini N, Aeinehband S, Karolinska Schizophrenia Project (KaSP) consortium, Erhardt S, Halldin C, Flyckt L, Farde L, Cervenka S. Molecular Psychiatry, online 14 February 2017. doi: 10.1038/mp.2016.247.

Common impotence drugs such as Viagra may have a life-prolonging effect on patients who have suffered a myocardial infarction, a paper published by researchers at Karolinska Institutet suggests. The finding, which is published in the scientific journal Heart, calls for the need of prospective studies of impotence drugs in heart attack patients others than only those who suffer from impotence – including women. More than twenty per cent of men between the ages of 60 and 70 are affected by impotence. Previous research has shown that otherwise healthy men with impotence run a higher risk of cardiovascular disease than men without these problems. Risk factors such as smoking, type 2 diabetes, obesity and inactivity are associated with both conditions. In the present study, the researchers looked at how impotence drugs affect survival after a myocardial infarction, something that has not previously been known. The study included all men under the age of 80 years in Sweden who suffered a first heart attack between 2007 and 2013 (43,145 individuals). Over seven per cent of this group took impotence drugs during a mean follow-up of three years. 33 per cent lower risk of death The risk of death was 33 per cent lower for the patients who had been given impotence drugs compared with those who had not received this treatment. Apart from a lower mortality rate, the risk of being admitted to hospital for heart failure was also 40 per cent lower in the treatment group. The effects were only seen for patients who received the most common type of impotence drug, namely phosphodiesterase-5-inhibitors (PDE-5-inhibitors) such as Viagra, Cialis or Levitra, indicating that it may be specifically these drugs that contribute to the reduced mortality. “Our most important finding is that it’s harmless to prescribe these drugs to men following a heart attack and that it may possibly even prolong their lives and protect against heart failure,” says Martin Holzmann, physician and associate professor at Karolinska Institutet’s Department of Medicine in Solna. “The results also open the way for randomised controlled studies with PDE5 blockers after heart attacks, which may include women as well.” Planning a follow-up study The results of the study need to be interpreted with a degree of caution since information was lacking on several potentially impacting factors. The researchers are now planning a follow-up study with almost 140,000 male patients with stable coronary artery disease, e.g. with prior myocardial infarction, or coronary angioplasty/bypass surgery. Account will then be taken of more factors, such as marital status, income and educational background, which might well influence if men receive impotence treatment or not, and in themselves contribute to longer survival after a heart attack. “We will be basing the forthcoming study on statistics that will help us investigate whether the drugs have different effects and whether the dose taken matters,” says Dr Holzmann. “If so, it may provide a strong indication that it is the drugs themselves that prolong survival and decrease the risk of heart failure.” The study was a collaboration between researchers at Karolinska Institutet and the University of Milano-Bicocca (Italy) and was financed by several bodies, including the Swedish Heart and Lung Foundation and Stockholm County Council. Text: Mårten Göthlin Publication 'Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction' Daniel P Andersson, Ylva Trolle Lagerros, Alessandra Grotta, Rino Bellocco, Mikael Lehtihet, Martin J Holzmann Heart, online 9 March 2017, doi: 10.1136/heartjnl-2016-310746

