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Karolinska Institutet is a medical university in Solna within the Stockholm urban area, Sweden, and one of Europe's largest and most prestigious medical universities. It was founded in 1810 on Kungsholmen on the west side of Stockholm; the main campus was relocated decades later to Solna, just outside Stockholm. A second campus was established more recently in Flemingsberg, Huddinge, south of Stockholm.Karolinska Institute is Sweden's third oldest medical school, after Uppsala University and Lund University . Research at Karolinska Institute accounts for more than 40% of all academic medical research in Sweden. Karolinska Institute consistently ranks among the top universities in the world on a number of prestigious ranking tables, and is currently the eighth best medical university in the world. According to the 2012 Times Higher Education World University Rankings, Karolinska Institute is ranked 32nd worldwide, 5th in Europe behind Oxford university, Cambridge university and UCL, 1st in the Nordic region and according to the 2011 Academic Ranking of World Universities, Karolinska Institute is ranked 11th in the world in the field of clinical medicine and pharmacology, 18th in life science and 3rd in pharmacy.The Karolinska University Hospital, located in Solna and Huddinge, is associated with the university as a research and teaching hospital. Together they form an academic health science centre. It is one of Sweden's largest centres for training and research, accounting for 30 percent of the medical training and 40 percent of the medical academic research conducted nationwide. While most of the medical programs are taught in Swedish, the bulk of the Ph.D. projects are conducted in English.A committee of the institute appoints the laureates for the Nobel prize in Physiology or Medicine. The Nobel Assembly at Karolinska Institutet is a body at Karolinska Institutet that awards the Nobel Prize in Physiology or Medicine. The Nobel Assembly consists of fifty professors from various medical disciplines at the Karolinska Institute. Wikipedia.


Gustafsson Sheppard N.,Karolinska Institutet
Journal of molecular endocrinology | Year: 2012

Estrogen receptor α (ERα) is initially overexpressed in two-thirds of all breast cancers and is involved in its development and proliferation. We previously reported that the RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1) interacts with the ERα promoter and that RBCK1 expression positively correlates with ERα levels, expression of ERα downstream target genes, and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERα expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERα expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERα expression has to be defined. Here, we show that ERα, RBCK1, and the RBCK1-interacting protein protein kinase C β 1 (PKCβ(I)) co-occupy a previously identified ERα binding region in the proximal ERα promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERα promoter B is facilitated by ERα, which in turn facilitates PKCβ(I) recruitment and PKCβ(I)-dependent histone modifications. Furthermore, ERα regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERα coactivator function of RBCK1. The interaction between RBCK1 and ERα was dependent on the E3 ubiquitin ligase domain of RBCK1 and the activating function-1 domain of ERα. The ligand-binding function of ERα does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERα expression is modulated in breast cancer cells.


Franco R.,University of Navarra | Franco R.,University of Barcelona | Cedazo-Minguez A.,Karolinska Institutet
Frontiers in Pharmacology | Year: 2014

Peering into the field of Alzheimer's disease (AD), the outsider realizes that many of the therapeutic strategies tested (in animal models) have been successful. One also may notice that there is a deficit in translational research, i.e., to take a successful drug in mice and translate it to the patient. Efforts are still focused on novel projects to expand the therapeutic arsenal to "cure mice." Scientific reasons behind so many successful strategies are not obvious. This article aims to review the current approaches to combat AD and to open a debate on common mechanisms of cognitive enhancement and neuroprotection. In short, either the rodent models are not good and should be discontinued, or we should extract the most useful information from those models. An example of a question that may be debated for the advancement in AD therapy is: In addition to reducing amyloid and tau pathologies, would it be necessary to boost synaptic strength and cognition? The debate could provide clues to turn around the current negative output in generating effective drugs for patients. Furthermore, discovery of biomarkers in human body fluids, and a clear distinction between cognitive enhancers and disease modifying strategies, should be instrumental for advancing in anti-AD drug discovery. © 2014 Franco and Cedazo-Minguez.


Mullers E.,Karolinska Institutet | Mullers E.,TU Dresden
Viruses | Year: 2013

Gag proteins play an important role in many stages of the retroviral replication cycle. They orchestrate viral assembly, interact with numerous host cell proteins, engage in regulation of viral gene expression, and provide the main driving force for virus intracellular trafficking and budding. Foamy Viruses (FV), also known as spumaviruses, display a number of unique features among retroviruses. Many of these features can be attributed to their Gag proteins. FV Gag proteins lack characteristic orthoretroviral domains like membrane-binding domains (M domains), the major homology region (MHR), and the hallmark Cys-His motifs. In contrast, they contain several distinct domains such as the essential Gag-Env interaction domain and the glycine and arginine rich boxes (GR boxes). Furthermore, FV Gag only undergoes limited maturation and follows an unusual pathway for nuclear translocation. This review summarizes the known FV Gag domains and motifs and their functions. In particular, it provides an overview of the unique structural and functional properties that distinguish FV Gag proteins from orthoretroviral Gag proteins. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Fowler T.,University of Birmingham | Zammit S.,University of Cardiff | Owen M.J.,University of Cardiff | Rasmussen F.,Karolinska Institutet
Archives of General Psychiatry | Year: 2012

Context: The strong association between lower IQ and risk for psychosis has led to the suggestion that the search for genes influencing cognition may provide a useful strategy for examining the genetic origins of psychosis. However, research in this area has generally used designs in which twin pairs are selected by case status and with assessment of IQ after the onset of psychosis rather than longitudinal population-based samples. Objective: To examine the relationship and shared genetic origin between premorbid IQ and psychotic disorders in a longitudinal population-based cohort. Design: Genetically informative longitudinal study. Setting: Population-based cohort in Sweden. Participants: Individuals were identified from the populationbased Swedish Multi-Generation Register and consisted of male sibling (n=369 960), monozygotic twin (n=1986), and dizygotic twin (n=2253) pairs born between January 1951 and December 1976. Their IQs were measured during compulsory military conscription. Main Outcome Measure: Individuals having a subsequent diagnosis of psychosis were identified via the Swedish National Hospital Discharge Register. Results: Heritability estimates for IQ and psychosis were similar to previous estimates, approximately 69% and 56%, respectively. However, the phenotypic correlation between IQ and psychosis was only-0.11, of which 91% was due to shared genetic influences. The proportion of genetic variance for psychosis shared with that for IQwas approximately 7%. Conclusions: Using IQ as a phenotype to identify genes that have an important role in the genetic origin of schizophrenia is unlikely to be a successful strategy. The low correlation seen in this study between premorbid IQ and psychosis vs the higher correlations reported in the literature with postmorbid IQ suggests the correlation between these phenotypes has more to do with the influence that the onset of psychosis has on cognitive functioning than with shared genetic origin. © 2012 American Medical Association.


Alexanderson H.,Karolinska Institutet
Current Rheumatology Reports | Year: 2012

Exercise is an important part of treatment in patients with idiopathic inflammatory myopathies. Improved functioning, ability to perform activities of daily living, and health-related quality of life have been reported in adult polymyositis, dermatomyositis, and also recently inclusion body myositis following different exercise regimens, with no signs of increased muscle inflammation. Intensive resistance training could reduce clinical disease activity and reduce expression of genes regulating inflammation and fibrosis in chronic polymyositis and dermatomyositis. Today, exercise research in adult myositis is focused on understanding mechanisms for muscle impairment and improved muscle function in relation to exercise and verifying results from small, open studies in larger settings. There are no studies evaluating the effects of exercise over weeks or months in juvenile dermatomyositis, other than a case report; however, there is to our knowledge an ongoing effort to evaluate the safety and effects of exercise in patients with juvenile dermatomyositis. © Springer Science+Business Media, LLC 2012.


Teh L.K.,University Technology of MARA | Bertilsson L.,Karolinska Institutet
Drug Metabolism and Pharmacokinetics | Year: 2012

Summary: CYP2D6 has received intense attention since the beginning of the pharmacogenetic era in the 1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, the large geographical and inter-ethnic differences in the genetic polymorphism and possible drug-induced toxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate the importance of the genetic polymorphism of CYP2D6 in different populations as well as some clinical implications and important drug interactions. © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX).


Antai D.,Karolinska Institutet
African Journal of Primary Health Care and Family Medicine | Year: 2011

Context: Childhood vaccinations are one of the most cost-effective means of reducing negative child health outcomes. Despite the benefits of immunisation, inequities persist both between and within rural-urban areas in Nigeria. Objectives: To assess the role of community contexts on rural-urban inequities in full immunisation uptake amongst children 12 months of age and older. Methods: Data from the 2003 Nigeria Demographic and Health Survey including 6029 live born children from 3725 women aged 15-49 years were examined using multilevel regression analysis. Results: Rural children were disadvantaged both in the proportion receiving full immunisation and individual vaccines. Contextual or community-level factors such as community prenatal care by doctor, community hospital delivery, and region of residence accounted for significant rural-urban inequities in full immunisation. Conclusion: This study stresses the need for community-level interventions aimed at closing rural-urban inequities in the provision of maternal and child health care services. © 2011. The Authors.


Holmgren L.,Karolinska Institutet
Biochemical and Biophysical Research Communications | Year: 2010

Horizontal or lateral gene transfer is an effective mechanism for the exchange of genetic information in bacteria allowing bacterial diversification and facilitating adaptation to new environments. Recent data demonstrate that DNA may also be transferred between somatic cells via the uptake of apoptotic bodies. This process allows transfer of viral genes that have been incorporated into the genome in a receptor-independent fashion. Transferred DNA is replicated and propagated in daughter cells in cell that have an inactivated DNA response which may impact tumor progression. © 2010 Elsevier Inc. All rights reserved.


Grompe M.,Oregon Health And Science University | Strom S.,Karolinska Institutet
Gastroenterology | Year: 2013

Animal models are used to study many aspects of human disease and to test therapeutic interventions. However, some very important features of human biology cannot be replicated in animals, even in nonhuman primates or transgenic rodents engineered with human genes. Most human microbial pathogens do not infect animals and the metabolism of many xenobiotics is different between human beings and animals. The advent of transgenic immune-deficient mice has made it possible to generate chimeric animals harboring human tissues and cells, including hepatocytes. The liver plays a central role in many human-specific biological processes and mice with humanized livers can be used to model human metabolism, liver injury, gene regulation, drug toxicity, and hepatotropic infections. © 2013 by the AGA Institute.


Mold J.E.,Karolinska Institutet | McCune J.M.,San Francisco General Hospital
Advances in Immunology | Year: 2012

The development of the adaptive immune system has been studied in the mouse primarily because it is easier to access fetal tissues and because there exists a rich array of probes for analysis of various components of the immune system. While much has been learned from this exercise, it is also clear that different species show substantial temporal variation in the development of the immune system during early life. In mice, for instance, mature α/β T cells first appear in the periphery during the final stages of fetal gestation and only increase in number after birth (. Friedberg and Weissman, 1974); in humans, on the other hand, the first mature α/β T cells are seen in peripheral tissues at 10-12 gestational weeks (g.w.) and are circulating in significant numbers by the end of the second trimester (. Ceppellini et al., 1971; Haynes et al., 1988; Hayward and Ezer, 1974; Kay et al., 1970). Although the functional implications of these differences remain unclear, it is likely that there are significant biological consequences associated with the relatively early development of the peripheral adaptive immune system in humans, for example, with respect to the development of peripheral tolerance as well as to the response to antigens that might cross the placenta from the mother (e.g., cells bearing noninherited maternal alloantigens, infectious agents, food antigens, and the like). Here, we will review studies of immune system ontogeny in the mouse and in humans, and then focus on the possible functional roles of fetal T cell populations during development and later in life in humans. © 2012 Elsevier Inc..


