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A new study in mice, conducted by researchers at Sweden’s Karolinska Institutet together with colleagues in Singapore and the United States, shows that our natural gut-residing microbes can influence the integrity of the blood-brain barrier, which protects the brain from harmful substances in the blood. According to the authors, the findings provide experimental evidence that our indigenous microbes contribute to the mechanism that closes the blood-brain barrier before birth. The results also support previous observations that gut microbiota can impact brain development and function. The blood-brain barrier is a highly selective barrier that prevents unwanted molecules and cells from entering the brain from the bloodstream. In the current study, being published in the journal Science Translational Medicine, the international interdisciplinary research team demonstrates that the transport of molecules across the blood-brain barrier can be modulated by gut microbes – which therefore play an important role in the protection of the brain.  The investigators reached this conclusion by comparing the integrity and development of the blood-brain barrier between two groups of mice: the first group was raised in an environment where they were exposed to normal bacteria, and the second (called germ-free mice) was kept in a sterile environment without any bacteria. “We showed that the presence of the maternal gut microbiota during late pregnancy blocked the passage of labeled antibodies from the circulation into the brain parenchyma of the growing fetus”, says first author Dr. Viorica Braniste at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. ”In contrast, in age-matched fetuses from germ-free mothers, these labeled antibodies easily crossed the blood-brain barrier and was detected within the brain parenchyma.” Maintained into adulthood The team also showed that the increased ‘leakiness’ of the blood-brain barrier, observed in germ-free mice from early life, was maintained into adulthood. Interestingly, this ‘leakiness’ could be abrogated if the mice were exposed to fecal transplantation of normal gut microbes. The precise molecular mechanisms remain to be identified. However, the team was able to show that so-called tight junction proteins, which are known to be important for the blood-brain barrier permeability, did undergo structural changes and had altered levels of expression in the absence of bacteria. According to the researchers, the findings provide experimental evidence that alterations of our indigenous microbiota may have far-reaching consequences for the blood-brain barrier function throughout life. “These findings further underscore the importance of the maternal microbes during early life and that our bacteria are an integrated component of our body physiology”, says Professor Sven Pettersson, the principal investigator at the Department of Microbiology, Tumor and Cell Biology. “Given that the microbiome composition and diversity change over time, it is tempting to speculate that the blood-brain barrier integrity also may fluctuate depending on the microbiome. This knowledge may be used to develop new ways for opening the blood-brain-barrier to increase the efficacy of the brain cancer drugs and for the design of treatment regimes that strengthens the integrity of the blood-brain barrier”. The study was funded with grants from the Swedish Research Council, the Swedish Brain Foundation, the research consortium TORNADO within the EU’s Seventh Framework Programme, Merieux Foundation, Wenner-Gren Foundation, Singapore Millenium foundation, and the Nanyang Technological University in Singapore. Professor Sven Pettersson is also affiliated to the Lee Kong Chian School of Medicine, The National Cancer Centre in Singapore and the Singapore Centre on Environmental Life Sciences Engineering at the Nanyang Technological University. View a press release about these findings Publication The gut microbiota influences the blood brain barrier permeability in mice Viorica Braniste, Maha Al-Asmakh, Czeslawa Kowa, Farhana Anuar, Afrouz Abbaspour, Miklos Toth, Agata Korecka, Nadja Bakocevic, Ng Lai Guan, Parag Kundu, Balazs Gulyas, Christer Halldin, Kjell Hultenby, Harriet Nilsson, Hans Hebert, Bruce T. Volpe, Betty Diamond, Sven Pettersson Science Translational Medicine, online 19th November 2014,  DOI: 10.1126/scitranslmed.3009759

A new study by researchers at Karolinska Institutet shows that a medium amount of physical activity in daily life lowers the risk of Parkinson’s disease, compared to a very low level physical activity. The study, which is being published online in the journal Brain, followed 43,368 individuals in Sweden during a 12 year period. The research team used the Swedish National March Cohort to analyse comprehensive information on physical activity of all kinds. They assessed household and commuting activity, occupational activity, leisure time exercise, and total daily physical activity according to data provided by 27,863 females and 15,505 males, as part of an extensive questionnaire. For the purpose of this study, physical activity was quantified into metabolic equivalent (MET) hours per day, based on estimated oxygen consumption associated with those activities. All participants were free of Parkinson’s disease in October 1997, the start of the follow-up period. Study participants were followed from this baseline until date of diagnosis with Parkinson’s disease, date of death, date of emigration, or the end of the follow-up period in December 2010, whichever