Researchers have been able to demonstrate the hereditary nature of certain forms of tinnitus. Bilateral tinnitus – that is, tinnitus in both ears – has been shown to depend on genetic factors, particularly in men. The twin study, which is published in the journal Genetics in Medicine, was conducted by researchers at Karolinska Institutet together with colleagues from the European research network TINNET. Ringing in the ears, a condition called tinnitus, is experienced by 15 per cent of people in Sweden as well as in Europe. For one or two per cent of the population, the symptoms are extremely distressing and impact adversely on daily activities, work and sleep. Tinnitus thus has negative social consequences for the sufferers, while being an important economic burden to society. Tinnitus prevalence increases with age and is thought to be related to a number of environmental factors but little research has been done on the subject. There are also no effective cures for the condition, due possibly to the heterogeneity of the condition. Unexpected results Using data from the Swedish Twin Registry, researchers at Karolinska Institutet have found evidence that in some cases tinnitus has genetic causes. “We’ve been able to show that different forms of tinnitus have a significant heritability and thus a dominant genetic influence over environmental factors,” says Christopher R. Cederroth at Karolinska Institutet’s Department of Physiology and Pharmacology. When the researchers first examined all forms of tinnitus they made the same conclusions on heritability as others have reported. It was only after grouping the subjects by sex and unilateral/bilateral tinnitus that they uncovered the genetic correlation. “This result is surprising and unexpected as it shows that, unlike the conventional view of tinnitus being driven by environmental factors, there is a genetic influence for bilateral tinnitus which is more pronounced in men” says Dr Cederroth. Considerable clinical relevance Their discovery also shows that bilateral and unilateral tinnitus constitute two separate sub-groups, only one of which is influenced by genetic factors. This, claims Dr Cederroth, not only has considerable clinical relevance but is also important from a public health perspective: “Tinnitus sufferers need better care and treatment than they’re currently getting. We need more genetic studies and a better molecular understanding of its generation, which could open unforeseen avenues to drug development.” The study was financed with grants from several bodies, including the Swedish Research Council, the Lars Hierta Memorial Foundation, the Magnus Bergvall Foundations, the Silent School Foundation and the Biomedicine and Molecular Biosciences European Cooperation in Science and Technology (COST) Action framework (TINNET, BM1306). Publication 'Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort' Iris Lianne Maas, Petra Brüggemann, Teresa Requena Navarro, Jan Bulla, Niklas K. Edvall, Jacob v.B. Hjelmborg, Agnieszka J. Szczepek, Barbara Canlon, Birgit Mazurek, Jose A. Lopez-Escamez, Christopher R. Cederroth. Genetics in Medicine, online 9 March 2017, doi: 10.1038/GIM.2017.4

Lars Larsson, Professor of neurophysiology specialising in muscular physiology, receives 6 milllion SEK during 3 years from the Erling-Persson Family Foundation for his research on a type of muscle paralysis that affects some patients in intensive care. In February The Erling-Persson Family Foundation donated to three different projects within medicine/life science/care in Sweden, and Professor Lars Larsson at Karolinska Institutet received funds for his project ”Acquired muscle paralysis in intensive care unit patients: Mechanisms, diagnosis/monitoring and treatment”. Lars Larsson is a professor at the Department of physiology and pharmacology. His research presentation: Muscular atrophy common in intensive care.  

2016 saw a dramatic increase in the number of cases of misconduct in research, says Jörgen Svidén, Administrative Director at the Central Ethical Review Board (CEPN). Many cases concerned Karolinska Institutet and Paolo Macchiarini’s research. Universities and other institutions of higher education investigate cases of misconduct in research themselves. But they can also request an opinion from the Central Ethical Review Board’s expert group when they want an unbiased opinion. “Normally we deal with two or three cases. In 2016 we received 17, eight of them from Karolinska Institutet. Five concerned Macchiarini in some way,” says Jörgen Svidén. Anyone who accuses someone of misconduct in research, or is him- or herself accused, can ask the