Liu M.A.,ProTherImmune | Liu M.A.,Karolinska Institutet
Immunological Reviews | Year: 2011

Summary: This review provides a detailed look at the attributes and immunologic mechanisms of plasmid DNA vaccines and their utility as laboratory tools as well as potential human vaccines. The immunogenicity and efficacy of DNA vaccines in a variety of preclinical models is used to illustrate how they differ from traditional vaccines in novel ways due to the in situ antigen production and the ease with which they are constructed. The ability to make new DNA vaccines without needing to handle a virulent pathogen or to adapt the pathogen for manufacturing purposes demonstrates the potential value of this vaccine technology for use against emerging and epidemic pathogens. Similarly, personalized anti-tumor DNA vaccines can also readily be made from a biopsy. Because DNA vaccines bias the T-helper (Th) cell response to a Th1 phenotype, DNA vaccines are also under development for vaccines against allergy and autoimmune diseases. The licensure of four animal health products, including two prophylactic vaccines against infectious diseases, one immunotherapy for cancer, and one gene therapy delivery of a hormone for a food animal, provides evidence of the efficacy of DNA vaccines in multiple species including horses and pigs. The size of these target animals provides evidence that the somewhat disappointing immunogenicity of DNA vaccines in a number of human clinical trials is not due simply to the larger mass of humans compared with most laboratory animals. The insights gained from the mechanisms of protection in the animal vaccines, the advances in the delivery and expression technologies for increasing the potency of DNA vaccines, and encouragingly potent human immune responses in certain clinical trials, provide insights for future efforts to develop DNA vaccines into a broadly useful vaccine and immunotherapy platform with applications for human and animal health. © 2010 John Wiley & Sons A/S.


Mkrtchian S.,Karolinska Institutet
Endocrine-Related Cancer | Year: 2015

The maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is tightly regulated by the unfolded protein response (UPR), a signal transduction pathway maintaining ER protein folding homeostasis. However, certain ER states are incompatible with cell survival and therefore the UPR may choose to eliminate severely disrupted cells by apoptosis. This is accomplished primarily through the activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). In the April 2015 issue of Endocrine-Related Cancer, researchers from the universities of South Carolina and Athens (Greece) suggested a novel mechanism of CHOP-mediated apoptosis connected with the suppression of a prominent cell cycle regulator with anti-apoptotic activity, p21. These findings and suggested clinical applications, such as potentiation of cancer chemotherapy and a novel therapeutic approach for type 2 diabetes, are discussed in the context of UPR. © 2015 Society for Endocrinology.


To assess the risk of epileptic seizures in people with and without epilepsy after vaccination with a monovalent AS03 adjuvanted pandemic A/H1N1 influenza vaccine (Pandemrix; Glaxo SmithKline, Sweden). Register based self controlled case series. Three Swedish counties (source population 750,000). 373,398 people (age 0-106, median 41.2) who were vaccinated. Vaccinated people with epileptic seizures, diagnosed as inpatients or outpatients, at any time from 90 days before until 90 days after any dose of vaccine. Endpoints were admission to hospital or outpatient hospital care with epileptic seizures as the main diagnosis. The effect estimate of relative incidence was calculated as the incidence of epileptic seizures in period after exposure relative to the incidence of epileptic seizures in two control periods, one before and one after vaccination. 859 people experienced epileptic seizures during the study period. There was no increased risk of seizures in people with previously diagnosed epilepsy (relative incidence 1.01, 95% confidence interval 0.74 to 1.39) and a non-significant decrease in risk for people without epilepsy (0.67, 0.27 to 1.65) during the day 1-7 risk period (where day 1 is the day of vaccination). In a second risk period (day 8-30), there was a non-significant increased risk of seizures in people without epilepsy (1.11, 0.73 to 1.70) but no increase in risk for those with epilepsy (1.00, 0.83 to 1.21). This study found no evidence of an increase in risk of presentation to hospital with epileptic seizures after vaccination with a monovalent AS03 adjuvanted pandemic H1N1 influenza vaccine.


Cao Y.,Karolinska Institutet
Discovery medicine | Year: 2010

The idea of promoting angiogenesis in ischemic tissues remains an undisputed therapeutic approach for the treatment of myocardium and skeletal muscles that lack sufficient blood supply. However, clinical experiences from several large trials indicated that delivery of proangiogenic factors to patients suffering from myocardial infarction and leg ischemia has not shown significant benefits. Despite continuous success in various animal disease models, why has this simple principle not shown proof of concept in patients? What has been missing in the trial deign? What are the differences between animal models and patients? What are the optimal components for promoting functional collateral networks? This brief review discusses molecular mechanisms underlying arteriogenesis and proposes novel approaches for improvement of therapeutic outcomes.


Kim H.S.,National Institute of Allergy and Infectious Diseases | Das A.,National Institute of Allergy and Infectious Diseases | Gross C.C.,National Institute of Allergy and Infectious Diseases | Bryceson Y.T.,Karolinska Institutet | Long E.O.,National Institute of Allergy and Infectious Diseases
Immunity | Year: 2010

Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-γ2, Ca2+ mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-Cbl. c-Cbl inhibited Vav1-dependent signals, given that c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2B4 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-Cbl. Inhibition of NK cell cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms. © 2010 Elsevier Inc. All rights reserved.


Kalager M.,Harvard University | Adami H.-O.,Karolinska Institutet | Bretthauer M.,University of Oslo | Tamimi R.M.,Harvard University
Annals of Internal Medicine | Year: 2012

Background: Precise quantification of overdiagnosis of breast cancer (defined as the percentage of cases of cancer that would not have become clinically apparent in a woman's lifetime without screening) due to mammography screening has been hampered by lack of valid comparison groups that identify incidence trends attributable to screening versus those due to temporal trends in incidence. Objective: To estimate the percentage of overdiagnosis of breast cancer attributable to mammography screening. Design: Comparison of invasive breast cancer incidence with and without screening. Setting: A nationwide mammography screening program in Norway (inviting women aged 50 to 69 years), gradually implemented from 1996 to 2005. Participants: The Norwegian female population. Measurements: Concomitant incidence of invasive breast cancer from 1996 to 2005 in counties where the screening program was implemented compared with that in counties where the program was not yet implemented. To adjust for changes in temporal trends in breast cancer incidence, incidence rates during the preceding decade were also examined. The percentage of overdiagnosis was calculated by accounting for the expected decrease in incidence following cessation of screening after age 69 years (approach 1) and by comparing incidence in the current screening group with incidence among women 2 and 5 years older in the historical screening groups, accounting for average lead time (approach 2). Results: A total of 39 888 patients with invasive breast cancer were included, 7793 of whom were diagnosed after the screening program started. The estimated rate of overdiagnosis attributable to the program was 18% to 25% (P < 0.001) for approach 1 and 15% to 20% (P < 0.001) for approach 2. Thus, 15% to 25% of cases of cancer are overdiagnosed, translating to 6 to 10 women overdiagnosed for every 2500 women invited. Limitation: The study was registry-based. Conclusion: Mammography screening entails a substantial amount of overdiagnosis. © 2012 American College of Physicians.


Woodruff T.M.,University of Queensland | Nandakumar K.S.,Karolinska Institutet | Tedesco F.,University of Trieste
Molecular Immunology | Year: 2011

Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases. © 2011 Elsevier Ltd.


Maegdefessel L.,Karolinska Institutet
Journal of Internal Medicine | Year: 2014

Cardiovascular disease remains the most prevalent cause of human morbidity and mortality in ageing Western societies. Basic and translational scientific efforts have focused on the development and improvement of diagnostic and therapeutic strategies to limit the burden of associated diseases, such as stroke and myocardial infarction, and diabetes mellitus and arterial hypertension. Progress in molecular medicine and biology has unravelled a complex epigenetic and post-transcriptional gene-regulating machinery in humans which may limit disease development. An increasing number of attractive molecular strategies, which use the potential of modulating noncoding RNAs, have surfaced over the last decade. Currently, the most extensively studied gene-regulating RNA subspecies are microRNAs, which have been shown to adjust the translational output of coding transcripts by enforcing their degradation and inhibiting their translation into protein. Key findings indicate that microRNAs act as crucial regulators in the majority of human pathologies. Thus, recent research has focused on detecting and modulating microRNAs for therapeutic and biomarker purposes. This review focuses on main and repeated discoveries regarding the role and the therapeutic and biomarker feasibility of microRNAs during cardiovascular disease development and exacerbation. © 2014 The Association for the Publication of the Journal of Internal Medicine.


Rajkumar S.V.,Rochester College | Gahrton G.,Karolinska Institutet | Bergsagel P.L.,Mayo Medical School
Blood | Year: 2011

In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice. © 2011 by The American Society of Hematology.


Fuxe J.,Karolinska Institutet | Vincent T.,Cornell University | De Herreros A.G.,Programa de Recerca en Cancer
Cell Cycle | Year: 2010

Tumor cells undergoing the epithelial-mesenchymal transition (EMT) acquire the capacity to migrate, invade the stroma and metastasize. EMT cells also acquire stem cell characteristics suggesting crosstalk between EMT and pathways involved in promoting cellular stemness (stem cell pathways) and that EMT may contribute to the generation of cancer stem cells. indeed, transforming growth factor-beta (TGFβ), a major inducer of EMT, cooperates with stem cell pathways like wnt, ras, Hedgehog and Notch to induce EMT. A molecular basis for this cooperative signaling is indicated by recent data showing that many EMT associated transcription factors like Snail1, Zeb1/2, Twist, β-catenin, Lef/TCF, Foxc2 and AP-1 interact with Smads and form EMT promoting Smad complexes (ePSC) engaged in either repressing epithelial genes or activating mesenchymal genes. Thus, formation and activation of ePSC represents a point of convergence between EMT and stem cell pathways. Here, we review our current understanding of the mechanisms involved in the transcriptional crosstalk between TGFβ and stem cell pathways and discuss how a fundament for the activation of these mechanisms may lead to the induction of EMT in tumors.


Brimer N.,University of Virginia | Lyons C.,University of Virginia | Wallberg A.E.,Karolinska Institutet | Vande Pol S.B.,University of Virginia
Oncogene | Year: 2012

Papillomavirus E6 oncoproteins associate with LXXLL motifs on target cellular proteins to alter their function. Using a proteomic approach, we found the E6 oncoproteins of cutaneous papillomaviruses Bovine Papillomavirus Type 1 (BPV-1) E6 and human papillomavirus (HPV) types 1 and 8 (1E6 and 8E6) associated with the MAML1 transcriptional co-activator. All three E6 proteins bind to an acidic LXXLL motif at the carboxy-terminus of MAML1 and repress transactivation by MAML1. MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells. BPV-1-induced papillomas show characteristics of repressed NOTCH signal transduction, including suprabasal expression of integrins, talin and basal type keratins, and delayed expression of the NOTCH-dependent HES1 transcription factor. These observations give rise to a model whereby papillomavirus oncoproteins, including BPV-1 E6, and the cancer-associated HPV-8 E6 repress NOTCH-induced transcription, thereby delaying keratinocyte differentiation. © 2012 Macmillan Publishers Limited All rights reserved.


