Integrative Molecular Phenotyping
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WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 54 min 23 sec ago

Thorough analysis reveals immune system dynamics

Wed, 30/08/2017 - 08:00
By combining new system-biological analyses and advanced data analysis, researchers at Karolinska Institutet have been able to monitor the maturation process of the immune system of leukaemia patients who have undergone stem cell transplantation. The technique, which reveals complex interactions between cells and proteins, can be used for other diseases to generate new knowledge about the regulation and dysregulation of the immune system, which can eventually give rise to new, improved immunological therapies. The study is published in Cell Reports. Immunotherapy is a rapidly growing field in which the immune system of patients is manipulated in order to fight disease, and in which considerable progress in the treatment of cancer, above all, has been reported in recent time. One of the best-established and most effective immunological therapies is allogeneic stem cell transplantation for leukaemia, in which the patient’s own diseased bone marrow is replaced by healthy donor material. In some patients, however, the grafted immune system fails to mature properly, which can cause serious infection, undesired attacks on healthy tissue or a cancer relapse. Complex interaction between cells Using advanced analytical tools, researchers at Karolinska Institutet have now studied the maturation process of the immune system in 26 leukaemia patients receiving treatment at Karolinska University Hospital. They monitored the patients for one year after completed stem cell transplantation and used mass cytometry to study the different cell types of the immune system and the ProSeek method for simultaneous protein analysis. The analyses were then combined with modern machine learning techniques for data analysis, which enabled the integration of all data and global analyses of the entire immune system in blood. “Previously, research has focused heavily on individual components, but the immune system is incredibly complex, involving many specialised cell types, and we think the important thing is precisely the interaction between these cells,” explains Petter Brodin, doctor and researcher at the Science for Life Laboratory (SciLifeLab) and Karolinska Institutet’s Department of Medicine in Solna. “Although such dynamic processes have been difficult to study due to technical limitations, it’s now possible thanks to breakthroughs in technology.” Can lead to more individualised treatments Dr Brodin has led the present study, which has been able to identify patterns that can be linked to clinical complications in the patients. The technique is also applicable to other diseases involving the immune system, such as autoimmune diseases, allergies and infections. It is hoped that more and larger studies of the dynamics and regulation of the immune system will provide new clues that open doors to new therapies and more individualised treatments. “This study can be seen as the first example of how extensive analyses and advanced data analysis, a concept we call precision immunology, can help us understand the function and dysfunction of the immune system and make the outcome of other immunological therapies more predictable,” he says. The study was financed by the Swedish Research Council, the Swedish Society for Medical Research, the Swedish Cancer Society, the Swedish Society of Medicine, the Swedish Childhood Cancer Foundation and Karolinska Institutet. Publication “Mass cytometry and topological data analysis reveal immune parameters associated with complications after allogeneic stem cell transplantation” Tadepally Lakshmikanth, Axel Olin, Yang Chen, Jaromir Mikes, Erik Fredlund, Mats Remberger, Brigitta Omazic, Petter Brodin Cell Reports, online 29 August 2017

Anti-inflammatory drugs can inhibit muscle growth

Mon, 28/08/2017 - 16:27
The long-term use of over-the-counter (OTC) anti-inflammatory drugs can inhibit muscle growth in young, healthy individuals engaging in weight training, according to a new study from Karolinska Institutet, reporting on the effects of ibuprofen on the skeletal muscles and published in Acta Physiologica. Most mild analgesic and antipyretic OTC drugs, apart from paracetamol, are of the NSAID (non steroidal anti-inflammatory drugs) kind. These drugs are some of the most widely consumed in the world, and they all inhibit the so-called COX enzymes. In the present study, healthy 18 to 35-year-old men and women were randomly assigned to two groups, one that took a relatively high dose of NSAID (1,200 mg ibuprofen, which is a normal 24-hour dose) and one a relatively low dose (75 mg acetylsalicylic acid) every day for eight weeks. During the same period, the participants also engaged in supervised weight-training exercises for the thigh muscles two to three times a week. The researchers then measured certain variables, such as muscle growth, muscle strength and anti-inflammatory markers in the muscles. Commonly used by athletes It was found that after eight weeks, the increase in muscle volume, as measured by MR imaging, was twice as large in the low-dose aspirin group as in the high-dose ibuprofen group. “The results are extremely interesting since the use of anti-inflammatory drugs is so globally widespread, not least amongst elite athletes and recreationally active individuals,” says principal investigator Tommy Lundberg, researcher at Karolinska Institutet’s Department of Laboratory Medicine. “We chose to look at the effect of ibuprofen as it is the most well-studied anti-inflammatory drug on the market, but we believe that high doses of all types of OTC NSAIDs have similar effects.” Muscle strength was also impaired with high doses of anti-inflammatory drugs, but not to such a pronounced extent. Analyses of muscle biopsies showed that classical markers for inflammation were inhibited in the muscles of the ibuprofen group. Partly contradicts studies in older populations “This suggests that muscular inflammation processes when combined with weight training are beneficial to the long-term development of new muscle mass, at least in the young,” says Dr Lundberg. “Our results suggest that young people who do weight training to increase their muscle mass should avoid regular high doses of anti-inflammatory drugs.” The results partly contradict studies in older populations, which have indicated that anti-inflammatory drugs can protect against age-related muscle-mass loss. The researchers think, therefore, that the mechanism regulating muscle mass differs between the old and the young. The study was financed by the Swedish Research Council for Sport Science, the Lars Hierta Memorial Foundation and the Swedish Research Council. Publication “High-doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults” Mats Lilja, Mirko Mandić, William Apró, Michael Melin, Karl Olsson, Staffan Rosenborg, Thomas Gustafsson, Tommy R Lundberg Acta Physiologica, online 21 August 2017. doi: 10.1111/apha.12948