expert group to issue an opinion. They cannot approach the group directly, however, but must go to the vice-chancellor responsible, who in turn can approach the Central Ethical Review Board’s expert group. Reluctance to handle cases internally “As a consequence of the Macchiarini case, there has been some reluctance to handle these cases internally. It would be strange otherwise,” says Anders Ekbom, acting Pro-Vice-Chancellor of Karolinska Institutet since 1 January. Anders Ekbom also says that the number of cases of misconduct increased markedly during 2016. Some have been able to be dismissed, others have been submitted to the CEPN for an opinion and a few others are still under assessment by KI. “Our problem is that it takes the central review board a long time to process a case.” Because the expert group’s members’ workload has increased, the government has decided to enlarge the group with two ordinary members and two substitutes. “This will also make things easier when it comes to bias. We have two members who are automatically disqualified on the grounds of bias every time anything concerns KI. Even if KI’s two members have not been in the least involved with for example Macchiarini, they do not participate if a case concerns KI. With more members, there is less risk that the group will be too small to issue an opinion,” Jörgen Svidén goes on. KI makes final decision The CEPN’s expert group does not make decisions but issues an expert opinion that the university can choose to abide by or reject. For example, the expert group considered that all the researchers involved in one of the Macchiarini cases were guilty of scientific misconduct, whereas in KI’s view only Macchiarini and the four researchers who had had in-depth knowledge of large parts of the process were. KI reasoned that researchers without detailed knowledge of the entire research could not be held responsible. Jörgen Svidén feels that the fact that it is only the vice-chancellor who can request an opinion from the expert group is a weakness. “In that respect it’s not entirely safe from a legal point of view. And the fact that a person who has been accused and found guilty cannot approach an authority to appeal is also a problem.   Text: Ann Patmalnieks   More on CEPN The Central Ethical Review Board is the appeals body for ethical reviews, its main task being to examine appeals from researchers who have been refused leave to appeal by the regional ethical review board. If the regional ethical review board cannot reach agreement on a case, they can also choose to submit it to the CEPN. The Central Ethical Review Board also has supervisory responsibility as regards the Ethical Review Act. “There are two occasions where the CEPN exercises supervision,” explains Jörgen Svidén. “If someone does not have a permit to conduct the research being carried on and if the person conducting the research goes outside the bounds of permit that was granted.” Proposal for a clearer procedure On 22 February the government’s special investigator presented her proposal for a new way to handle cases concerning investigation of misconduct in research. The proposal will now be circulated for comment. The investigation proposes a clearer and legally safer procedure. Among other things, it is proposed that a new authority, the Misconduct Board, take over the task of investigating suspected misconduct in research from the university where the accusation is made. The authority would also take over the duties currently carried out by the Central Ethical Review Board’s expert group. The report also discusses a uniform definition of scientific misconduct in research. The present lack of such a definition means that different universities can define misconduct in research in their own way – and make decisions as to whether there has been any misconduct on the basis of its own investigation. Karolinska Institutet is going to make changes to its own procedure for handling misconduct pending the new legislation. But the provisions of the Higher Education Ordinance still apply; the university itself investigates cases of suspected dishonesty/misconduct once an accusation has been received by the vice-chancellor. The pro-vice-chancellor says that the internal procedure must be faster, more transparent and safer. “During the spring we’re going to try to implement a similar procedure to that being proposed by the government, with a KI board to investigate reports of dishonesty. Both the person reporting dishonesty and the person being reported must have greater judicial security,” says acting Pro-Vice-Chancellor Anders Ekbom. Text: Madeleine Svärd Huss