came first. In that time 286 cases of Parkinson’s disease were identified. More than six hours per week In the study’s multivariable-adjusted model, compared with participants who spent less than two hours per week on household and commuting activity, those who spent more than six hours per week on the same types of activities had a 43% lower risk of developing Parkinson’s disease. Compared with a low level of total physical activity, a medium level of total physical activity (a mean of 39.1 MET hours per day) was associated with a 45% lower Parkinson’s disease risk in males. In women the results were not as consistent, but the protective effect of physical activity in this group was supported when researchers summarized all available evidence from published prospective cohort studies. Leisure time exercise was not associated with Parkinson’s disease risk when analysed alone. “One of many strengths of this study is that all information on physical activity and daily energy output was assessed before the disease occurrence, making recall bias and reverse causation less likely. The results show that a few hours spent at the gym do not have the protective effect that one would wish, but it is the physical activity in daily life that is of greater importance”, says Karin Wirdefeldt, researcher at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics, and Department of  Clinical Neuroscience, who headed the study.“ First study-author is Fei Yang, doctoral student at the Department of Medical Epidemiology and Biostatistics. The work was funded by the Swedish Research Council, the Swedish Cancer Association, ICA Sweden, Ericsson, Karolinska Institutet and the Stockholm County Council. Find a press release from Oxford University Press about this study Publication Physical activity and risk of Parkinson’s disease in the Swedish National March Cohort Fei Yang, Ylva Trolle Lagerros, Rino Bellocco, Hans-Olov Adami, Fang Fang, Nancy L. Pedersen, Karin Wirdefeldt Brain, online 19th 2014, DOI: 10.1093/brain/awu323

Professor Vladimir Hachinski, London, Ontario, and Professor Bo Norrving, Lund is jointly awarded the Karolinska Stroke Award for Excellence in Stroke Research 2014. Professors Hachinski and Norrving received the award from Vice Chancellor Anders Hamsten, Karolinska Institutet, in connection with the ongoing ESO Karolinska Stroke Update meeting in Stockholm. The award is 100,000 Swedish kronor and is shared between the awardees, for “their leading role in clinical stroke research, in particular the understanding of stroke syndromes, pathophysiological mechanisms of stroke and cerebrovascular diseases, and the organisation of stroke services.” Among professor Hachinski most important discoveries are the key role of the insula of the brain for sudden death and, together with other researchers, the ischaemia-amyloid – inflammation link between Alzheimer disease and stroke, paving the way for novel therapeutic approaches. Professor Norrving was corresponding author of the Swedish Aspirin Low Dose Trial (SALT), a landmark publication in the Lancet in 1991, later included in Vintage Papers from Lancet of the most important papers from 1823 to 2005. His main research activities have been focused on stroke epidemiology, stroke syndromes, small vessel disease, ultrasound, neuroimaging, clinical genetics, clinical trials and organisation of stroke services. Read more avout Stroke Update 2014.

A recent study published in the journal PNAS shows that young capillary vessels rejuvenate aged pancreatic islets. The finding challenges prevailing views on the causes of age-dependent impaired glucose balance regulation, a condition that often develops into diabetes type 2. The international research team behind the study now suggests that targeting inflammation and fibrosis in the small blood vessels of the pancreatic islets may offer a new way of treatment for age-dependent dysregulation of blood glucose levels. “This is an unexpected but highly important finding, which we expect will have a significant impact on diabetes research in the future. The results indicate that beta cell function does not decline with age, and instead suggest that islet function is threatened by an age-dependent impairment of vessels that support them with oxygen and nutrients”, says Per-Olof Berggren at the Rolf Luft Research Center for Diabetes and Endocrinology at Karolinska Institutet, who led the study together with Alejandro Caicedo at University of Miami Miller School of Medicine and Hong Gil Nam at DGIST in Republic of Korea. Beta cells are located in the pancreatic islets and secrete the hormone insulin, that play a key role in regulating blood glucose levels. Ageing may lead to a progressive decline in glucose regulation which may contribute to diabetes development. Generally, it has been assumed that this is due to reduced capacity of the beta cell to secrete insulin or multiply. “In the study we challenged the view that the age-dependent impairment in glucose homeostasis is solely due to intrinsic, dysfunction of islet cells, and hypothesized that it is instead affected by systemic aging factors”,  says first author Joana Almaça at the Diabetes Research Institute, University of Miami.  Replacing the islet vasculature  In marked contrast to the widely held notion that the insulin-producing pancreatic beta cell loses function with wear and tear, the researchers now show that mouse and human beta cells are fully functional at advanced age. When replacing the islet vasculature in aged islet grafts with young capillaries, the investigators found that the islets were rejuvenated and glucose homeostasis fully restored.  “While expanding beta cell mass may still be desirable for future diabetes therapy, improving the local environment of the otherwise healthy aged beta cell could prevent age-associated deterioration in glucose homeostasis and thereby promote healthy ageing, which is conceptually novel and highly exciting”, says Per-Olof Berggren. The work conducted at Karolinska Institutet was mainly funded by the Swedish Research Council, the Swedish Diabetes Association, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, the Family Erling-Persson Foundation and European Research Council. View a press release about these findings Publication Young Capillary Vessels Rejuvenate Aged Pancreatic Islets Joana Almaça, Judith Molina, Rafael Arrojo, Rafael Arrojo e Drigo, Midhat H. Abdulreda, Won Bae Jeon, Per-Olof Berggren, Alejandro Caicedo, and Hong Gil Nam PNAS, Online Early Edition the week of Nov 17-Nov 21, 2014, doi: 10.1073/pnas.1414053111

Karolinska Institutet’s new doctors of medicine, all of whom held their public defences in the spring, officially received their degrees last Friday (14 November). Tribute was also paid at the ceremony to the year’s jubilee doctors and KI awarded its Gold Medal for the first time since the bicentenary in 2010 – to university chancellor Harriet Wallberg, KI’s former president (vice-chancellor). In the November gloom of Stockholm’s City Hall, lit only by candles that spread a warm light along the balustrade, the spotlight trained on the new doctors seemed even stronger. All 117 new doctors received their doctoral hat and diploma from Dean of Doctoral Education Anders Gustafsson, as cannon fired a salute from the City Hall waterfront to mark the end of up-to five year’s work as doctoral students and its culminating in academic theses.  “It’s all about hard work and trying to solve problems,” said Professor Gustafsson, who quoted Nobel literature laureate Samuel Beckett’s words on never giving up: “Try again. Fail again. Fail better.” Fourteen jubilee doctors, who received their degrees from Karolinska Institutet 50 years ago, were also celebrated, amongst them anti-doping specialist Professor Arne Ljungqvist, to whom the government recently decided to award a medal in recognition of his work. Vice-Chancellor Anders Hamsten expressed his sincere thanks to the jubilee doctors for their contributions to science and for having prepared the way for new generations. Professor Hamsten also awarded Karolinska Institutet’s Gold Medal to Professor Harriet Wallberg for her “exceptional contributions” to the university. Of particular note in this regard was the fundraising campaign that she initiated during her university presidency (2004–2012) and that generated proceeds of a billion kronor for research and for Aula Medica, which opened in 2013. Photo credit: Ulf Sirborn and Stefan Zimmerman

Patients who have been treated for cancer of the central nervous system (brain tumours) in childhood or adolescence can show affected self-perception and self-identity in adulthood. This is concluded in a recent study from Karolinska Institutet in Sweden which is being published in the scientific journal Neuro-Oncology. Undesirable persistent late-effects affect a considerable number of adults who survived childhood central nervous system (CNS) cancer. The study followed 700 adult survivors diagnosed 1992-2001 with a childhood CNS tumour. The study group covered all adult brain tumour survivors in Sweden at the time of start of study. Patients were compared with a control group selected from the general population. In addition to health and function, researchers also studied how the illness, the brain tumour treatment and the aftermath affected patients’ psychological identity, i.e. their self-perception and self-esteem in contexts where these play a significant role, such as family, friends, work and sports. Physical body image and an overall self-esteem index were also covered. In addition to specific medical and treatment information collected from medical registers, late-effects status and self-perception factors were addressed using a standardised self-report questionnaire. The results demonstrate that the late-effects of CNS cancer of childhood are not restricted to health and physical and neuro-psychological function. The illness experience as a whole, with the increased risk for tumour/treatment-related damage intrudes upon on self-perception and contribute to shaping of psychological identity. Compared with the general  population, survivors had less favourable outcomes in several of studied aspects. Negative self-perception A negative instead of positive self-perception was more common among survivors. In the contexts of work and friends, for example, 22%and 30% of patients had a negative self-perception compared with 8% and 17% in the control group. In context of family, though, self-perception parcelled that of the general population. Earlier radiation treatment towards the brain and permanent physical scars increased the risk for an adverse effect on self-perception in adulthood. “The study confirms that these patients are in the risk zone for a wide spectrum of late-effects”, says Krister K. Boman, principal investigator at the Department of Women’s and Children’s Heath at Karolinska Institutet. In addition to health-related, neuro-cognitive and function problems they also engage personality factors linked to identity, mental health and psychological well-being. The results bear witness of the width of the psychological consequence of brain tumour illness in