Toivanen S.,Karolinska Institutet
Stroke Research and Treatment | Year: 2012

In adult life, many of the social determinants of health are connected to working life. Yet, our knowledge of the role of work-related factors for the risk of stroke is fairly limited. In contemporary occupational health research, the Demand-Control Model (DCM) is frequently used to measure work stress. Previous literature reviews of the association of work stress and cardiovascular disease (CVD) do not include stroke as a specific outcome. Results regarding work stress and the risk of CVD are less evident in working women. With the focus on working women, the purpose of the present paper was to review the current research into the DCM in relation to stroke and to scrutinize potential gender differences. A literature search was performed and eight studies from three countries were identified. Based on the reviewed studies, there is some evidence that high psychological demands, low job control, and job strain are associated with increased stroke risk in women as well as in men. Any major reduction in deaths and disability from stroke is likely to come from decreasing social inequalities in health, and reducing work stress has a potential to contribute to a reduced risk of stroke in working populations. © 2012 Susanna Toivanen.


Kronvall G. Antimicrobial resistance 1979-2009 at Karolinska hospital, Sweden: normalized resistance interpretation during a 30-year follow-up on Staphylococcus aureus and Escherichia coli resistance development. APMIS 2010; 118: 621-39. To utilize a material of inhibition zone diameter measurements from disc diffusion susceptibility tests between 1979 and 2009, an objective setting of epidemiological breakpoints was necessary because of methodological changes. Normalized resistance interpretation (NRI) met this need and was applied to zone diameter histograms for Staphylococcus aureus and Escherichia coli isolates. The results confirmed a slow resistance development as seen in Northern countries. The S. aureus resistance levels for erythromycin, clindamycin and fusidic acid in 2009 were 3.2%, 1.8% and 1.4% with denominator correction. A rise in resistance to four antimicrobials in 1983 was probably because of a spread of resistant Methicillin Susceptible Staphylococcus Aureus (MSSA). For E. coli, the denominator-corrected resistance levels in 2009 were 27% for ampicillin, around 3% for third-generation cephalosporins, 0.1% for imipenem, 2.5% for gentamicin, 19% for trimethoprim, 4.5% for co-trimoxazole, 1.2% for nitrofurantoin and 9% for ciprofloxacin. The temporal trends showed a rise in fluoroquinolone resistance from 1993, a parallel increase in gentamicin resistance, a substantial increase in trimethoprim and sulphonamide resistance in spite of decreased consumption, and a steady rise in ampicillin resistance from a constant level before 1989. A short review of global resistance surveillance studies is included. © 2010 The Author. Journal Compilation © 2010 APMIS.


Allgulander C.,Karolinska Institutet
Current Opinion in Psychiatry | Year: 2010

Purpose of review: The present paper reviews recent studies on the clinical presentation of generalized anxiety disorder (GAD) and the current level of evidence for treatment with medications and psychotherapy. Recent findings: An apprehensive state of mind, regardless of the quality of stimuli, is at the core of GAD, causing a pervasive cognitive dysfunction that is separate from that seen in depression and obsessive compulsive disorder. When treatments reduce anxiety-related symptoms and insomnia, patients report a restoration of social functioning, probably as a consequence of improved decision-making, cooperative skills, and risk assessment. Late-onset GAD symptoms in the elderly may be caused or aggravated by cerebrovascular events, loneliness, bereavement, substance use, and the prospect of death. Insomnia in GAD may be primary or caused by common medications. Practice guidelines fail to capture the needs of the entire range of patients with GAD as they build on patients without comorbidity who have been selected for phase III trials. They are also biased to reduce cost. Summary: The past 10 years have seen a range of safe and effective treatments for GAD. Late-onset GAD presents a new challenge to researchers and practitioners. The current state of knowledge about GAD does not justify radical revisions of the diagnostic criteria in the ongoing revisions of the Diagnostic and Statistical Manual of Mental Disorders-IV and the International Statistical Classification of Diseases-10 nosologies. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Background: Patients with Parkinson's disease (PD) or Parkinsonian syndromes often report excessive daytime sleepiness (EDS). The aim of this study was to evaluate the effects of the psychostimulant modafinil on elderly, institutionalized, severely impaired PD patients with EDS. Method: A three-week open study on ten institutionalized PD patients scoring >10 points on the Epworth Sleepiness Scale (ESS) with modafinil eventually on 100 mg twice a day. Patients were assessed at the start, week 1, and week 3 with ESS, Clinical Global Impression (CGI) scale severity of PD and appetite. Results: Reduction of ESS score and PD severity over time were found as well as a significant increase in appetite and reduction in CGI score. Conclusion: Modafinil 100 mg twice a day was safe and modestly effective for the treatment of EDS in elderly, institutionalized PD patients. Sustaining wakefulness throughout all stages of PD is crucial for participating in life, maintaining social life, and improving quality of life. © 2010 Lökk, publisher and licensee Dove Medical Press Ltd.


Hearing difficulties is a large public health problem, prognosticated to be the ninth leading burden of disease in 2030, and may also involve large consequences for work capacity. However, research regarding sickness absence and disability pension in relation to hearing difficulties is scarce. The aim was to gain knowledge about hearing difficulties or other ear-related diagnoses and sickness absence and disability pension through conducting a systematic literature review of published studies. Studies presenting empirical data on hearing difficulties or ear-related diagnoses and sick leave or disability pension, published in scientific peer-reviewed journals, were included. Studies were sought for in three ways: in literature databases (Pub-Med, Embase, PsycInfo, SSCI, and Cochrane) through March 2011, through scrutinising lists of references, and through contacts. Identified publications were assessed for relevance and data was extracted from the studies deemed relevant. A total of 18 studies were assessed as relevant and included in this review, regardless of scientific quality. Fourteen studies presented empirical data on hearing difficulties/ear diagnoses and sick leave and six on these conditions and disability pension. Only two studies presented rate ratios or odds ratios regarding associations between hearing difficulties and sick leave, and only two on hearing difficulties and risk of disability pension. Both measures of hearing difficulties and of sick leave varied considerable between the studies. Remarkably few studies on hearing difficulties in relation to sickness absence or disability pension were identified. The results presented in them cannot provide evidence for direction or magnitude of potential associations.


Tomson T.,Karolinska Institutet | Tomson T.,Karolinska University Hospital | Landmark C.J.,Oslo University College | Battino D.,IRCCS Foundation Carlo Besta Neurological Institute
Epilepsia | Year: 2013

Summary Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.


Tiselius H.-G.,Karolinska Institutet
Scandinavian Journal of Urology | Year: 2013

During the past four decades there have been dramatic developments in the methods used for active stone removal from the urinary tract, and the need for open surgery has been almost entirely replaced by extracorporeal shockwave lithotripsy, percutaneous surgery, ureteroscopy and retrograde intrarenal surgery. Residual fragments and the pronounced risk of recurrent stone formation remain important problems for the future development of urolithology and for the optimal low-risk management of this large group of patients. It is emphasized that all aspects of the care of patients with stone disease are the responsibility of the urologist. © Informa Healthcare.


Darpo B.,Karolinska Institutet | Garnett C.,Certara
British Journal of Clinical Pharmacology | Year: 2013

Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma concentrations are often achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether 'early QT assessment' can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies ('early QT assessment') and what we believe is needed to achieve the same high confidence in the data as we currently obtain from data from the TQT study. The power to exclude a QTc effect exceeding 10ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies. © 2012 The British Pharmacological Society.


Xu X.J.,Karolinska Institutet
EXS | Year: 2010

Since the discovery of galanin in 1983, one of the most frequently suggested physiological function for this peptide is pain modulation at the level of the spinal cord. This notion, initially based on the preferential distribution of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular, and functional studies. It is generally agreed that spinally applied galanin produces a biphasic, dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an endogenous inhibitory role, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small molecule ligands of galanin receptors have been developed, which may lead to the development of analgesic drugs, which affects the galanin system at the spinal cord level.


Liu M.A.,ProTherImmune | Liu M.A.,Karolinska Institutet
Immunity | Year: 2010

Efforts to make vaccines against infectious diseases as well as immunotherapies for cancer, autoimmune diseases and allergy have utilized a variety of heterologous expression systems, including viral and bacterial vectors, as well as DNA and RNA constructs. This review explores the immunologic rationale and provides an update of insights obtained from preclinical and clinical studies of such vaccines. © 2010 Elsevier Inc.


Cao Y.,Karolinska Institutet | Langer R.,Massachusetts Institute of Technology
Science Translational Medicine | Year: 2010

Drugs that block angiogenesis are important components of first-line therapies for a number of human cancers. However, some of these agents have undesirable effects on the patient. Optimal delivery systems must be developed to maximize clinical benefits and minimize adverse effects in cancer patients. In this Perspective, we discuss these drug-related issues and propose ways to optimize antiangiogenic therapy by the development of new drug delivery systems.


Chevance F.F.V.,University of Utah | Le Guyon S.,Karolinska Institutet | Hughes K.T.,University of Utah
PLoS Genetics | Year: 2014

We developed a bacterial genetic system based on translation of the his operon leader peptide gene to determine the relative speed at which the ribosome reads single or multiple codons in vivo. Low frequency effects of so-called "silent" codon changes and codon neighbor (context) effects could be measured using this assay. An advantage of this system is that translation speed is unaffected by the primary sequence of the His leader peptide. We show that the apparent speed at which ribosomes translate synonymous codons can vary substantially even for synonymous codons read by the same tRNA species. Assaying translation through codon pairs for the 5′- and 3′- side positioning of the 64 codons relative to a specific codon revealed that the codon-pair orientation significantly affected in vivo translation speed. Codon pairs with rare arginine codons and successive proline codons were among the slowest codon pairs translated in vivo. This system allowed us to determine the effects of different factors on in vivo translation speed including Shine-Dalgarno sequence, rate of dipeptide bond formation, codon context, and charged tRNA levels. © 2014 Chevance et al.


Ahlin A.,Karolinska Institutet | Fasth A.,Gothenburg University
Current Opinion in Hematology | Year: 2015

Purpose of review We update and summarize the recent findings in conventional treatment and hematopoietic stem cell transplantation in chronic granulomatous disease (CGD). We also summarize the contemporary view on when hematopoietic stem cell transplantation should be the preferred treatment of choice in CGD. Recent findings Azole antifungal treatment in CGD has improved survival. With prolonged survival, inflammatory complications are an emerging problem in CGD. Several studies now present excellent results with stem cell transplantation in severe CGD, also with reduced intensity conditioning. Summary Several lines of evidence now suggest that stem cell transplantation should be the preferred treatment of choice in severe CGD, if there is an available donor. This should be performed as soon as possible to avoid severe sequelae from infection and inflammation. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Henriques-Normark B.,Karolinska Institutet | Tuomanen E.I.,St Jude Childrens Research Hospital
Cold Spring Harbor Perspectives in Medicine | Year: 2013

The pneumococcus is the classic Gram-positive extracellular pathogen. The medical burden of diseases it causes is amongst the greatest in theworld. Intense study for more than 100 years has yielded an understanding of fundamental aspects of its physiology, pathogenesis, and immunity. Efforts to control infection have led to the deployment of polysaccharide vaccines and an understanding of antibiotic resistance. The inflammatory response to pneumococci, one of the most potent in medicine, has revealed the double-edged sword of clearance of infection but at a cost of damage to host cells. In virtually every aspect of the infectious process, the pneumococcus has set the rules of the Gram-positive pathogenesis game. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Knapp S.,University of Oxford | Sundstrom M.,Karolinska Institutet
Current Opinion in Pharmacology | Year: 2014

Protein kinases have emerged as one of the most important drug target families for the treatment of cancer. To date, 28 inhibitors with reported activity versus one or multiple kinases have been approved for clinical use. However, the majority of new clinical trials are focused on new subindications using already approved kinase inhibitors or target well validated kinase targets with novel inhibitors. In contrast, relatively few clinical trials have been initiated using specific inhibitors that inhibit novel kinase targets, despite significant validation efforts in the public domain. Analysis of the target validation history of first in class kinase inhibitors revealed a long delay between initial disease association and development of inhibitors. As part of this analysis, we have investigated which first in class inhibitor that entered phase I clinical trials over the last five years and also considered which research approaches that were used to validate them. © 2014 Elsevier Ltd.