From 1 July 2018 some major changes will be made regarding Swedish ethical reviews. The Ministry of Education and Research has proposed that a new organisation come into effect on that date. Today’s six regional ethical review boards will be brought together under a new authority, the Ethical Review Authority, where the boards will be administrative regions. Applications will be submitted digitally instead of on paper and cases will be passed to the region that has time via en electronic administration system. The aim is to increase efficiency and ensure more uniform application of rules. “Procedures and assessment methods tend to differ a little at present,” says Helena Hallgren Lönn, Administrative Director at the regional ethical review board in Stockholm. When the changes come into effect KI will no longer be the host authority. “One advantage of that is that it will be clearer that we are independent of the research community,” Helena Hallgren Lönn goes on. Karolinska Institutet’s acting Pro-Vice-Chancellor Anders Ekbom wants to get a full picture of the changes when the draft proposal lands on his desk before commenting on them in detail. But he can see a distinct advantage with the present system where KI is the host university since the regional ethical review board in Stockholm has good local knowledge. “At the same time I see a need for a more uniform assessment system at the ethical review boards,” he says.   Text: Ann Patmalnieks and Madeleine Svärd Huss

The regional ethical review board in Stockholm found itself under increased pressure last year. Administrative Director Helena Hallgren Lönn thinks researchers have become more aware as a result of the Macchiarini case. “We are feeling greater pressure in general. Most researchers want to abide by the rules,” she says. Ethical reviews exist to protect people in connection with research, and they are carried out by the ethical review boards. The board in Stockholm is one of six regional ethical review boards in the country and is based at Karolinska Institutet’s Solna campus. Many of the applications come from researchers at KI but the ethical review board is an independent authority. KI is a so-called host authority and among other things provides premises. An ethical review of a research project is needed when it concerns people in some way. “It might be when the researcher processes sensitive personal data, takes biological samples, or carries out physical procedures, or when people are affected physically or mentally. The board weighs the potential gains against the risk to the individual,” Helena Hallgren Lönn goes on. Noticeable increase Approximately half of the applications concern changes to projects that are already running. This might for example be the case when research has shown previously unknown risks or when researchers wish to make new analyses of material already collected. “We’ve been seeing a slight increase for a number of years, but in 2016 it was noticeable. Researchers are beginning to study the decisions they have received to see if they need to add anything,” Helena Hallgren Lönn continues. Since there are many questions that concern ethical reviews, the regional ethical review board in Stockholm now holds special two-hour seminars on ethical review. The number of enquiries received by phone and e-mail and the number of people visiting in person have also increased. A lot to learn “A researcher who does not submit applications so often has quite a lot to learn,” says Helena Hallgren Lönn. “If they uncertain, we recommend them to enlist the help of senior researchers. This also brings the ethical discussions to the fore.  The Ethical Review Act does not cover student projects. But Helena Hallgren Lönn nonetheless recommends that they contact the board if there is anything that can be expected to be included in a research project at a later date. In such cases it is possible to apply for an advisory opinion. “It’s a pity if you realise it too late. A student project may come to be further developed and become something interesting. Unfortunately, it’s not possible to be granted a permit afterwards,” she says.   Text: Ann Patmalnieks Photo: Ulf Sirborn   Many applications to process In 2016, the board had a total of 2,415 cases, an increase of 12.5 per cent compared to the previous year. KI accounted for 636 of the applications, over half of which concerned changes to projects that had already been approved. About 15 of the roughly 2,000 decisions made every year re appealed. Applicants who appeal may have had their entire project refused or conditions have been stipulated that they feel are unreasonable. Those whose applications are approved may also have certain conditions imposed, for example that they must make the information given to the participants clearer. The researchers must observe any conditions; other wise they will be breaking the law. These are the most common errors An application involves a significant amount of paperwork. It must among other things contain a research plan and a description of how the risks are to be managed and how information is to be given to the test subjects. Common errors include: the form has been filled out in English instead of Swedish, it is not clear who the principal is, the wrong person has signed the application, attachments are missing, the letter to the test subjects is missing or is not in a format that is appropriate for the target group, there is no interview guide (the board needs to check that the questions are relevant and reasonable from an ethical standpoint), or the researcher’s own ethical considerations have not been stated. Helena Hallgren Lönn’s best tips – how to get it right: 1) Is it your first application? Get help from colleagues who have more experience. 2) Allow sufficient time for your application to be processed! It may take a while to grant a permit – often because the application is incomplete. 3) Be thorough. Make sure that you have included all the attachments and that you have filled in all fields in the application form. 4) Create a file for your application from the very beginning. You may need to refer to earlier decisions during the course of your research project, for example if circumstances change. 5) Think about whether student projects can be expected to be part of a research project at a later date. A permit cannot be granted afterwards.

When researcher and oncologist Peter Strang writes textbooks, he does so with a certain distance: everything is based on fact. Writing a novel requires a different kind of presence, such as for example trying to imagine what it is like to have been diagnosed with cancer and to be a patient. In his first work of fiction I skuggan av sommaren [In the shadow of summer], Libris förlag, Peter Strang captures existential questions that cannot be accommodated in a non-fictional work, he says. He also undertakes a voyage of discovery through his own emotional life in his novel about Jacob, who in the midst of life is struck down by cancer. The new book centres around Jacob, 34 years old, newly separated and tired of life, who is diagnosed with cancer and wonders whether he will have the strength to fight. At the oncology clinic he strikes up a friendship with 40-year-old father of small children Mats, who is prepared to do anything to get well. Jacob also gets support from his friend Mikael, who is in good health. “The story itself is about the importance of friendship when something like this happens. But it is also about the feeling that many people get when they are diagnosed with cancer of an invisible wall appearing between them and the healthy world outside. That they have been put inside some kind of glass dome,” says Peter Strang. Is it possible for a healthy person to really have any deep understanding of what it mans to be given a life-threatening diagnosis? Peter Strang says that existentially speaking we are rather alone when we fall ill, at the same time as we are in particularly great need of friendship. But the only ones who can really understand are those who are in the same boat as ourselves. “People who are ill know that their close relatives wish them well, but unlike the person who is ill they are healthy and it is that feeling I want to give a face to,” Peter Strang goes on. The book is existentially reflective and is intended for both care staff and the general public, whether they be healthy or sick. “Cancer is an extremely loaded disease and it felt important to put it into words in an entirely new language. And describe what different choices people can make when it comes to cancer,” Peter Strang says.   Text: Helena Mayer A professor of palliative medicine Peter Strang is professor of palliative medicine, in particular palliative oncology, at Karolinska Institutet and senior physician at Stockholms Sjukhem. During his 30 years in the profession he has written textbooks, books of reflection and short stories. I skuggan av sommaren, Libris förlag, was published on 28 February 2017. Photo: Libris förlag/Creative Commons.