childhood, and of the necessity of adequate support, and of psychosocial rehabilitation resources. These findings allow for specifying the need for early and continued preventative measures for these patients.” Researchers point to that the findings verify the importance of intensified preventative measures in health care, and a follow-up plan extended into adulthood that meets the specific needs of adult patients who survived paediatric brain cancer. In addition to measures against earlier known problems, medical health care has to attend to that CNS diseases and treatment intrudes upon long-term personality development. The study was conducted with funding from Swedish Childhood Cancer Foundation and Karolinska Institutet research grants. View a press release about the study Publication Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population Hörnquist L, Rickardsson J, Lannering B, Gustafsson G, Boman KK Neuro-Oncology, early online 20 October  2014; doi:10.1093/neuonc/nou289

A novel registry study from Karolinska Institutet in Sweden suggests that beta blockers may benefit also patients suffering from a relatively unknown form of heart failure called HFPEF, which today lacks well-established treatment. HFPEF involves an impaired ability of the heart to fill with blood, and affects nearly 2 per cent of the population. These new findings are being published in the scientific periodical JAMA. Heart failure was for a long time defined as reduced ability to contract the heart and pump oxygenated blood out to the rest of the body. This condition is often caused by long-standing high blood pressure or a previous heart attack. Men are affected more often than women, and there are several treatments improving symptoms and survival. However, in recent years it has become clear that a new type of heart failure is equally common and serious. This type of heart failure, called HFPEF or heart failure with preserved ejection fraction, involves a reduced ability in the heart to relax and fill with blood. HFPEF is more common at old age and affects women more often than men. Until recently, there was no treatment against this disorder. In the current study, a Swedish team comprising researchers from Karolinska Institutet, Linköping University, Stockholm South General Hospital, Danderyd Hospital and Karolinska University Hospital analysed data from 42,000 patients from the nation-wide Swedish Heart Failure Registry. According to the findings, patients with HFPEF who were treated with beta blockers had better survival than untreated patients. The difference persisted after adjustment for a large number of other factors, such as patient age, general health, socioeconomic and other factors, and the final decrease in mortality was 7 per cent in the group treated with beta blockers. Damage the heart in the long-term In heart failure, stress hormones such as adrenaline are secreted and damage the heart in the long-term. Beta blockers protects against this damaging effect. In randomized trials in patients with reduced ability to contract the heart, beta blockers have been shown to reduce mortality. However, this is the first comprehensive study regarding the effect of beta blockers in patients with HFPEF. In a previous study, the Swedish team also reported that HFPEF patients could benefit from other similar heart drugs, such as ACE-inhibitors and angiotensin receptor blockers. Researchers now plan to proceed with randomized clinical trials. "This study was large and rigorous, but still cannot prove that beta blockers are beneficial in HFPEF”, says Principal Investigator Lars H. Lund, Docent at Karolinska Institutet. “However, it provides a rationale for performing large-scale randomized trials with this inexpensive category of drugs, which we now plan to go through with. Sweden has unique capabilities to implement such randomized studies in the context of the major Swedish quality registries.” The work was financed by the Swedish Research Council, The Swedish Heart-Lung Foundation, the Stockholm County Council and the Swedish Association of Local Authorities and Regions. View a press release about this study Publication Association between Use of Beta-Blockers and Mortality in Patients with Heart Failure and Preserved Ejection Fraction Lars H. Lund, Lina Benson, Ulf Dahlström, Magnus Edner, Leif Friberg JAMA. 2014;312(19):2008-2018. doi:10.1001/jama.2014.15241

A new immunological mechanism in atherosclerosis and cardiovascular disease has been presented in a study from Karolinska Institutet in Sweden. The study is being published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, and also indicates a possible treatment method for these diseases. Atherosclerosis is an inflammatory process where lipidsin the form of LDL cholesterol (‘bad cholesterol’) are stored in the artery walls. The activation of the immune system in the form of T-cells, among others, plays a vital role, particularly for rupturing the atherosclerotic plaques which, the primary cause of myocardial infarction and stroke. LDL is only taken up in the artery wall after modification, a process where oxidation is one probable underlying cause. Enzymes in the artery walls can also modify LDL making it inflammatory. Most basic scientific studies in the field are based mouse models with genetic changes as mice cannot develop arteriosclerosis or cardiovascular disease. Plaque cells and blood Together with his research team, Dr. Johan Frostegård, Professor of Medicine at the Institute of Environmental Medicine at Karolinska Institutet, has studied inflammatory and immune defence