Studies have shown that long-term sick leave is a strong predictor of disability pension. However, few have aimed to disentangle the effect of sick leave and of health status. The objective of this study was to investigate whether there is an association between long-term sick leave and disability pension and unemployment, when taking health status into account. The study was based on the Stockholm Public Health Cohort, restricted to 13,027 employed individuals (45.9% men) aged 18-59 in 2002 and followed until 2007. Hazard ratios (HR) with 95% Confidence Interval (CI) were estimated by Cox regression models adjusting for socio-demographic factors and five measures of health status. Having been on long-term sick leave increased the risk of disability pension (HR 4.01; 95% CI 3.19-5.05) and long-term unemployment (HR 1.45; 95% CI 1.05-2.00), after adjustment for health status. The analyses of long-term sick leave due to specific illness showed that the increased risk for long-term unemployment was confined to the group on sick leave due to musculoskeletal (HR 1.70 95% CI 1.00-2.89) and mental illness (HR 1.80 95% CI 1.13-2.88) and further that there was an increased risk for short-term unemployment in the group on sick leave due to mental illness (HR1.57 95%CI 1.09-2.26). Long-term sick leave increases the risks of both disability pension and unemployment even when taking health status into account. The results support the hypothesis that long-term sick leave may start a process of marginalization from the labor market.


Lindstrom B.R.,Karolinska Institutet
Emotion (Washington, D.C.) | Year: 2012

The effects of emotional stimulus content on attention are well-known. In contrast, the impact of emotional information on higher executive control functions is undetermined. To elucidate the role of negative emotion in cognitive control, 56 adult female participants performed a combined working memory and response inhibition task, with threat-relevant (spider and snake) and neutral (flower and mushroom) stimuli. Threat-relevant stimuli impaired performance, by causing prolonged response times to working memory items and increased response inhibition error rate relative to neutral stimuli. The impaired response inhibition was only evident when threat-relevant stimuli co-occurred with working memory matches, in line with a common resource pool view of executive functions and emotion processing. Individual differences in reported fear of spiders were associated with differences of inhibitory control, while fear of snakes was associated with impaired overall accuracy on working memory trials. The results are discussed in relation to the dual-competition framework for interaction between executive functions and emotion (Pessoa, 2009). (PsycINFO Database Record (c) 2012 APA, all rights reserved).


Bjorck S.,Regionens Hus | Palaszewski B.,Regionens Hus | Friberg L.,Karolinska Institutet | Bergfeldt L.,Gothenburg University
Stroke | Year: 2013

Background and Purpose: Atrial fibrillation (AF) is a major risk factor for ischemic stroke. This study aims to update the knowledge about AF and associated stroke risk and benefits of anticoagulation. Methods: We extracted data from the hospital, specialized outpatient, and primary healthcare and drug registries in a Swedish region with 1.56 million residents. We identified all individuals who had received an AF diagnosis during the previous 5 years; all stroke events during 2010; and patients with AF aged ≥50 years who had received warfarin during 2009. Results: AF had been diagnosed in 38 446 subjects who were alive at the beginning of 2010 (prevalence of 3.2% in the adult [≥20 years] population); ≈46% received warfarin therapy. In 2010, there were 4565 ischemic stroke events and 861 intracranial hemorrhages. AF had been diagnosed in 38% of ischemic events (≥50% among those aged ≥80 years) and in 23% of intracranial hemorrhages. An AF diagnosis was often lacking in hospital discharge records after stroke events. Warfarin therapy was associated with an odds ratio of 0.50 (confidence interval, 0.43-0.57) for ischemic stroke and, despite an increased risk of intracranial hemorrhage, an odds ratio of 0.57 (confidence interval, 0.50-0.64) for the overall risk for stroke. Conclusions: AF is more common than present guidelines suggest. The attributable risk of AF for ischemic stroke increases with age and is close to that of hypertension in individuals aged ≥80 years. Because a majority of patients with AF with increased risk for stroke had not received anticoagulation therapy, there is a large potential for improvement. © 2013 American Heart Association, Inc.


van Leeuwen I.M.M.,Karolinska Institutet
Oncotarget | Year: 2012

Cyclotherapy is a promising endeavor to improve cancer treatment by tackling the dose-limiting side effects of chemotherapy, especially for cancers harboring mutations in the TP53 tumor suppressor. In this particular context, pre-treatment with a p53 activator halts proliferation in healthy tissue, while leaving the p53-deficient tumor susceptible to conventional chemotherapy. © Ingeborg et al.


Romling U.,Karolinska Institutet | Galperin M.Y.,U.S. National Center for Biotechnology Information | Gomelsky M.,University of Wyoming
Microbiology and Molecular Biology Reviews | Year: 2013

Twenty-five years have passed since the discovery of cyclic dimeric (3'→15') GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di- GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di- GMP research that will give us a deeper understanding of this truly universal bacterial second messenger. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Andersson T.B.,Astrazeneca | Andersson T.B.,Karolinska Institutet
Handbook of Experimental Pharmacology | Year: 2010

Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (<12 days) in humans including the phase III clinical trials did not indicate any hepatotoxic potential. Increased hepatic enzyme levels were first observed at a higher frequency when evaluating the long-term (>35 days) use of ximelagatran (incidence of>3× upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT>3× ULN and total bilirubin >2 ×ULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1'07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity. © 2010 Springer-Verlag Berlin Heidelberg.


Cao Y.,Karolinska Institutet
Nature Reviews Endocrinology | Year: 2014

Systemic administration of antiangiogenic drugs that target components of the vascular endothelial growth factor A (VEGF-A; VEGF) signal transduction pathway has become a viable therapeutic option for patients with various types of cancer. Nevertheless, these drugs can drive alterations in healthy vasculatures, which in turn are associated with adverse effects in healthy tissues. VEGF is crucial for vascular homeostasis and the maintenance of vascular integrity and architecture in endocrine organs. Given these critical physiological functions, systemic delivery of drugs that target VEGF signalling can block VEGF-mediated vascular functions in endocrine organs, such as the thyroid gland, and lead to endocrine dysfunction, including hypothyroidism, adrenal insufficiency and altered insulin sensitivity. This Review discusses emerging evidence from preclinical and clinical studies that contributes to understanding the mechanisms that underlie the vascular changes and subsequent modulations of endocrine function that are induced by targeted inhibition of VEGF signalling. Understanding these mechanisms is crucial for the design of antiangiogenic drugs with minimal associated adverse effects that will enable effective treatment of patients with cancer.


Fredholm B.B.,Karolinska Institutet
Experimental Cell Research | Year: 2010

There are four adenosine receptors, A1, A2A, A2B and A3, together forming a defined subgroup of G protein coupled receptors. They are well conserved and widely expressed. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20-200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed-as in the basal ganglia, on fat cells and in the kidney. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development. © 2010 Elsevier Inc.


AIM: To determine if glutamate injected into the healthy temporomandibular joint (TMJ) evokes pain through peripheral N-methyl-D-aspartate (NMDA) receptors and if such pain is influenced by sex or sex steroid hormones. METHODS: Sixteen healthy men and 36 healthy women were included and subjected to two randomized and double-blind intra-articular injections of the TMJ. Experimental TMJ pain was induced by injection of glutamate (1.0 mol/L) and NMDA block was achieved by co-injection of the NMDA antagonist ketamine (10 mmol/L). The TMJ pain intensity in the joint before and during a 25-minute postinjection period was continuously recorded on an electronic visual analog scale (0 to 10). Estradiol, progesterone, and testosterone levels in serum were analyzed. RESULTS: Glutamate-induced pain showed a median (25/75 percentile) duration of 8.3 (5.2/12.2) minutes. The peak pain intensity was 6.1 (4.2/8.2), the time to peak was 50 (30/95) seconds, and the area under the curve was 59 (29/115) arbitrary units. The women reported higher maximum pain intensity than the men and shorter time to peak. The sex hormone levels were not significantly related to the glutamate-induced TMJ pain. NMDA block significantly reduced the glutamate-induced TMJ pain, mainly in the women. There were no significant correlations between sex hormone levels and the effects of NMDA block for any pain variable. CONCLUSION: Glutamate evokes immediate pain in the healthy human TMJ that is partly mediated by peripheral NMDA receptors in the TMJ.


Linnarsson S.,Karolinska Institutet
Experimental Cell Research | Year: 2010

DNA sequencing has revolutionized biomedicine, and progress in the field has been unrelenting since it was invented over 30. years ago. The complete DNA sequence of the human genome was obtained as the culmination of a decade of work by a large number of scientists. Less than ten years later, so-called 'next-generation' instruments now make it possible for a single lab to produce the same amount of data in a week. But while the instruments are increasingly automated, upstream sample processing remains a challenge. Here I review the current state of the art in preparing genomic and RNA samples for high throughput sequencing. © 2010 Elsevier Inc.


Neilson J.R.,Baylor College of Medicine | Sandberg R.,Karolinska Institutet
Experimental Cell Research | Year: 2010

Precisely directed cleavage and polyadenylation of mRNA is a fundamental part of eukaryotic gene expression. Yet, 3′ end heterogeneity has been documented for thousands of mammalian genes, and usage of one cleavage and polyadenylation signal over another has been shown to impact gene expression in many cases. Building upon the rich biochemical and genetic understanding of the 3′ end formation, recent genomic studies have begun to suggest that widespread changes in mRNA cleavage and polyadenylation may be a part of large, dynamic gene regulatory programs. In this review, we begin with a modest overview of the studies that defined the mechanisms of mammalian 3′ end formation, and then discuss how recent genomic studies intersect with these more traditional approaches, showing that both will be crucial for expanding our understanding of this facet of gene regulation. © 2010 Elsevier Inc.


Weigelt J.,Karolinska Institutet
Experimental Cell Research | Year: 2010

The field of structural genomics emerged as one of many 'omics disciplines more than a decade ago, and a multitude of large scale initiatives have been launched across the world. Development and implementation of methods for high-throughput structural biology represents a common denominator among different structural genomics programs. From another perspective a distinction between "biology-driven" versus "structure-driven" approaches can be made. This review outlines the general themes of structural genomics, its achievements and its impact on biomedicine and drug discovery. The growing number of high resolution structures of known and potential drug target proteins is expected to have tremendous value for future drug discovery programs. Moreover, the availability of large numbers of purified proteins enables generation of tool reagents, such as chemical probes and antibodies, to further explore protein function in the cell. © 2010 Elsevier Inc.