Oxygen therapy has no effect on patients with suspected heart attack

Mon, 28/08/2017 - 15:47
Oxygen therapy has been used to treat patients with suspected heart attack for decades despite the lack of scientific evidence. A new study by researchers at Karolinska Institutet reveals that oxygen therapy does not improve survival in patients with heart attack symptoms and normal oxygen levels in the blood. The study is published in the prestigious New England Journal of Medicine (NEJM) and was presented today at the European Society of Cardiology (ESC) Congress. This prospective, randomised, open-label trial enrolled 6 629 patients with suspected heart attack from 35 hospitals across Sweden. Half of the patients were assigned to oxygen given through an open face mask and the other half to room air without a mask. The researchers found that the mortality rate one year after randomisation, the risk of a new heart attack or the risk of heart muscle injury was not statistically different between the two groups. Using the Swedeheart registry, this study is the first large-scale randomised trial of oxygen therapy in patients with suspected heart attack to be large enough to reveal meaningful findings on mortality and morbidity. Could change the recommendations worldwide The European Society of Cardiology (ESC) guidelines recommend oxygen for patients who are breathless, hypoxic, or have heart failure. They add that the systematic use of oxygen in patients without heart failure or dyspnoea (shortness of breath) “is at best uncertain”. ESC guidelines have gradually shifted towards more restrictive use of oxygen. However, the general use of oxygen therapy in all patients with symptoms of a heart attack is still widespread in the world. Therefore, the study results will likely have an immediate impact on clinical practice and future guidelines. First author of the study is Robin Hofmann, medical doctor and researcher at Karolinska Institutet’s Department of Clinical Science and Education, Södersjukhuset (KI SÖS). The research was supported by the Swedish Heart–Lung Foundation, the Swedish Research Council and the Swedish Foundation for Strategic Research. Publication “Oxygen Therapy in Suspected Acute Myocardial Infarction” Robin Hofmann, Stefan K. James, Tomas Jernberg, Bertil Lindahl, David Erlinge, Nils Witt, Gabriel Arefalk, Mats Frick, Joakim Alfredsson, Lennart Nilsson, Annica Ravn-Fischer, Elmir Omerovic, Thomas Kellerth, David Sparv, Ulf Ekelund, Rickard Linder, Mattias Ekström, Jörg Lauermann, Urban Haaga, John Pernow, Ollie Östlund Johan Herlitz, and Leif Svensson The New England Journal of Medicine (NEJM), online 28 August 2017

Coronary artery bypass surgery effective in patients with type 1 diabetes

Mon, 28/08/2017 - 14:48
Coronary artery bypass surgery (CABG) is the best method of treating artherosclerotic coronary arteries in diabetes patients with multivessel disease, even in the presence of type 1 diabetes, a new study from Karolinska Institutet reports, clearing up a question in the current recommendation. The study is published in Journal of the American College of Cardiology (JACC). International guidelines recommend coronary artery bypass surgery (CABG) over the use of balloon catheters (in a process called percutaneous coronary intervention, or PCI) to widen artherosclerotic coronary arteries in diabetes patients with two or more diseased coronary vessels. However, since the underlying research has not differentiated between patients with type 2 diabetes and the less common type 1 diabetes, it has been unclear whether the recommendation applies to both types. “Since type 1 diabetes is a different disease with different complications, it’s never been given that the treatment should be the same as with type 2 diabetes,” says Martin Holzmann, researcher at Karolinska Institutet’s Department of Medicine in Solna. Dr Holzmann and his colleagues have now followed up all patients with type 1 diabetes who underwent so-called revascularization of two or more narrowed coronary vessels, a procedure for improving blood circulation in the heart, in Sweden between the years 1995 and 2013. Increased risk of heart disease Their results show that patients who underwent revascularization using PCI ran a 45 per cent higher risk of fatal heart disease and a 47 per cent higher risk of myocardial infarction during the average 10-year follow-up time than patients who were treated with CABG. They were also five times more likely to need further PCI or CABG treatment. “The results suggest that CABG should also be the preferred procedure for patients with type 1 diabetes and two or more diseased coronary vessels, as currently stated in guidelines for diabetes patients” says Dr Holzmann. Could impact on medical practice The researchers also found that the relative number of CAGB procedures declined dramatically over the study period. Between 1995 and 2000, CAGB accounted for 58 per cent of revascularizations in patients with type 1 diabetes and at least two diseased coronary vessels, a figure that was down to only 5 per cent between 2007 and 2013. Dr Holzmann hopes that their findings will impact on medical practice. “PCI is easier to perform and isn’t so invasive for the patient, so there are arguments in favour of this method too,” Dr Holzmann explains. “But both randomised studies and registry studies have shown unequivocally that CABG is the best revascularization method for diabetes patients with at least two diseased coronary vessels. We’ve now found corroborating evidence for this and confirmed that it applies to all diabetes patients.” The study received no specific financing. Dr Martin J Holzmann holds a research position financed by the Swedish Heart and Lung Foundation and has received consultancy honoraria from Actelion and Pfizer. Publication PCI Versus CABG in Patients With Type 1 Diabetes and Multivessel Disease.  Thomas Nyström, Ulrik Sartipy, Stefan Franzén, Björn Eliasson, Soffia Gudbjörnsdottir, Mervete Miftaraj, Bo Lagerqvist, Ann-Marie Svensson and Martin J. Holzmann. Journal of the American College of Cardiology, online 26 August 2017.

Karolinska Institutet falls in reputation survey

Wed, 23/08/2017 - 15:41
For the second year running, Karolinska Institutet’s (KI’s) placement in a reputation survey conducted by the research agency Kantar Sifo has fallen from (a score of) 59 to 47, where where 100 signifies an excellent reputation and 0 a weak reputation. “It’s not at all good that the general public have low confidence in us. But at the same time this result was not entirely unexpected. KI has been going through a very turbulent period during which the Macchiarini case has overshadowed the university’s operations and activities and all the excellent research and education that have been going on here. We take the result most seriously and our focus is on continuing to proceed systematically with measures to rectify previous shortcomings,” says new Vice-Chancellor Ole Petter Ottersen in a comment on the survey. Kantar Sifo agree that it is probably the turbulence in the media around Paolo Macchiarini that has had an impact and continues to do so this year. The survey also indicates that by far the most important channel for the general public to find information about KI is in fact the picture painted by the media and the survey’s respondents perceive the publicity given to the university as distinctly negative. “When the public spotlight goes out, KI nevertheless has good prerequisites to recover – but the journey back will probably take time,” says Kantar Sifo opinion survey manager Toivo Sjörén.