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Researchers at Karolinska Institutet and KTH Royal Institute of Technology in Sweden have contributed to a recent discovery that the heart is filled with the aid of hydraulic forces, the same as those involved in hydraulic brakes in cars. The findings, which are presented in the journal Scientific Reports, open avenues for completely new approaches to the treatment of heart failure. The mechanisms that cause blood to flow into the ventricles of the heart during the filling, or diastolic, phase are only partly understood. While the protein titin in the heart muscle cells is known to operate as a spring that releases elastic energy during filling, new research at Karolinska Institutet and KTH suggests that hydraulic forces are equally instrumental. Hydraulic force, which is the pressure a liquid exerts on an area, is exploited in all kinds of mechanical processes, such as car brakes and jacks. In the body, the force is affected by the blood pressure inside the heart and the size difference between the atria and ventricles. During diastole, the valve between the atrium and the ventricle opens, equalising the blood pressure in both chambers. The geometry of the heart thus determines the magnitude of the force. Hydraulic forces that help the heart’s chambers to fill with blood arise as a natural consequence of the fact that the atrium is smaller than the ventricle. Measured the size of both chambers Using cardiovascular magnetic resonance (CMR) imaging to measure the size of both chambers during diastole in healthy participants, the researchers found that the atrium is smaller effectively throughout the filling process. “Although this might seem simple and obvious, the impact of the hydraulic force on the heart’s filling pattern has been overlooked,” says Dr. Martin Ugander, a physician and associate professor who heads a research group in clinical physiology at Karolinska Institutet. “Our observation is exciting since it can lead to new types of therapies for heart failure involving trying to reduce the size of the atrium.” Disorders of the filling phase are common Heart failure is a common condition in which the heart is unable to pump sufficient quantities of blood around the body. Many patients have disorders of the filling phase, often in combination with an enlarged atrium. If the atrium gets larger in proportion to the ventricle, it reduces the hydraulic force and thus the heart’s ability to be filled with blood. “Much of the focus has been on the ventricular function in heart failure patients,” says Dr. Elira Maksuti at KTH’s Medical Imaging Unit and recent PhD from KI’s and KTH’s joint doctoral programme in medical technology. “We think it can be an important part of diagnosis and treatment to measure both the atrium and ventricle to find out their relative dimensions.” The study was the result of a multidisciplinary collaboration between Karolinska Institutet, KTH and Lund University in Sweden and Washington University in St. Louis, USA and was financed with grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, Stockholm County Council and Karolinska Institutet.   View a video from KTH     Publication Hydraulic forces contribute to left ventricular diastolic filling Maksuti E, Carlsson M, Arheden H, Kovács SJ, Broomé M, Ugander M. Scientific Reports, online 2 March 2017, doi: 10.1038/srep43505.

An international team of scientists, including researchers from Karolinska Institutet and Karolinska University Hospital, have conducted a clinical study on a new treatment for high-risk neuroblastoma, an exceedingly aggressive form of cancer that only develops in babies and young children. According to the researchers, the results demonstrate that the new treatment both increases survival and reduces undesirable effects. “This is a significant step forwards for these seriously ill children,” says consultant Per Kogner, professor of paediatric oncology at the Department of Women’s and Children’s Health, who led the Swedish arm of the study. The preparation tested is the new pharmaceutical combination busulfan-melphalan, which is given in high doses followed by stem cell transplantation. In all, 1347 children from 18 countries were included in a so called phase 3 study, of which 598 children were randomised to be treated with busulfan-melphalan or standard therapy. The research team found that the survival rate for those who received this new treatment increased by 38 to 50 per cent, while the risk of life-threatening adverse effects decreased from 10 to 4 per cent. Before the age of two Neuroblastoma only develops in babies and small children, usually before the age of two. The tumours arise in the sympathetic nervous system but also often appear inside the adrenal glands and in the spinal cord. Approximately 20 children a year are diagnosed with the disease in Sweden, which means that international cooperation is necessary for there to be studies large enough for researchers to build on in the development of new therapies. The current collaboration study is published in The Lancet Oncology and has been coordinated by Professor Ruth Ladenstein at the MedUni Vienna in Austria. The research was financed with grants from the EU’s fifth framework programme and St. Anna Kinderkrebsforschung, Austria. In Sweden, financing was provided mainly by the Swedish Childhood Cancer Foundation, the Swedish Cancer Society and the Swedish Research Council Publication Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, Forjaz de Lacerda A, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D, for the SIOP Europe Neuroblastoma Group (SIOPEN) The Lancet Oncology, online 1 March 2017, http:// dx.doi.org/10.1016/ S1470-2045(17)30070-0