Arner E.S.J.,Karolinska Institutet
Experimental Cell Research | Year: 2010

The defining entity of a selenoprotein is the inclusion of at least one selenocysteine (Sec) residue in its sequence. Sec, the 21st naturally occurring genetically encoded amino acid, differs from its significantly more common structural analog cysteine (Cys) by the identity of a single atom: Sec contains selenium instead of the sulfur found in Cys. Selenium clearly has unique chemical properties that differ from sulfur, but more striking are perhaps the similarities between the two elements. Selenium was discovered by Jöns Jacob Berzelius, a renowned Swedish scientist instrumental in establishing the institution that would become Karolinska Institutet. Written at the occasion of the bicentennial anniversary of Karolinska Institutet, this mini review focuses on the unique selenium-derived properties that may potentially arise in a protein upon the inclusion of Sec in place of Cys. With 25 human genes encoding selenoproteins and in total several thousand selenoproteins yet described in nature, it seems likely that the presence of that single selenium atom of Sec should convey some specific feature, thereby explaining the existence of selenoproteins in spite of demanding and energetically costly Sec-specific synthesis machineries. Nonetheless, most, if not all, of the currently known selenoproteins are also found as Cys-containing non-selenoprotein orthologues in other organisms, wherefore any potentially unique properties of selenoproteins are yet a matter of debate. The pKa of free Sec (approximately 5.2) being significantly lower than that of free Cys (approximately 8.5) has often been proposed as one of the unique features of Sec. However, as discussed herein, this pKa difference between Sec and Cys can hardly provide an evolutionary pressure for maintenance of selenoproteins. Moreover, the typically 10- to 100-fold lower enzymatic efficiencies of Sec-to-Cys mutants of selenoprotein oxidoreductases, are also weak arguments for the overall existence of selenoproteins. Here, it is however emphasized that the inherent high nucleophilicity of Sec and thereby its higher chemical reaction rate with electrophiles, as compared to Cys, seems to be a truly unique property of Sec that cannot easily be mimicked by the basicity of Cys, even within the microenvironment of a protein. The chemical rate enhancement obtained with Sec can have other consequences than those arising from a low redox potential of some Cys-dependent proteins, typically aiming at maintaining redox equilibria. Another unique aspect of Sec compared to Cys seems to be its efficient potency to support one-electron transfer reactions, which, however, has not yet been unequivocally shown as a Sec-dependent step during the natural catalysis of any known selenoprotein enzyme. © 2010 Elsevier Inc.


Omidvarnia A.,University of Queensland | Fransson P.,Karolinska Institutet | Metsaranta M.,University of Helsinki | Vanhatalo S.,University of Queensland | Vanhatalo S.,University of Helsinki
Cerebral cortex (New York, N.Y. : 1991) | Year: 2014

The spontaneous brain activity exhibits long-range spatial correlations detected using functional magnetic resonance imaging (fMRI) signals in newborns when (1) long neuronal pathways are still developing, and (2) the electrical brain activity consists of developmentally unique, intermittent events believed to guide activity-dependent brain wiring. We studied this spontaneous electrical brain activity using multichannel electroencephalography (EEG) of premature and fullterm babies during sleep to assess the development of spatial integration during last months of gestation. Correlations of frequency-specific amplitudes were found to follow a robust bimodality: During low amplitudes (low mode), brain activity exhibited very weak spatial correlations. In contrast, the developmentally essential high-amplitude events (high mode) showed strong spatial correlations. There were no clear spatial patterns in the early preterm, but clear frontal and parieto-occipital modules at term age. A significant fronto-occipital gradient was also seen in the development of the graph measure clustering coefficient. Strikingly, no bimodality was found in the fMRI recordings of the fullterm babies, suggesting that early EEG activity and fMRI signal reflect different mechanisms of spatial coordination. The results are compatible with the idea that early developing human brain exhibits intermittent long-range spatial connections that likely provide the endogenous guidance for early activity-dependent development of brain networks. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.


Falk A.,Karolinska Institutet
Molecular Psychiatry | Year: 2016

Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.89. © 2016 Macmillan Publishers Limited


Cao Y.,Karolinska Institutet
Experimental Cell Research | Year: 2010

Modulation of angiogenesis for disease therapy was proposed nearly 40. years ago and today various protein and chemical molecules are available for the treatment of human malignant and ophthalmological disorders. Angiogenesis research has emerged, as one of the most comprehensive research areas, in biomedicine and development of novel drugs by targeting angiogenesis has become one of the main focuses among pharmaceutical giants. If 30% of annually 12. million new cancer cases worldwide receive antiangiogenic therapy, over 60. million cancer patients would be treated by the end of 2060. In this mini-review, I discuss current available antiangiogenic drugs and future therapeutic options based on the angiogenesis principle. © 2010 Elsevier Inc.


Hawley J.A.,Australian Catholic University | Hawley J.A.,Liverpool John Moores University | Hargreaves M.,University of Melbourne | Joyner M.J.,Mayo Medical School | And 2 more authors.
Cell | Year: 2014

Exercise represents a major challenge to whole-body homeostasis provoking widespread perturbations in numerous cells, tissues, and organs that are caused by or are a response to the increased metabolic activity of contracting skeletal muscles. To meet this challenge, multiple integrated and often redundant responses operate to blunt the homeostatic threats generated by exercise-induced increases in muscle energy and oxygen demand. The application of molecular techniques to exercise biology has provided greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses, and recent discoveries offer perspectives on the mechanisms by which muscle "communicates" with other organs and mediates the beneficial effects of exercise on health and performance. ©2014 Elsevier Inc.


D'Amato M.,Karolinska Institutet
Neurogastroenterology and Motility | Year: 2013

Background: The functional gastrointestinal disorders (FGID), and in particular irritable bowel syndrome (IBS), pose a considerable burden on health care and society, and negatively impact quality of life. These are common conditions of unknown etiology, and symptom-based criteria are currently the sole nosological tools for their clinical classification. Major insight into FGID pathophysiology is therefore needed and, in recent years, increasing hope has been put on genetic research for the identification of causative pathways. This is more advanced in IBS compared with other FGID, but it has still provided often indecipherable results and no unequivocal evidence of a pathogenetic role for any particular gene. Although thousands of genetic variants have been undoubtedly linked to human disease in hundreds of genome-wide association studies (GWAS), no similar effort has yet even been attempted in FGID. If meaningful, robust, and reproducible results are to be obtained for IBS and other FGID, we must shift gear and adopt these powerful hypothesis-free approaches through concerted actions and allocation of adequate resources. Provided these are in place, the major challenge will be, inevitably, the choice of the target phenotype(s) beyond a descriptive symptom-based classification. Purpose: In view of these much awaited developments, salient results and difficulties inherent to IBS gene discovery are briefly summarized here. © 2013 John Wiley & Sons Ltd.


Bjorkegren J.L.M.,Mount Sinai School of Medicine | Bjorkegren J.L.M.,Karolinska Institutet | Bjorkegren J.L.M.,University of Tartu | Kovacic J.C.,Mount Sinai School of Medicine | And 2 more authors.
Journal of the American College of Cardiology | Year: 2015

Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities. © 2015 American College of Cardiology Foundation.


Repair of radiation damaged cells can be carried out through their interactions with intracellular substances that can supply the needed energy for repair. These substances may be viewed as forming a pool of repair molecules that through chemical reactions with lesions can lead to cell recovery from the initial radiation insult by deposition of dose D. Presently, time evolution of mean concentrations of interacting substances is obtained by solving the corresponding rate equations given by a coupled system of second-order non-linear differential equations that are imposed by the mass action law. For cell surviving fractions after irradiation, the most important quantity is the time-dependent concentration of lethal lesions. Our main working hypothesis is that pool substances are capable of repairing the inflicted injury to any cell molecules, including deoxyribonucleic acid which is generally viewed as the most critical target of radiation. The previous solution of these rate equations is only formal as it is expressed by yet another equation of an implicit, transcendental form. In the earlier applications, this formal solution has only been tackled by numerical means that, however, have no connection with any of the myriad of the usual explicit forms of cell surviving fractions. This drawback effectively discouraged researchers from further explorations of the otherwise attractive pool methodology. Such a circumstance is unfortunate in light of a clear and advantageous radiobiological interpretation of the parameters of this theoretical formalism of chemical kinetics.The present study is aimed at rescuing the pool methodology by solving the underlying transcendental equation for lethal lesions uniquely, exactly and explicitly in terms of the principal value Lambert W0 function. This is a single-valued and dose-dependent function, which can be readily and accurately computed either from the available fast numerical algorithms or by employing the existing simple closed expressions with a quotient of elementary, logarithmic functions. Another distinct advantage of this analytical result is the known behaviors of W0 at small and large doses. This permits an easy and immediate identification of the final D0 (or D37) dose and the extrapolation number n. Such a circumstance offers new possibilities within the presently proposed "Pool Repair Lambert" (PRL) model for analysis of problems encountered in assessing cell survival after exposure to various modalities of radiation, including different schedules (acute, fractionated) for the same radiation quality. Importantly, the PRL model is universally applicable to all doses with a smooth passage from low through intermediate to high doses. As to applications in radiotherapy, this feature is particularly important for treatment schedules with high-doses per fraction as in stereotactic radiosurgery and stereotactic body radiotherapy. © 2014 Springer International Publishing Switzerland.


Sjoholm A.,Karolinska Institutet
Pharmaceuticals | Year: 2010

Although advances have been achieved in the management of type 2 diabetes, current treatment options for patients with this disease still fail to address disease progression, glycaemic control remains suboptimal and therapies are often associated with weight gain and hypoglycaemia. Thus, new antidiabetes therapies are being sought. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that have been the recent focus of research. The physiological action of GLP-1, in particular, has demonstrated its potential in addressing the therapeutic needs of patients with type 2 diabetes. To exploit this action, liraglutide, a human GLP-1 analogue that shares 97% of its amino acid sequence identity with native GLP-1, has been developed. In a recent phase 3 trial programme (LEAD, Liraglutide Effect and Action in Diabetes), treatment with liraglutide was associated with substantial improvements in glycaemic control and low risk of hypoglycaemia. In addition, reductions in weight and systolic blood pressure were reported. There is also an indication that liraglutide is capable of improving β-cell function and increasing β-cell mass. Thus, liraglutide may overcome the limitations with current therapies and help to address the unmet clinical needs of patients with type 2 diabetes.


PURPOSE: Lymph node dissection in patients with prostate cancer may increase complications. An association of lymph node dissection with thromboembolic events was suggested. We compared the incidence and investigated predictors of deep venous thrombosis and pulmonary embolism among other complications in patients who did or did not undergo lymph node dissection during open and robot-assisted laparoscopic radical prostatectomy.MATERIALS AND METHODS: Included in study were 3,544 patients between 2008 and 2011. The cohort was derived from LAPPRO, a multicenter, prospective, controlled trial. Data on adverse events were extracted from patient completed questionnaires. Our primary study outcome was the prevalence of deep venous thrombosis and/or pulmonary embolism. Secondary outcomes were other types of 90-day adverse events and causes of hospital readmission.RESULTS: Lymph node dissection was performed in 547 patients (15.4%). It was associated with eightfold and sixfold greater risk of deep venous thrombosis and pulmonary embolism events compared to that in patients without lymph node dissection (RR 7.80, 95% CI 3.51-17.32 and 6.29, 95% CI 2.11-18.73, respectively). Factors predictive of thromboembolic events included a history of thrombosis, pT4 stage and Gleason score 8 or greater. Open radical prostatectomy and lymph node dissection carried a higher risk of deep venous thrombosis and/or pulmonary embolism than robot-assisted laparoscopic radical prostatectomy (RR 12.67, 95% CI 5.05-31.77 vs 7.52, 95% CI 2.84-19.88). In patients without lymph node dissection open radical prostatectomy increased the thromboembolic risk 3.8-fold (95% CI 1.42-9.99) compared to robot-assisted laparoscopic radical prostatectomy. Lymph node dissection induced more wound, respiratory, cardiovascular and neuromusculoskeletal events. It also caused more readmissions than no lymph node dissection (14.6% vs 6.3%).CONCLUSIONS: Among other adverse events we found that lymph node dissection during radical prostatectomy increased the incidence of deep venous thrombosis and pulmonary embolism. Open surgery increased the risks more than robot-assisted surgery. This was most prominent in patients who were not treated with lymph node dissection. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.