KI research projects in European innovation competition final

Wed, 23/08/2017 - 14:40
The finalists in the EIT Awards competition have been announced and among them are two medical engineering projects from KI. The finalists from KI are the projects “Stockholm3”, a test (blood sample) that makes it possible to detect the risk of aggressive prostate cancer, and “MULTI-MODE”, an e-health tool for predicting and preventing dementia in risk patients. The prize is awarded by the European Institute of Innovation & Technology (EIT) for projects that advance European innovation and tackle global challenges in the areas of climate change, digitalisation, energy, health, food and raw materials. The two projects are nominated in the “Venture” category, where the prize is worth EUR 50,000. The awards ceremony will be held in Budapest on 16 October during EIT’s annual innovation forum, INNOVEIT. Three of the 21 finalists are from Sweden. In addition to the two KI projects, “ICARO-EU” from KTH Royal Institute of Technology is also competing.

Oral contraceptives linked to reduced risk of rheumatoid arthritis

Fri, 18/08/2017 - 10:12
Taking oral contraceptives is associated with a lowered risk of developing rheumatoid arthritis, finds a new observational study by researchers at Karolinska Institutet published in Annals of the Rheumatic Diseases. But no significant link was found for breastfeeding after accounting for various potentially influential factors. The researchers analysed data from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) to find out if there is a link between the development of rheumatoid arthritis and use of oral contraceptives and/or breastfeeding among adult women who had had at least one child. The study included women aged 18 and above, living in defined areas of Sweden between 1996 and 2014. During this timeframe, 2809 women were diagnosed with rheumatoid arthritis. 5312 women randomly selected from the general population and matched for age acted as a control group. Significantly reduced risk The women were asked about their contraceptive and reproductive histories, their lifestyle, their education and whether they had breastfed their children. In addition, blood samples were taken to check for ACPA (anti-citrullinated protein) antibodies. Nine out of 10 people who test positive for ACPA antibodies will have rheumatoid arthritis, and the presence of these antibodies may indicate more serious disease. The risk of developing ACPA-positive rheumatoid arthritis was 15 per cent lower in current users of oral contraceptives and 13 per cent lower in past users compared with women who had never used an oral contraceptive. Using the Pill for more than seven years was associated with a 19 per cent lower risk of developing both ACPA-positive and ACPA-negative rheumatoid arthritis. However, no firm conclusions can be drawn about cause and effect in an observational study, and the researchers lacked information about the dose or type of oral contraceptive. Breastfeeding did not have the same effect Although a lower risk was also found among women who had breastfed at least one child, this was not significant after having accounted for potentially influential factors. The study was carried out by Cecilia Orellana at the Department of Clinical Neuroscience and Camilla Bengtsson at the Institute of Environmental Medicine, Karolinska Institutet, among others. The research was supported by grants from the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, King Gustav V’s 80-year foundation, Vinnova, the Swedish Foundation for Strategic Research, the Swedish Rheumatic Foundation, the Stockholm County Council, the Insurance Company AFA, the Innovative Medicines Initiative-supported BTCure project, and the National Institutes of Health. This news article is based on a press release from Annals of the Rheumatic Diseases. Publication Cecilia Orellana, Saedis Saevarsdottir, Lars Klareskog, Elizabeth W. Karlson, Lars Alfredsson and Camilla Bengtsson. “Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study”. Annals of the Rheumatic Diseases, online 17 August 2017. doi 10.1136/annrheumdis-2017-211620

Killing bacteria by hacking plastics with silver and electricity

Mon, 14/08/2017 - 10:48
Researchers at the Swedish Medical Nanoscience Center at Karolinska Institutet have developed an innovative way of hacking conducting plastics so as to prevent bacterial growth using silver nanoparticles and a small electrical current. The method, which could prove to be useful in preventing bacterial infections in hospitals, is presented in the scientific journal Advanced Healthcare Materials. Hospital wards are full of plastic surfaces, plastic tubes and plastic devices, each one potentially harbouring dangerous microbes. Bacteria are capable of surviving for a long time on plastic surfaces, from which they can spread to patients and cause infections. Effective combination of small attacks While both large electrical currents and high silver concentrations are known to kill bacteria, they also pose a risk to humans, which is why their use in hospitals is limited. New research lead by Professor Agneta Richter-Dahlfors at Karolinska Institutet’s Department of Neuroscience shows that it is not necessary to use dangerous concentrations of silver or large currents in order to kill bacteria, if these are used in combination. “By targeting the bacteria on several fronts at the same time, the effect of different small attacks becomes larger than when each factor is acting on its own”, explains Agneta Richter-Dahlfors. The research team focussed on the notorious hospital pathogen Staphylococcus aureus. They found that applying tiny electrical currents to a conducting plastic surface had no effect on bacterial growth. On a similar surface exposing an attached layer of silver nanoparticles, bacterial growth was reduced. However, application of a tiny electrical current to the latter surface enhanced the effect of attached silver nanoparticles, and the bacteria were completely destroyed. Electrical fields weaken bacterial cells “It’s a phenomenon known as the bioelectric effect, whereby electrical fields weaken bacterial cells against external attacks”, says PhD student Salvador Gomez-Carretero at Karolinska Institutet's Department of Neuroscience. “We use electrical signals to increase the antimicrobial activity of the silver nanoparticles. This reduces the amount of silver needed, which is beneficial for both the patient and the environment.” In the future, the researchers hope that this technology will help to keep surfaces in hospitals and other settings requiring high hygienic standards free from bacteria that can cause life-threatening infections. “It has not yet been tested in the clinic, but we believe this technology could be a good approach to limiting the spread of infectious bacteria and the incidence of hospital-acquired infections” says Professor Richter-Dahlfors. The study was financed by the Swedish Research Council, Vinnova, Carl Bennet AB and the Swedish Medical Nanoscience Center. Publication Salvador Gomez-Carretero, Rolf Nybom and Agneta Richter-Dahlfors. Electroenhanced Antimicrobial Coating Based on Conjugated Polymers with Covalently Coupled Silver Nanoparticles Prevents Staphylococcus aureus Biofilm Formation. Advanced Healthcare Materials, online 14 August 2017. doi: 10.1002/adhm.201700435.