reactions in atherosclerosis and cardiovascular disease using plaque cells and blood from patients with cardiovascular disease. The researchers have observed that the lipids (phospholipids) in modified LDL appear to be one of the primary causes. The research team has shown that LDL that is modified by enzymes in the artery walls can activate dendritic cells, which in turn play a key role in activating the T-cells. Non-modified, regular LDL on the other hand had no effect on these cells in the study. The research also indicates the possible existence of a mechanism, namely that stress proteins (also called heat shock proteins) are expressed, which is decisive when modified LDL activates the dendritic cells and T-cells. The study shows that a plasma protein Annexin A5 decreases inflammation and modulates immune reactions to modified LDL, which creates a protective effect. “Studying the inflammatory process and immune reactions directly in cells from people with cardiovascular disease is a unique opportunity to discover the causes and new mechanisms behind the disease's progression. We have shown that modified LDL can play a key role and that stress proteins have a major significance to immune defence reaction,” says Johan Frostegård. Fighting inflammatory process With the new results, Dr. Frostegård and his team hope to find a strategy for fighting the inflammatory process. “We have shown that Annexin 5 is a possible new therapy for fighting inflammation and supports the immune defence system is a positive way. We hope to develop this protein into a new type of anti-inflammatory treatment for atherosclerotic disease,” he says. The study was funded with grants from the Torsten Söderberg Foundation, Vinnova, the EU, and RMR. Johan Frostegård is also specialist consultant at the Emergency Clinic at Karolinska University Hospital, Huddinge in Stockholm County. The researchers and their European partners have applied for a larger EU grant to fund the continuing basic research studies and also treatment studies on patients with cardiovascular disease, which is backed by several patents. View a press release about the findings Publication Induction of dendritic cell-mediated T cell activation by modified but not native LDL in humans and inhibition by Annexin A5: involvement of heat shock proteins Liu A, Ming J, Fiskesund R, Ninio E, Karabina S, Bergmark C, Frostegård AG, Frostegård J Arteriosclerosis, Thrombosis, and Vascular Biology, published online before print November 13, 2014,doi: 10.1161/ATVBAHA.114.304342  

Researchers at Karolinska Institutet have succeeded in explaining how stem cells in the brain change to allow one type of stem cell to produce different cell types at different stages. In a study being published in the journal Neuron, researchers show that the signal molecule TGF-beta acts as a time signal that regulates the nerve stem cells' potential at different stages of the brain's development – knowledge that may be significant for future pharmaceutical development. The human brain consists of thousands of different types of nerve cells that are all formed out of what in simple terms can be described as immature stem cells. It has long been known that the neural stem cells change as the human brain develops and ages. One type of stem cell can produce multiple types of nerve cells at different stages of the brain's development. In this process, ageing stem cells also gradually become more limited in their development potential and lose the ability to develop the maturated cell types that form during the early stages. How neural stem cell identity and potential is regulated over time has been poorly understood. But in the study being published, researchers at the Department of Cell and Molecular Biology at Karolinska Institutet present a molecular time mechanism that can help explain neuronal stem cell regulation and therefore also the occurrence of cellular diversity in the brain. “TGF-beta functions as an important time signal that controls when a stem cell should stop producing one type of nerve cell and instead start producing another, while also gradually limiting the stem cell's  future development capacity,” says Johan Ericson, Professor of Developmental Biology, who led the study. Mass-prduction of nerve cells In their work, the researchers also show how TGF-beta can be used in stem cell cultures to mass-produce nerve cells which in turn produce the signalling substance serotonin. Today the brain's serotonin system is already a known target for the treatment of depression, and according to researchers it should be possible to use time signals in pharmaceutical development based on stem cells. “This is the first known signalling molecule that regulates the potential of neuronal stem cells”, says Johan Ericson. “With a better understanding of how potential is regulated, it could be possible to broaden the development spectrum of ageing stem cells, allowing them to regain their capacity to produce cell types from earlier development stages, which in the long-term perspective could be relevant to future treatment methods for neurodegenerative disease”. The research was funded by grants from the Swedish Foundation for Strategic Research (SSF), Knut and Alice Wallenberg Foundation, Swedish Research Council, Swedish Cancer Society and Swedish Brain Foundation. View a press release about this research Publication Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS  José M. Dias, Zhanna Alekseenko, Joanna M. Applequist and Johan Ericson Neuron, online 13 November 2014, DOI: http://dx.doi.org/10.1016/j.neuron.2014.10.033