Geraci M.,University College London | Bottai M.,Karolinska Institutet
Statistics and Computing | Year: 2014

Dependent data arise in many studies. Frequently adopted sampling designs, such as cluster, multilevel, spatial, and repeated measures, may induce this dependence, which the analysis of the data needs to take into due account. In a previous publication (Geraci and Bottai in Biostatistics 8:140-154, 2007), we proposed a conditional quantile regression model for continuous responses where subject-specific random intercepts were included to account for within-subject dependence in the context of longitudinal data analysis. The approach hinged upon the link existing between the minimization of weighted absolute deviations, typically used in quantile regression, and the maximization of a Laplace likelihood. Here, we consider an extension of those models to more complex dependence structures in the data, which are modeled by including multiple random effects in the linear conditional quantile functions. We also discuss estimation strategies to reduce the computational burden and inefficiency associated with the Monte Carlo EM algorithm we have proposed previously. In particular, the estimation of the fixed regression coefficients and of the random effects' covariance matrix is based on a combination of Gaussian quadrature approximations and non-smooth optimization algorithms. Finally, a simulation study and a number of applications of our models are presented. © 2013 Springer Science+Business Media New York.


Zhao J.,Karolinska University Hospital | Lendahl U.,Karolinska Institutet | Nister M.,Karolinska University Hospital
Cellular and Molecular Life Sciences | Year: 2013

In eukaryotic cells, the shape of mitochondria can be tuned to various physiological conditions by a balance of fusion and fission processes termed mitochondrial dynamics. Mitochondrial dynamics controls not only the morphology but also the function of mitochondria, and therefore is crucial in many aspects of a cell's life. Consequently, dysfunction of mitochondrial dynamics has been implicated in a variety of human diseases including cancer. Several proteins important for mitochondrial fusion and fission have been discovered over the past decade. However, there is emerging evidence that there are as yet unidentified proteins important for these processes and that the fusion/fission machinery is not completely conserved between yeast and vertebrates. The recent characterization of several mammalian proteins important for the process that were not conserved in yeast, may indicate that the molecular mechanisms regulating and controlling the morphology and function of mitochondria are more elaborate and complex in vertebrates. This difference could possibly be a consequence of different needs in the different cell types of multicellular organisms. Here, we review recent advances in the field of mitochondrial dynamics. We highlight and discuss the mechanisms regulating recruitment of cytosolic Drp1 to the mitochondrial outer membrane by Fis1, Mff, and MIEF1 in mammals and the divergences in regulation of mitochondrial dynamics between yeast and vertebrates. © 2012 The Author(s).


Hunt M.C.,Dublin Institute of Technology | Siponen M.I.,Karolinska Institutet | Alexson S.E.H.,Karolinska University Hospital
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

The importance of peroxisomes in lipid metabolism is now well established and peroxisomes contain approximately 60 enzymes involved in these lipid metabolic pathways. Several acyl-CoA thioesterase enzymes (ACOTs) have been identified in peroxisomes that catalyze the hydrolysis of acyl-CoAs (short-, medium-, long- and very long-chain), bile acid-CoAs, and methyl branched-CoAs, to the free fatty acid and coenzyme A. A number of acyltransferase enzymes, which are structurally and functionally related to ACOTs, have also been identified in peroxisomes, which conjugate (or amidate) bile acid-CoAs and acyl-CoAs to amino acids, resulting in the production of amidated bile acids and fatty acids. The function of ACOTs is to act as auxiliary enzymes in the α- and β-oxidation of various lipids in peroxisomes. Human peroxisomes contain at least two ACOTs (ACOT4 and ACOT8) whereas mouse peroxisomes contain six ACOTs (ACOT3, 4, 5, 6, 8 and 12). Similarly, human peroxisomes contain one bile acid-CoA:amino acid N-acyltransferase (BAAT), whereas mouse peroxisomes contain three acyltransferases (BAAT and acyl-CoA:amino acid N-acyltransferases 1 and 2: ACNAT1 and ACNAT2). This review will focus on the human and mouse peroxisomal ACOT and acyltransferase enzymes identified to date and discuss their cellular localizations, emerging structural information and functions as auxiliary enzymes in peroxisomal metabolic pathways. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. © 2012 Elsevier B.V..


Michaelis-Menten second-order chemical kinetics is used to describe the three main mechanisms for surviving fractions of cells after irradiation. These are a direct yield of lethal lesions by single event inactivation, metabolic repair of radiation lesions and transformation of sublethal to lethal lesions by further irradiations. The mass action law gives a system of time-dependent differential equations for molar concentrations of the invoked species that are the DNA substrates as lesions, enzyme repair molecules, the product substances, etc. The approximate solutions of these coupled rate equations are reduced to the problem of finding all the roots of the typical transcendental equation axe-bx}=c with x ≥ 0 being a real variable, where a, b and c are real constants. In the present context, the unique solution of this latter equation is given by x=(1/b)W0(bc/a) where W0 is the principal-branch real-valued Lambert function. Employing the concept of Michaelis-Menten enzyme catalysis, a new radiobiological formalism is proposed and called the "Integrated Michaelis-Menten" (IMM) model. It has three dose-range independent parameters ingrained in a system of the rate equations that are set up and solved by extracting the concentration of lethal lesions whose time development is governed by the said three mechanisms. The indefinite integral of the reaction rate is given by the Lambert W0 function. This result is proportional to the sought concentration of lethal lesions. Such a finding combined with the assumed Poisson distribution of lesions yields the cell surviving fraction after irradiation. Exploiting the known asymptotes of the Lambert W0 function, the novel dose-effect curve is found to exhibit a shoulder at intermediate doses preceded by the exponential cell kill with a non-zero initial slope and followed by the exponential decline with the reciprocal of the D0 or D0 dose as the final slope. All three dose regions are universally as well as smoothly covered by the Lambert function and, hence, by the ensuing cell surviving fractions. The outlined features of the proposed IMM model stem from a comprehensive mechanistic description of radiation-lesion interactions by means of kinetic rate equations. They are expected to be of critical importance in new dose-planning systems for high doses per fraction where the conventional linear-quadratic radiobiological modeling is demonstrably inapplicable. © 2014 Springer International Publishing Switzerland.


Fisone G.,Karolinska Institutet | Bezard E.,University of Bordeaux Segalen
International Review of Neurobiology | Year: 2011

Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by the development of dystonic and choreic motor complications, or dyskinesia. This chapter describes the molecular mechanisms implicated in the emergence and manifestation of l-DOPA-induced dyskinesia (LID). Particular emphasis is given to the role played in this condition by abnormalities in signal transduction at the level of the medium spiny neurons (MSNs) of the striatum, which are the principal target of l-DOPA. Recent evidence pointing to pre-synaptic dysregulation is also discussed. © 2011 Elsevier Inc.


Mcgaha T.L.,University of Toronto | Mcgaha T.L.,A+ Network | Karlsson M.C.I.,Karolinska Institutet
Immunological Reviews | Year: 2016

Apoptotic cells drive innate regulatory responses that result in tolerogenic immunity. This is a critical aspect of cell physiology as apoptotic cells expose potentially dangerous nuclear antigens on the surface in apoptotic blebs, and failure in their recognition, phagocytosis, or destruction can cause dramatic autoimmunity in experimental models and is linked to development and progression of systemic pathology in human. The marginal zone is a specialized splenic environment that serves as a transitional site from circulation to peripheral lymphoid structures. The marginal zone serves a key role in trapping of particulates and initiation of innate responses against systemic microbial pathogens. However in recent years, it has become clear the marginal zone is also important for initiation of immune tolerance to apoptotic cells, driving a coordinated response involving multiple phagocyte and lymphocyte subsets. Recent reports linking defects in splenic macrophage function to systemic lupus erythematosus in a manner analogous to marginal zone macrophages in lupus-prone mice provide an impetus to better understand the mechanistic basis of the apoptotic cell response in the marginal zone and its general applicability to apoptotic cell-driven tolerance at other tissue sites. In this review, we discuss immune responses to apoptotic cells in the spleen in general and the marginal zone in particular, the relationship of these responses to autoimmune disease, and comparisons to apoptotic cell immunity in humans. © 2016 John Wiley & Sons A/S.


Helleday T.,Karolinska Institutet
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: Poly (ADP-ribose) polymerase (PARP) and other DNA repair inhibitors are currently tested in numerous clinical trials, with variable success. Inhibitors are used in monotherapy, for example, PARP inhibitors in BRCA mutated cancers, or more widely in combination treatments. DNA repair inhibitors have, as chemotherapy, great potential for long-term disease control, or potentially even cures. However, the design of clinical trials using DNA repair inhibitors is intricate, as these inhibitors may also potentiate normal tissue toxicity without improving overall disease control. RECENT FINDINGS: Recent findings of mechanism of action of PARP inhibitors and other DNA repair inhibitors are presented, and how the underlying genetic background and interplay between DNA repair pathways influence the choice of tumour location and combination strategies. The hallmark of individualized cancer therapy is to be able to genetically distinguish the responding subclass of cancer patients, and it is widely used when targeting oncogenes. The PARP inhibitors in BRCA mutated cancers also demonstrate that this approach is possible in a synthetic lethal context. SUMMARY: There is strong proof-of-concept for DNA repair inhibitors being a useful anticancer strategy in well designed clinical trials. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.


Leu M.,Karolinska Institutet | Giovannucci E.,Harvard University
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2011

Vitamin D may influence blood pressure through the renin-angiotensin system, parathyroid hormone levels, myocardial function, inflammation, and vascular calcification. In the past several years, a number of high-quality prospective studies have examined 25(OH)vitamin D (25(OH)D) levels in relation to risk of cardiovascular disease (CVD). Studies consistently show that levels of 25(OH)D below 20-25 ng/mL are associated with an increased risk of CVD incidence or mortality. Risk appears especially elevated at 25(OH)D levels below 10 or 15 ng/mL. It is unclear if levels higher that 25 ng/mL provide further benefits for CVD disease. Currently, results from randomized clinical trials are sparse and do not allow a definitive conclusion. Given other potential benefits of vitamin D, and low potential for toxicity, deficient levels below 25-30 ng/mL should be avoided and treated when identified. Further observational and randomized clinical trial data are important to better characterize the optimal range for 25(OH)D. © 2010 Elsevier Masson SAS. All rights reserved.