Karolinska Institutet number one in Sweden in innovation ranking

Fri, 11/08/2017 - 11:38
Karolinska Institutet (KI) is ranked 38 of 200 in the science magazine Nature's innovation ranking, Nature Index 2017 Innovation, which measures how companies and organizations use the university's research results. KI is the highest ranking Swedish university and the only one to enter the top 50. The Nature Index Innovation report is based on how often research from academia and other public research institutions is cited in patents owned by non-academic organizations, for example companies in the IT, pharmaceutical and biomedical industries.  "While one should bhe cautious about drawing far-reaching conclusions from rankings, this is an important indication of how KI stands in relation to other universities and a confirmation that we conduct high-quality research that is relevant to society at large,” says Ole Petter Ottersen, Vice-Chancellor at KI who took office on August 1. To enter Nature Index Innovation, a university must have many publications in high-ranking scientific journals, and research findings that are applicable and cited in patents. "This ranking provides a very interesting way to determine how university research contributes to the development of products of benefit to our society. It measures how third parties use our research findings to develop quality products and services," says Richard Cowburn, responsible for business collaboration at Karolinska Institutet. USA in the top American universities fill 38 of the top 50 spots in the Nature Index 2017 rankings; among the top five are Scripps Research Institute, San Diego, followed by Rockefeller University, New York; Massachusetts Institute of Technology, Boston; University of Massachusetts Medical School, Worcester and The University of Texas Southwestern Medical Center, Dallas. KI is one of six European universities in the top 50. Other Swedish universities appearing in the list are Uppsala University and Stockholm University. Nature Index Innovation bases its ranking on Lens, which is an open web-based tool that measures research's impact on innovations.

New insight into how immune cells are formed

Thu, 10/08/2017 - 13:14
In contrast to what has been previously believed, development of blood stem cells to mast cells, a type of specialised immune cell, does not depend on a growth factor called stem cell factor. This has been demonstrated in a new collaborative study by researchers at Karolinska Institutet and Uppsala University, and published in the scientific journal Blood. The results could pave the way for new treatments for certain types of blood diseases. Allergy and asthma affect a high percentage of the population. Mast cells are specialised immune cells that play an important role not only in these conditions but also in other diseases such as mastocytosis, a haematologic disease involving an increased number of mast cells. It has been commonly understood that the growth factor stem cell factor, which stimulates mast cell development, is essential for the formation of mast cells. Now researchers at Karolinska Institutet and Uppsala University have shown that this is not the case. The researchers analysed mast cells and their progenitors in blood from patients with chronic myeloid leukaemia, a disease of the blood. “When the patients were treated with the drug imatinib (Glivec), which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change. We were thus able to conclude that mast cell progenitors did not require stem cell factor”, says Professor Gunnar Nilsson at the Department of Medicine, Solna, and the Centre of Excellence for Systemic Mastocytosis at Karolinska Institutet, and Visiting Professor at the Department of Medical Sciences, Uppsala University, who led the study. Could lead to new treatments By culturing the mast cell progenitor cells present in blood, which are relatively uncommon (about 10 cells per million white blood cells), the researchers found that mast cell progenitors could survive, divide and partially mature without stem cell factor. Instead, development can take place with the factors interleukin 3 and 6. “The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example for mastocytosis for which treatment with imatinib/Glivec is not effective. One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases”, comments Joakim Dahlin, Researcher at the Department of Medicine, Solna, at Karolinska Institutet and first author of the study. The research has been financed with support from the Swedish Research Council, the Swedish Cancer Society, Ollie and Elof Ericsson’s Foundation, Hans von Kantzow’s Foundation, Tore Nilson’s Foundation, the Cancer and Allergy Foundation, The Cancer Research Funds of Radiumhemmet and Karolinska Institutet. Publication Joakim S Dahlin, Maria Ekoff, Jennine Grootens, Liza Löf, Rose-Marie Amini, Hans Hagberg, Johanna S Ungerstedt, Ulla Olsson-Strömberg, Gunnar Nilsson. KIT signaling is dispensable for human mast cell progenitor development. Blood, online 8 August 2017. doi: 10.1182/blood-2017-03-773374.

Method developed that gives researchers better conditions for studying insulin-producing cells

Wed, 09/08/2017 - 16:14
Researchers have established a unique method enabling them to study the function of insulin-producing cells under conditions that are similar to those in humans. This can pave the way to development of new medicines for the treatment of diabetes. Beta cells in the pancreas produce the hormone insulin, which plays a key role in the regulation of blood glucose levels. In diabetes, there is a partial or complete loss of beta cell function. In order to understand how insulin-producing beta cells function, it is essential to be able to study them in a model that reflects the physiological and pathological processes in humans. The cornea as a window into the body In previous studies, Professor Per-Olof Berggren’s research group has shown that the structure and function of the hormone secreting part of the pancreas, the islets of Langerhans, are different in mice to those in humans, while those in monkeys are similar to those in humans. There is therefore a medical need to be able to study the islets of Langerhans in live monkeys. In a new study, recently published in the scientific journal Cell Reports, the researchers have developed a unique method for monitoring the function of insulin secreting beta cells from monkeys that have been transplanted into the anterior chamber of the eye of the same monkeys. This enables the cornea to be used as a window into the body, and to study beta cell function non invasively for a longer period of time.  “By using this human-like model, we have shown that blood vessels have an active and dynamic role with regard to the function of the islets of Langerhans in monkeys. This is an important study contributing to increased understanding of the physiology and pathology of human islets of Langerhans”, states Per-Olof Berggren, Professor at the Rolf Luft Research Centre for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery at Karolinska Institutet and Visiting Professor at Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, who has led the study. Idetify new regulatory steps Per-Olof Berggren points out that in the future, use of this technique will enable identification of not only new regulatory steps for the insulin secreting beta cells’ function and survival, but also of new medicines targeting these regulatory steps, which will be critical for treatment of diabetes. It may also be possible eventually to use this technique in the clinic to monitor the function of the hormone-secreting part of the pancreas.   The study has been conducted in collaboration between researchers at Karolinska Institutet, Lee Kong Chian School of Medicine, Nanyang Technological University and Singapore Eye Research Institute, Singapore General Hospital, Singapore. Publikation Pancreatic islet blood flow dynamics in primates Juan A. Diez, Rafael Arrojo e Drigo, Xiaofeng Zheng,Olga V. Stelmashenko,  Minni Chua, Rayner Rodriguez-Diaz, Masahiro Fukuda, Martin Köhler, Ingo Leibiger, Sai Bo Bo Tun, Yusuf Ali, George J. Augustine, Veluchamy A. Barathi, and Per-Olof Berggren, Cell Reports 20, 1–12, 8 August 2017, doi:10.1016/j.celrep.2015.08.05  

Hormone from fat tissue can give protection against PCOS

Wed, 09/08/2017 - 13:42
Obesity and reduced insulin sensitivity are common in polycystic ovary syndrome, PCOS. New research based on animal studies, and to be published in the journal PNAS, reveals that the hormone adiponectin can protect against these changes. Polycystic ovary syndrome, PCOS, affects more than one in ten women of fertile age. It is characterised by high levels of the male sex hormone testosterone and disrupted ovulation, which can cause infertility. PCOS is also often associated with overweight and an impaired ability to respond to the glucose-regulating hormone insulin, so-called insulin resistance. This in turn results in an increased risk of type 2 diabetes. An international research team, led by the University of Gothenburg and Karolinska Institutet, has previously shown that women with PCOS have lower levels of the fat tissue-derived hormone adiponectin. Furthermore, there is a strong link between low adiponectin levels, increased waistline, large fat cells and insulin resistance in these women. A causal relationship between the low adiponectin levels and the metabolic disturbances in PCOS has however not been proven. In this new study, the researchers therefore looked at two types of genetically modified female mice. In one group they studied mice with elevated levels of adiponectin, and in the other mice with a total lack of adiponectin. Half of the mice in each group received male sex hormone, which induces PCOS symptoms in normal mice. Mice with high levels of adiponectin were shown to be protected against PCOS-related metabolic disorders such as insulin resistance and abdominal obesity. However, adiponectin did not protect against disruption of ovulation. “The results show that adiponectin plays an important role in fat tissue function and probably also in the development of obesity and insulin resistance in women with PCOS. A drug that acts similarly as adiponectin may therefore be an effective future treatment of the metabolic disorders that affect women with PCOS”, says the researchers behind the study. The study has been financed in part by Vetenskapsrådet (Swedish Research Council), Novo Nordisk fonden, (Novo Nordisk Foundation), Diabetesfonden, Diabetes Wellness fonden (Diabetic Wellness Foundation), Adlerbertska fonden (Adlerbertska Foundation) and the Strategic Research Program (SRP) Diabetes Karolinska Institutet. Publication Adiponectin protects against development of metabolic disturbances in a PCOS mouse model. Anna Benrick, Belén Chanclón, Peter Micallef, Yanling Wu, Laila Hadi, John M. Shelton, Elisabet Stener-Victorin, Ingrid Wernstedt Asterholm. Proceedings of the National Academy of Sciences (PNAS), online 8 August 2017, doi: 10.1073/pnas.1708854114

Receptor dynamics provide new potential for pharmaceutical developments

Wed, 09/08/2017 - 13:14
The dynamics among certain so-called G protein-coupled receptors, of vital importance for the function of cells in the body, are different than previously believed.  This has been reported by researchers from Karolinska Institutet in the journal Nature Communications. As these types of receptors are the target for many different medicines, the new finding opens the doors to completely new opportunities within pharmacology and pharmaceutical development. G protein-coupled receptors belong to one of the largest protein families, with around 800 representatives in the human body that send numerous signals around the body. These receptors are found in the cell membrane and are activated by messenger molecules outside the cell, such as adrenaline, dopamine, histamine and endorphins. The receptors are not only important for cellular function by interpreting messages from outside the cell and subsequently activating signals inside the cell, they are also the target for a number of different and important medicines. Examples of such are betablockers, antihistamines, morphine and L-DOPA. Individually or in pairs The discovery of G protein-coupled receptors resulted in a Nobel Prize in Chemistry in 2012. It has been known for some time now that the receptors can act either individually or in pairs, as so-called dimers. Their capacity to function in different constellations has been seen as a challenge, but also an opportunity for pharmacology and pharmaceutical development. To date, the hypothesis has been that G protein-coupled receptors function either as individual receptors or in pairs, and that this is stable. An international team of researchers, led by a group from Karolinska Institutet, has now shown that a specific G protein-coupled receptor named Frizzled 6 (FZD6) can switch between acting in pairs and as an individual receptor, and that this switch is of vital importance for activation of the receptor. FZD6 is important for embryonic development and is significantly expressed in lung tissue. The new study demonstrates that the receptor acts in pairs when it is inactive, and that stimulation with messenger molecules results in the dimer separating into individual receptors, triggering the signals inside the cell. Pave the way for new medicines It remains to be seen whether the same dynamics can be found when activating other G protein-coupled receptors that can act in pairs. As such, the finding may pave the way for the development of new medicines that exploit the dynamics of these receptors. “It may be possible to develop pharmaceutical substances that have an inactivating effect by keeping active receptors in pairs, or vice versa, that activate the receptors by breaking down the dimers. Even if FZD6 cannot be considered a well-defined target for pharmaceutical development, the new concept of receptor dynamics is of utmost interest for many other G protein-coupled receptors and pharmaceutical treatment of many important diseases,” explains Gunnar Schulte, head of the group of researchers at the Department of Physiology and Pharmacology, Karolinska Institutet. He has carried out the study in cooperation with Julian Petersen and Shane Wright from the same Department, along with researchers from Uppsala University, SciLifeLab and the Hebrew University of Jerusalem, Israel. The research was made possible primarily via financing from Karolinska Institutet (KID), the Swedish Research Council, the Swedish Cancer Society, Science for Life Laboratory, the Swedish Foundation for Strategic Research, the Knut & Alice Wallenberg Foundation, Marie Curie ITN, Engkvists Stiftelser (charitable foundation), the Lars Hierta Memorial Foundation, Czech Science Foundation, COST Actions and Israel Science Foundation. Publication Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Julian Petersen, Shane C. Wright, David Rodríguez, Pierre Matricon, Noa Laha, Aviv Vromen, Assaf Friedler, Johan Strömqvist, Stefan Wennmalm, Jens Carlsson & Gunnar Schulte, Nature Communications, online 9 August 2017.