Wetterberg L.,Karolinska Institutet
Nordic Journal of Psychiatry | Year: 2012

This report covers a millennium, from year 1000 when Sweden had only 0.4 million people until today's 9.4 million. In the 13th century, the first Swedish legal text about the mentally ill and the first hospital to treat them are documented. Control, care and cure of the ill have been shaped by social and cultural changes from time to time, e.g. King Gustav Vasa introduced a paradigm shift of care after the Reformation, when he altered Catholic buildings into state hospitals. He also ordered that medical texts should no longer be written in Latin but in Swedish. The first book dealing with mental illnesses was published in 1578. Laypersons ran the mental hospitals for centuries until the medical perspective and doctors were engaged in the 1800s. To advance the hospital doctors' competence and skill, a Swedish Psychiatric Association was established in 1905. Severely psychotic patients could not be effectively treated until the introduction of chlorpromazine in the 1950s and there is still no cure available. Following the deinstitutionalization, from more than 35,000 beds 50 years ago down to about 4500 today, the request for outpatient treatment increased. Mandatory training in psychotherapies for all psychiatrists started in the 1970s. A major "psychiatry reform", with the hope of improving the situation for the mentally ill, and to reduce the stigma, was introduced in Sweden in 1995. The historic long-term effect of the reform cannot yet be fully evaluated. © 2012 Informa Healthcare.


Masocha W.,Kuwait University | Kristensson K.,Karolinska Institutet
Virulence | Year: 2012

The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear. In this review we present the current understanding of the processes utilized by two human neuropathogenic parasites, Trypanosoma brucei spp and Toxoplasma gondii, to go across the BBB and consequences of CNS invasion. We also describe briefly other parasites that can invade the brain and how they interact with or circumvent the BBB. The roles played by parasite-derived and host-derived molecules during parasitic and white blood cell invasion of the brain are discussed. © 2012 Landes Bioscience.


Rodriguez-Wallberg K.A.,Karolinska Institutet | Rodriguez-Wallberg K.A.,Karolinska University Hospital | Oktay K.,Institute for Fertility Preservation
Cancer Treatment Reviews | Year: 2012

Infertility following treatment of cancer is a quality of survival's recognized issue and efforts should be made to help young cancer patients retaining their fertility potential. Options to preserve fertility in female patients include well established methods such as shielding to reduce radiation damage to reproductive organs, fertility-sparing surgery and emergency in vitro fertilization after controlled ovarian stimulation, aiming at freezing embryos. Transfer of frozen/thawed embryos today is a clinical routine in fertility clinics worldwide and it has been used for over 25. years. Mature oocytes after ovarian stimulation can also be frozen unfertilized, nevertheless overall pregnancy rates after fertilization of frozen-thawn oocytes are still relatively lower than those with embryo freezing. Remaining fertility preservation options are still in development and include the freezing of immature oocytes aiming at later in vitro maturing and fertilizing them and the cryopreservation of ovarian tissue for future retransplantation or for in vitro growth and maturation of follicles, both still experimental. © 2011 Elsevier Ltd.


Ljungqvist O.,Karolinska Institutet
Journal of Parenteral and Enteral Nutrition | Year: 2012

This lecture reviews the current understanding of how insulin resistance, as a marker of the metabolic stress, is involved in recovery after major surgery. Insulin resistance develops as a graded response related to the magnitude of the operation. It lasts for weeks after medium-size surgery and affects all parts of body metabolism. Although hyperglycemia develops, muscle and fat uptake is reduced and other non-insulin-sensitive cells have an increase in glucose uptake as a result of the elevated glucose levels. Reduced glucose uptake and storage in muscle along with loss of lean body mass help explain reduced muscle function that will impair mobilization. The increased uptake of glucose in non-insulin-sensitive cells is involved in the development of several of the most common postoperative complications, including infections and cardiovascular problems. Many of the perioperative treatments in use are outdated, and modern care involves a multimodal approach with several treatments, such as preoperative carbohydrate treatment instead of overnight fasting, continuous epidural anesthesia for postoperative pain care, early feeding, and mobilization, all of which affect insulin by reducing the stress and enhancing recovery. Most of the previous mandatory catabolic responses to surgery can be avoided, resulting in substantially faster recovery and fewer complications. Methods to implement these modern treatments have been developed and used in Europe, resulting in improved care and shorter length of stay. © 2012 American Society for Parenteral and Enteral Nutrition.


BACKGROUND AND PURPOSE—: High adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower risk of hypertension, the major risk factor for stroke. We examined whether adherence to the DASH diet is inversely associated with the incidence of stroke. METHODS—: The study population comprised 74 404 men and women (45–83 years of age), without stroke at baseline, from the Cohort of Swedish Men and the Swedish Mammography Cohort. Diet was assessed with a food-frequency questionnaire. A modified DASH diet score was created based on consumption of vegetables, fruits, legumes and nuts, whole grains, low-fat dairy, red meat and processed meat, and sweetened beverages. Stroke cases were identified through linkage to the Swedish National Patient and Cause of Death Registers. Relative risks and 95% confidence intervals were estimated using Cox proportional hazards regression model. RESULTS—: During 882 727 person-years (mean, 11.9 years) of follow-up, 3896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages were ascertained. The modified DASH diet score was statistically significantly inversely associated with the risk of ischemic stroke (P for trend=0.002), with a multivariable relative risk of 0.86 (95% confidence interval, 0.78–0.94) for the highest versus the lowest quartile of the score. The modified DASH diet score was nonsignificantly inversely associated with intracerebral hemorrhage (corresponding relative risk=0.81; 95% confidence interval, 0.63–1.05) but was not associated with subarachnoid hemorrhage. CONCLUSIONS—: These findings indicate that high adherence to the DASH diet is associated with a reduced risk of ischemic stroke. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01127698 and NCT01127711 for the Swedish Mammography Cohort and the Cohort of Swedish Men, respectively. © 2016 American Heart Association, Inc.


Jenkinson P.M.,University of Hertfordshire | Preston C.,Karolinska Institutet
Consciousness and Cognition | Year: 2015

No previous study has simultaneously examined body ownership and agency in healthy subjects during mirror self-observation. We used a moving rubber hand illusion to examine how both body ownership and agency are affected by seeing (i) the body moving in a mirror, compared with (ii) directly viewing the moving hand, and (iii) seeing a visually identical hand rotated by 180°. We elicited ownership of the hand using direct visual feedback, finding this effect was further enhanced when looking at the hand in a mirror, whereas rotating the hand 180° abolished ownership. Agency was similarly elicited using direct visual feedback, and equally so in the mirror, but again reduced for the 180° hand. We conclude that the reflected body in a mirror is treated as 'special' in the mind, and distinct from other external objects. This enables bodies and actions viewed in a mirror to be directly related to the self. © 2015 Elsevier Inc..


Song H.,Karolinska Institutet
The Cochrane database of systematic reviews | Year: 2013

Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Albeit generally benign, uterine fi broids can have a major impact on women's health and quality of life by contributing to abnormal uterine bleeding and causing pelvic pressure symptoms (such as increased urinary frequency, pelvic pain and constipation). Traditional treatments for symptomatic fi broids include a variety of surgical techniques. However, because of the high recurrence rate, as well as possible pain and infertility caused by the formation of postoperative adhesions, this approach may not be advisable. Safer and more effective medical therapy has long been awaited. Both in vitro studies and clinical trials have suggested that use of the aromatase inhibitors (AIs), a class of anti-oestrogens, might inhibit fi broid growth, thereby eliminating the need for surgery. To evaluate the effectiveness and safety of aromatase Inhibitors (AIs) in women with uterine fibroids. We searched the following databases (from inception to August 21, 2013): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and PsycINFO. In addition, the reference lists of included trials were searched, and experts in the field were contacted. Randomised controlled trials (RCTs) in women of reproductive age comparing the effects of any AI versus placebo, no treatment or any medical treatment/surgery were included. Selection of eligible trials, assessment of trial quality and data extraction were performed independently by two review authors. If data were available, we planned to calculate odds ratios (ORs) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CIs). Only one trial involving 70 participants was included. This trial did not report our primary review outcome (relief of symptoms of fibroids). The only secondary review outcomes reported by this trial were adverse effects (hot flushes) and reduction in fibroid size. Significantly fewer women reported hot flushes in the letrozole group than in the GnRHa group (0/33 vs 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a gonadotrophin-releasing hormone (GnRH) agonist (GnRHa) by 32% after 12 weeks of treatment; these proportions were not significantly different. The included trial did not report data on fibroid volume in a form that permitted calcuation of an odds ratio. Morevoer it was unblinded and included only 60/70 women in analysis. Evidence is insufficient to support the use of AI drugs in the treatment of women with uterine fibroids.


Standard observational studies have reported a robust correlation between maternal smoking during pregnancy and risk of ADHD in offspring. In the accompanying article, Obel et al. used sibling-comparisons to explore the extent to which unmeasured familial confounding explains this association. This commentary highlights three important implications of the study. At a general level, Obel et al. illustrates how (1) family-based quasi-experimental designs and (2) national registers can be used to address confounding in risk factor studies of psychopathology. At a more specific level, the study suggests that maternal smoking during pregnancy is probably not a causal risk factor for ADHD. © 2016 Association for Child and Adolescent Mental Health.


MacCarrone M.,Biomedical University of Rome | MacCarrone M.,European Center for Brain Research | Guzman M.,Complutense University of Madrid | MacKie K.,Indiana University | And 3 more authors.
Nature Reviews Neuroscience | Year: 2014

Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence. © 2015 Macmillan Publishers Limited.


Grillner S.,Karolinska Institutet
Current Biology | Year: 2015

Summary The motor cortex is often considered the main controller for movement, but a new study shows that well-trained paw movements can be performed with equal precision after lesions of the entire motor cortex; the motor cortex is, however, required for learning a new task in naïve animals. © 2015 Elsevier Ltd.


Genetic and diet-induced rodent obesity models provide outstanding opportunities to study the role of angiogenesis and vascular remodeling in modulation of adipogenesis and obesity. In this study, we describe methods to quantitatively study adipose angiogenesis and vascular remodeling on the basis of immunohistochemical analyses. Fresh white adipose tissue or brown adipose tissue are prepared for whole mount, cryosectioned and paraffin-embedded samples, followed by staining with specific markers such as platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, CD34, isolectin B4 or alpha-smooth muscle actin. Adipocytes are visualized by staining lipid droplets with 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-3-dodecanoic acid (BODIPY) 558/568 C(12). This protocol may take 2-5 d to obtain results. In the view of the crucial roles of vasculature in modulation of adipogenesis and obesity, this protocol is valuable for studying the molecular mechanisms of angiogenesis in obese adipose tissues and for assessing the anti-obesity activity of angiogenesis modulators.


Helgesson G.,Karolinska Institutet
Medicine, Health Care and Philosophy | Year: 2015

An update of the widely acknowledged recommendations on how to handle authorship in research, issued by the International Committee of Medical Journal Editors (ICMJE), was issued in August, 2013. While the revised recommendations contain several clarifications compared to earlier versions, one arguably important aspect is still not addressed: the relationship between authorship and intellectual involvement in research. In this paper, it is argued that the ICMJE authorship criteria are flawed in this respect: they do not explicitly require of authors of scientific papers that they do research. It is further suggested that unless academic authorship clearly reflects to what extent individual researchers have been intellectually involved in the research and to what extent they have merely contributed with research-related work, they will, in many cases, be misleading about research merits. © 2014, Springer Science+Business Media Dordrecht.