Improved diagnostics for patients with traumatic brain injuries

Fri, 04/08/2017 - 09:02
A new study published in PLOS Medicine shows that by improving the classification of patients with traumatic brain injuries, a more accurate diagnosis and prognosis can be made. The results are the product of a collaboration between Karolinska Institutet, Karolinska University Hospital and Helsingfors University Hospital. Traumatic brain injury (TBI) is one of the most common causes of death and permanent disability in people worldwide. Traumatic brain injuries are caused by external forces directed towards the head such as falls, car accidents or physical abuse. This may result in bleeding inside the skull, in or around the brain. Previously, TBI was considered a disease of the young. Yet, today more and more elderly people are affected and treated for TBI because of the aging population and the increasing use of antithrombotic medications.   Patients who are suspected of having a bleed inside the skull are primarily diagnosed by computed tomography (CT) scanning of the brain. The CT scan provides a rapid diagnosis and shows if there are any bleedings that requires acute neurosurgical interventions. However, interpreting the results of CT scans is highly complex, particularly as different types of bleedings are often found. Various types of CT classification systems have been developed to standardise the interpretation of CT images in patients with traumatic brain injury (TBI). These take into consideration information from the CT scan and are used to determine the severity of the injury and to estimate patient outcome. “The problem with the earlier CT classification systems is that they are very crude and based on old patient materials. Improved and more updated CT classification systems have long been necessary”, says the study’s first author, Eric Thelin, doctor and researcher at the Department of Clinical Neuroscience, Karolinska Institutet. In order to get more information from CT scans, researchers and doctors at Karolinska Institutet and Karolinska University Hospital as well as Helsingfors University Hospital have developed a new way of classifying the brain injuries one can see using CT, the so-called “Stockholm CT score” or “Helsinki CT score”. A collaboration study has compared 1,115 patients who were treated for TBI in the Department of Neurosurgery Intensive Care Units in Stockholm and Helsinki. “The results show that by making a correct assessment of the first images obtained by CT, we can better predict how well the patients will fare. This is extremely useful as it gives the clinicians better information as to how their care can be optimised”, comments Eric Thelin. The study showed that classification using the Stockholm or Helsinki CT score can more reliably predict how well patients will progress in the next 6 to 12 months than previously used classification systems. It also found that the extent of diffuse brain injury a type of injury that without good treatment options, was the type of injury that most affected the patients’ prognosis. “Unfortunately, up to date there is little we can do to treat these diffuse brain injuries. But, aided by our results, we know that future research should be directed into the treatment of diffuse brain injuries. Finding effective treatment strategies for patients affected by this type of injury must be prioritised”, comments Rahul Raj, Adjunct Professor in Experimental Neurosurgery at Helsingfors University Hospital. The study has been financed by Svenska Läkaresällskapet [The Swedish Society of Medicine], Maire Taponens stiftelse [Maire Taponen’s Foundation], Maud Kuistilas minnesstiftels [Maud Kuistilas Memorial Foundation], Eemil Aaltonens stiftelse [Eemil Aaltonen’s Foundation], Ella och Georg Ehrnrooths stiftelse {Ella and Georg Ehrnrooth’s Foundation], Liv & Hälsa [Life and Health], den svenska kulturfonden i Finland [The Swedish Cultural Foundation in Finland], den finsk-norska medicinska stiftelsen [The Finnish-Norwegian Medical Foundation] and Finlands medicinska stiftelse [The Finnish Medical Foundation]. Publication Evaluation of novel computerized tomography scoring systems in human traumatic brain injury: An observational, multicenter study Thelin EP, Nelson DW, Vehviläinen J, Nyström H, Kivisaari R, Siironen J, Svensson M, Skrifvars MB, Bellander BM, Raj R PLOS Medicine, 3 August 2017, doi: 10.1371/journal.pmed.1002368.  

Heartburn medicine can increase risk of kidney disease

Wed, 02/08/2017 - 18:01
People who take proton pump inhibitors for stomach acid reflux run a greater risk of chronic kidney disease than those who take H2-receptor antagonists for the same complaint, a new study published in Gastroenterology reports. Proton pump inhibitors (PPIs) are amongst the most widely sold drugs in the world, including Sweden. Last year, almost ten per cent of the Swedish population took them to alleviate heartburn or prevent stomach ulcers. The first drug, Omeprazol, was launched at the end of the 1980s under the name Losec, but today there are numerous similar products on the market. These drugs spare many people the necessity of having to undergo ulcer surgery and as they are also very effective against heartburn they are extremely popular. Earlier research suggested that PPI’s may be associated with an increased risk of kidney disease. For this present study, researchers at Karolinska Institutet compared the risk of kidney damage on taking PPIs with the somewhat less potent H2-receptor antagonists. The observation study was conducted on some 100,000 long-term users of PPIs from Stockholm and just under 10,000 equally long-term users of H2-receptor antagonists. They found that PPI users had a 26 per cent higher risk of developing chronic kidney disease compared to those who used H2-receptor antagonists and that there was also a correlation between PPI and acute kidney disease. The risk of kidney damage also increased with higher dose taken. The team stresses that the study only indicates a correlation and does not imply causation. However, since millions of people take these drugs every day, a relatively rare adverse reaction can affect a large number of people. “Doctors need to weigh up the pros and cons much more when prescribing PPIs, and revise periodically the need to continue or not with the treatment” says lead author Juan Jesus Carrero, docent at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics. “Many people take PPIs for years and without a clear indication. These drugs should not be taken if they’re not needed, the dose should be cut to the minimum necessary. The possibility to use a H2-receptor antagonist instead should be also contemplated. There might also be reason for patients on long-term PPI medication to take annual kidney function tests. We hope that our results will make the public and the prescribing doctors more aware of the risks of this adverse reaction.” The study was carried out in collaboration with Stockholm County Council, Leiden University (Netherlands) and Johns Hopkins University (USA), and financed by grants from several bodies, including the Swedish Heart and Lung Foundation. None of the researchers have reported any commercial interest in the study. Publication Association Between Proton Pump Inhibitor Use and Risk o Progression of Chronic Kidney Disease. Derk C.F. Klatte, Alessandro Gasparini, Hong Xu, Pietro de Deco, Marco Trevisan, Anna L.V. Johansson, Björn Wettermark, Johan Ärnlöv, Cynthia J. Janmaat, Bengt Lindholm, Friedo W. Dekker, Josef Coresh, Morgan E. Grams, Juan J. Carrero. Gastroenterology, online 2 August 2017, DOI: http://dx.doi.org/10.1053/j.gastro.2017.05.046.

Mutations occurring after fertilisation could play a role in autism

Wed, 26/07/2017 - 15:33
A new study published in the journal Nature Neuroscience, looking at some 6,000 families, demonstrates that mutations that occur after fertilisation play an important role in autism.  Over the last decade, mutations in more than 60 different genes have been linked to autism spectrum disorders (ASD). Some of these are spontaneous, non-inherited mutations and are present in only a few of our cells. Such mutations can occur in a sperm or egg, or in some of the embryo’s cells after fertilisation. These mutations are called postzygotic mutations, PZMs, or somatic mutations. The later the PZMs occur during embryonal development, the fewer the cells that will carry them, making it more difficult to detect them. If the mutation occurs in a very small percentage of the cells, there is a risk it will be missed during regular gene mapping, so-called exome sequencing. To detect PZMs, researchers in the new study used data that had previously been collected from 5,947 families who had a child with autism spectrum disorder. They then re-sequenced parts of the DNA from these children using three independent sequencing techniques in parallel. This mapping revealed that 7.5% of the children had autism spectrum disorder that was related to PZMs. Of these, 83% had not been detected at the original analysis of their genome. Some PZMs affect genes that are known to be linked with autism or other neuropsychiatric disorders, while others affect genes that are known to be active in brain development but have not previously been linked with ASD. By comparing sequencing data, which is primarily on DNA from blood, with data from the public brain banks, which shows when in development (from fetus to adult) these genes are expressed, the researchers also discovered the time point in development when the mutations occurred, and in which areas of the brain they occurred. These analyses showed that PZMs in individuals with ASD occur disproportionately often in the amygdala. “This was exciting for us because the amygdala has been proposed as a region of the brain that is important in autism. The study contributes by further supporting the hypothesis that complex disturbances in the brain, such as epilepsy, intellectual disorders, schizophrenia and brain malformations, can originate from non-inherited mutations that occur at a certain point in prenatal development”, says Christina Hultman, Professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and responsible for Swedish data on autism. Publication Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Elaine T Lim et al, Nature Neuroscience, online 17 July 2017, doi: 10.1038/nn.4598

New strategy against childhood cancer

Wed, 26/07/2017 - 15:16
Neuroblastoma is a cancer in children that originates in the sympathetic nervous system and has a high mortality. Current treatment includes chemotherapy and radiotherapy with their potentially severe side effects; there is therefore an urgent need for a new improved drug.  One potential treatment strategy is to use a drug to target deviant molecular signalling caused by changes in genes. The Wingless (Wnt) signalling pathway is important in the development of nerve cells. One current study has shown that approximately one in four neuroblastoma patients have at least one gene change in the part of the Wnt signalling pathway that is important for cell maturation and migration, the so-called Rho/Rac signalling pathway. “Our results indicate that the signalling molecule Rho and the enzyme Rho kinase, ROCK, have been activated in neuroblastoma patients. High expression of the ROCK enzyme has been shown to be linked to poorer survival of the patients”, comments Cecilia Dyberg, researcher at the Department of Women's and Children's Health, Karolinska Institutet and first author of the study which will be published in the journal PNAS. In studies on cells in vitro and in mice, the researchers observed that when they inhibited ROCK, the tumour cells differentiated, i.e. they matured to less harmful cells, and the tumours stopped growing. The researchers also saw that inhibiting the ROCK enzyme caused the MYCN oncogene, which is linked to the incidence of neuroblastoma, to be degraded to a greater extent and disappear. In some parts of the world, the drug used to target ROCK is used clinically to treat diseases other than cancer, and researchers believe that similar drugs targeting Rho/Rac signalling can be a new promising treatment for neuroblastoma. This research has been financed by grants from the Swedish Childhood Cancer Foundation, the Swedish Research Council, Swedish Cancer Society, the Swedish Foundation for Strategic Research, Märta and Gunnar V. Philipson’s Foundation, Mary Béve’s Foundation for Childhood Cancer Research, Eva and Oscars Ahrén’s Foundation, Magnus Bergvall’s Foundation, Anna-Brita and Bo Castegren’s Memorial Foundation and the Cancer Research Funds of Radiumhemmet. Publications Rho-associated kinase is a therapeutic target in neuroblastoma Cecilia Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, Thale K. Olsen, David Forsberg, Eric Herlenius, Tommy Martinsson, Bertha Brodin, Per Kogner, John Inge Johnsen and Malin Wickström. PNAS, Proceedings of the National Academy of Sciences, online 24 July 2017, doi: 10.1073/pnas.1706011114

Higher calcium levels and risk of coronary artery disease

Wed, 26/07/2017 - 10:22
A genetic predisposition to higher blood calcium levels was associated with an increased risk of coronary artery disease and heart attack, according to a study published by JAMA. Calcium has a vital role in many biological processes in the body such as blood clotting. It is unclear whether lifelong elevated serum calcium may be causally associated with coronary artery disease (CAD) risk. Susanna C. Larsson, PhD, of the Karolinska Institutet, Stockholm, and colleagues conducted a method of analysis using genetic information known as mendelian randomization to examine the association of serum calcium with CAD and myocardial infarction (MI; heart attack). Mendelian randomization is the use of genetic variants that have a specific influence on possible risk factors to assess associations with explicit outcomes. The analysis included 184,305 individuals (60,801 CAD cases [approximately 70 percent with MI] and 123,504 noncases) and six genetic variants related to serum calcium levels. The researchers found that a genetic predisposition to higher serum calcium levels was associated with an increased risk of CAD and heart attack. “Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown,” the authors write. Publication Association of Genetic Variants Related to Serum Calcium Levels with Coronary Artery Disease and Miocardial Infarction Susanna C. Larsson, Stephen Burgess, Karl Michaëlsson JAMA, 25 juli 2017, 2017;318(4):371-380, doi:10.1001/jama.2017.8981

Reduction in dental care and inferior oral health subsequent to dementia diagnosis

Wed, 26/07/2017 - 08:00
Subsequent to a diagnosis of dementia, the patient’s contact with the dental care services diminishes and oral health is impaired. This has been revealed by a major register-based study from Karolinska Institutet published in the scientific journal Alzheimer’s & Dementia. Researchers at Karolinska Institutet, using register data, have examined utilisation of dental health services and oral health among a large number of individuals before and after a dementia diagnosis. Information on diagnoses and cognitive function has been compiled for around 58,000 persons registered in the Swedish Dementia Registry, SveDem, from 2007 to 2015. Information relating to dental health was obtained from Tandhälsoregistret (dental health registry). “We observed that the number of visits to dentists saw a dramatic decrease after a dementia diagnosis and that the reduction in utilisation of dental health services was more predominant with patients who experienced a more rapid degeneration in cognitive function,” explains Maria Eriksdotter, Professor of Geriatrics at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. A low MMSE score (Mini-Mental State Examination) – a method used to indicate cognitive impairment – represented a risk factor in terms of losing teeth. Poor oral health, tooth decay and loosening of teeth may cause pain, reduced quality of life and difficulties eating, resulting in poor nutrition. “It may be the case that patients forget to visit the dentist or put other types of health care first, as dental care is separate from other medical services. We require better organisation to detect these patients and ensure that they attend their dental health check-ups,” says Gunilla Sandborgh Englund, Professor at the Department of Dental Medicine, Karolinska Institutet. The research has been financed by Alzheimerfonden (the Swedish Alzheimer foundation), Stockholm County Council (the SOF project), the Swedish Research Council and the Swedish Association of Local Authorities and Regions. Publication Dental care utilization in patients with different types of dementia. A longitudinal nationwide study of 58037 individuals, Seyed-Mohammad Fereshtehnejad, Sara Garcia-Ptacek, Dorota Religa, Jacob Holmer, Kåre Buhlin, Maria Eriksdotter, Gunilla Sandborgh-Englund, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, online 8 July 2017, doi: 10.1016/j.jalz.2017.05.004

Professor Allen Counter is dead

Thu, 20/07/2017 - 13:47
The brain researcher and neurophysiologist Professor Allen Counter has passe away after a time of illness. Counter was a professor at Harvard University and foreign adjunct professor at Karolinska Institutet, KI. He had strong ties to Sweden, and in 2004 he was appointed General Council of Sweden to Boston and New England. “Allen was a true friend of KI and Sweden, and through his extensive international network or in research, health care, politics, industry and the arts, he contributed in a unique way to strengthen KI in the international arena. Allen will be deeply missed”, says Jan Hillert, Head of the Department of Clinical Neuroscience, where Counter was a foreign adjunct professor. ´ Counter was a clinical professor of neurology at Harvard University and worked as a neurophysiologist at the Massachusetts General Hospital in Boston, USA. He also played d a key role as the Head of the Harvard Foundation for Intercultural and Race Relations. Counter was very successful in attracting research funding from the private sector. Counter had longstanding and strong ties to KI and Sweden. He joined KI as a visiting researcher in 1978 and remained connected to KI until his death. He earned his Ph D at KI’s Department of Physiology in 1992, and was appointed visiting professor in 2009. In 2015 he was appointed foreign adjunct professor. Counter collaborated with many scientists at KI, especially Professor Erik Borg, Professor Tom Brismar, Professor Lou Brundin and Professor Tomas Olsson. "Allen remained extremely loyal to KI and he was equally as loyal as a colleague and friend", says Professor Tomas Olsson. Counter also collaborated with researchers at other universities in Sweden, especially Professor Göran Laurell at the Department of Surgical Sciences at Uppsala University. Counter’s research evolved around the inner ear and brain development. Allen Counter was 73 years old.

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