Lu D.,Karolinska Institutet
The Cochrane database of systematic reviews | Year: 2013

Endometriosis is a chronic, recurring condition that can develop during the reproductive years. It is characterised by the development of endometrial tissue outside the uterine cavity. It is the most common cause of pelvic pain in women. This endometrial tissue development is dependent on oestrogen produced primarily by the ovaries and, therefore, traditional management has focused on suppression of ovarian function. Mounting evidence shows that altered immune function plays a crucial role in the genesis and development of endometriosis. In this review we considered modulation of the inflammation as an alternative approach. To determine the effectiveness and safety of anti-tumour necrosis factor-α (anti-TNF-α) treatment in the management of endometriosis in premenopausal women. For the first publication of this review, we searched for trials in the following databases (from their inception to August 2009): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and PsycINFO. In addition, we searched all reference lists of included trials and contacted experts in the field in an attempt to locate trials. We reran this search to 3 September 2012 for this update. Randomised controlled trials (RCTs) comparing anti-TNF-α drugs with placebo, no treatment, medical treatment, or surgery for pelvic pain associated with endometriosis were included. Two review authors independently selected trials for inclusion, assessed trial quality, and extracted data using data extraction forms. The domains assessed for risk of bias were sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. We used risk ratios (RR) for reporting dichotomous data with 95% confidence intervals (CI), whilst we expressed continuous data as mean differences (MD). We assessed statistical heterogeneity using the I(2) statistic. Only one trial involving 21 participants was included. The results showed no evidence of an effect of infliximab, one of the known anti-TNF-α drugs, on pelvic pain reduction using the Biberoglu-Behrman (BB) score (0 to 3 scale) for participants (MD -0.14, 95% CI -0.43 to 0.15), the BB score for clinicians (MD -0.14, 95% CI -0.39 to 0.11), or a visual analogue pain score (VAS, 100 mm scale) (MD -5.60, 95% CI -16.10 to 4.90), or on the use of pain killers (ibuprofen, g/day) (MD -0.10, 95% CI -0.30 to 0.10). There was no evidence of an increase in adverse events in the infliximab group compared with placebo (RR 3.73, 95% CI 0.22 to 63.66). We found no evidence of clinical benefits of infliximab for endometriotic lesions, dysmenorrhoea, dyspareunia, or pelvic tenderness. To date, there is no trial that has reported a cost-effectiveness analysis of anti-TNF-α drugs, or the odds of recurrence. This review was updated in 2012. The results of the original review published in 2010 remain unchanged. There is still not enough evidence to support the use of anti-TNF-α drugs in the management of women with endometriosis for the relief of pelvic pain.


Warner M.,University of Houston | Gustafsson J.-A.,University of Houston | Gustafsson J.-A.,Karolinska Institutet
Molecular Psychiatry | Year: 2015

In the last decade of the twentieth century, two nuclear receptors were discovered in our laboratory and, very surprisingly, were found to have key roles in the central nervous system. These receptors have provided some novel insights into the etiology and progression of neurodegenerative diseases and anxiety disorders. The two receptors are estrogen receptor beta (ERβ) and liver X receptor beta (LXRβ). Both ERβ and LXRβ have potent anti-inflammatory activities and, in addition, LXRβ is involved in the genesis of dopaminergic neurons during development and protection of these neurons against neurodegeneration in adult life. ERβ is involved in migration of cortical neurons and calretinin-positive GABAergic interneurons during development and maintenance of serotonergic neurons in adults. Both receptors are present in magnocellular neurons of the hypothalamic preoptic area including those expressing vasopressin and oxytocin. As both ERβ and LXRβ are ligand-activated transcription factors, their ligands hold great potential in the treatment of diseases of the CNS. © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15.


Mathot L.,Uppsala University | Stenninger J.,Karolinska Institutet
Cancer Science | Year: 2012

The so-called "seed and soil" hypothesis proposed by Stephen Paget in 1889 to explain the metastatic behavior of cancer cells and the homing of certain cancers to "selected" sites has been a well-recognized phenomenon for over a century. What advances have been made to increase our understanding of this phenomenon and what does it really implicate in terms of targets for therapy? © 2011 Japanese Cancer Association.


Bartonek A.,Karolinska Institutet
Pediatric Physical Therapy | Year: 2010

Purpose: To describe motor development toward ambulation in children with myelomeningocele. Methods: Forty-three children were followed prospectively from 6 months to 6 years of age. Results: Walking function had been achieved at the 1-year follow-up in 2 of 38 children, at the 1.5-year follow-up in 7 of 39, at the 2-year follow-up in 14 of 36, at the 3-year follow-up in 21 of 28, at the 4-year follow-up in 28 of 36, and at the 6-year follow-up in 30 of 38. At the 6-year follow-up, spasticity was present in 22 of 38 children, 42 of 43 used orthoses, and 9 children had not achieved ambulation expected with respect to muscle function. Conclusions: In children with myelomeningocele, walking starts in some during the first year of life and is seen increasingly more frequently until 6 years of age. Motor development before ambulation varies among children with similar muscle function. An increased incidence of spasticity is found among those not having achieved ambulation with respect to muscle function. Copyright © 2010 Section on Pediatrics of the American Physical Therapy Association.


Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.186. © 2015 Macmillan Publishers Limited


Balter K.,Karolinska Institutet
Current opinion in oncology | Year: 2012

Dietary guidelines are important tools for educating the general public and helping health professionals promote good health and prevent chronic diet-related diseases. However, it is of major public health relevance that the effect of the guidelines per se is evaluated to make sure that they serve their purpose. The aim of this article is to review the current research on dietary guidelines and their effect on cancer risk and mortality. Since the last 30-40 years, most industrialized countries have had dietary guidelines. The guidelines are based on thorough reviews of the current scientific evidence regarding dietary intake and health. Potential health benefits associated with good adherence to the guidelines have been evaluated in observational studies during the last 15 years, with an increase in the number of studies during the most recent years. Available data on the potential association between dietary guidelines and cancer are limited and inconclusive. A meta-analysis of studies on overall cancer risk shows no protective effect for good adherence to the dietary guidelines as compared with poor adherence. However, good adherence was associated with a 21% reduced risk of colorectal cancer, and 22% reduced cancer-specific mortality.


Faulds M.H.,Karolinska Institutet
Current opinion in oncology | Year: 2012

Metabolic disease and cancer are two of the leading causes of death worldwide. This review focuses on the potential increased relative risk for the development of cancer in a population with a rapidly increasing incidence of metabolic disturbances. A large number of recent epidemiological and prospective studies link metabolic syndrome-associated diseases to an increased risk for development of, as well as mortality from, several types of cancer. In patients diagnosed with metabolic disorders, the incidence of gastrointestinal, glandular and reproductive tract cancers is significantly higher compared to the general population. In line with that, hyperglycemia has recently been shown to be an independent risk factor for overall cancer incidence. Disorders connected to the metabolic syndrome have been shown to have profound impacts on the incidence and progression of cancer. Continued efforts to make lifestyle interventions, such as weight loss and increased physical activity in the general population, are clearly warranted as a contribution to efforts aimed at decreasing the development of and mortality from cancer. Progression in this field requires a better understanding of the underlying mechanisms behind the cancer-promoting effects associated with disturbed energy balance.


Zaravinos A.,University of Cyprus | Zaravinos A.,Karolinska Institutet
Oncotarget | Year: 2014

Human papilloma virus (HPV)-associated head and neck carcinoma is quite heterogeneous and most of the tumors arise in the oral cavity, oropharynx, hypopharynx and larynx. HPV was just recently recognized as an emerging risk factor for oropharyngeal squamous cell carcinoma (OSCC). HPV(+) tumors represent 5-20% of all head and neck squamous-cell carcinomas (HNSCCs) and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. Different carcinogenic mechanisms are most likely implicated in cervical and oropharyngeal carcinogenesis. The most certain carcinogenic genotype for the head and neck region and the most common high-risk HPV genotype, HPV-16, is frequently detected in OSCC. A combination of p16INK4A expression and molecular detection of HPV DNA is the gold standard for the viral identification in tissue and exfoliated cell samples. Differences in the biology of HPV(+) and HPV(-) OSCC may have implications for the management of patients. New immunotherapy drugs based on the release of the co-inhibitory receptors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) have currently emerged. The goal of therapeutic cancer vaccination is inculcation of a persistent, tumor antigen-specific T cell response which kills tumor cells. The efficacy of the current HPV vaccines, Cervarix and Gardasil, in preventing HPV-related HNSCC is at present unknown. Treatment de-escalation is recommended as the current management of HPV-induced HNSCCs.


Frostegard J.,Karolinska Institutet
Expert Review of Clinical Immunology | Year: 2015

Atherosclerosis is the major cause of cardiovascular disease (CVD), which represents the major cause of death. During recent years, it has become clear that atherosclerosis is a chronic inflammatory condition where immunity could play an important role. Usually, it is when atherosclerotic plaques rupture that CVD follows, but some cases of CVD can occur without apparent atherosclerosis. In systemic lupus erythematosus, the risk of CVD is very high and the prevalence of atherosclerotic plaques, including vulnerable ones, is increased. A combination of traditional and non-traditional risk factors is implicated for the prediction of CVD in systemic lupus erythematosus. Traditional risk factors include hypertension, dyslipidemia, smoking and diabetes, though the exact importance of each of these in systemic lupus erythematosus is not clear. Anti-phospholipid antibodies, systemic inflammation and low levels of natural antibodies such as those against phosphorylcholine (anti-PC) are examples of non-traditional risk factors. Control of disease activity and disease manifestations and of established risk factors is important. © 2015 Informa UK, Ltd.


Background: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and Interleukin-1B (IL-1β) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. Methods: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-α, IL-1β, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). Results: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-α and IL-1β, regulated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. Summary: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-α and IL-1β, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis. © 2013 Boström, Lundberg.


Lonnqvist P.-A.,Karolinska Institutet | Lonnqvist P.-A.,Karolinska University Hospital
Paediatric Anaesthesia | Year: 2015

A number of different adjuncts to local anesthetics can be used to prolong and optimize postoperative pain relief following regional anesthesia in children. The present text provides a slightly opinionated but evidence-based argument in favor of this practice. © 2014 John Wiley & Sons Ltd.


Sjolander A.,Karolinska Institutet | Greenland S.,University of California at Los Angeles
Statistics in Medicine | Year: 2013

In observational studies of the effect of an exposure on an outcome, the exposure-outcome association is usually confounded by other causes of the outcome (potential confounders). One common method to increase efficiency is to match the study on potential confounders. Matched case-control studies are relatively common and well covered by the literature. Matched cohort studies are less common but do sometimes occur. It is often argued that it is valid to ignore the matching variables, in the analysis of matched cohort data. In this paper, we provide analyses delineating the scope and limits of this argument. We discuss why the argument does not carry over to effect estimation in matched case-control studies, although it does carry over to null-hypothesis testing. We also show how the argument does not extend to matched cohort studies when one adjusts for additional confounders in the analysis. Ignoring the matching variables can sometimes reduce variance, even though this is not guaranteed. We investigate the trade-off between bias and variance in deciding whether adjustment for matching factors is advisable. © 2013 JohnWiley & Sons, Ltd.


Helgesson G.,Karolinska Institutet
Genome Medicine | Year: 2011

In a time when the challenge of people being over-researched and experiencing research fatigue is increasingly discussed, low participation rates and potential sample biases are a growing concern in genetic research. In a recent study assessing factors relevant to successful recruitment of patients with myocardial infarction to a genetic study, enrollment site was identified as the most important factor associated with patient participation, whereas patient-level factors such as race, gender and education played a limited or no role. These results underline the importance of appropriate recruitment routines at enrollment sites in order to reach high levels of participation in genetic research. © 2011 BioMed Central Ltd.


Moshe S.L.,Yeshiva University | Perucca E.,University of Pavia | Ryvlin P.,Idee | Ryvlin P.,University of Lausanne | Tomson T.,Karolinska Institutet
The Lancet | Year: 2015

Summary Epilepsy affects 65 million people worldwide and entails a major burden in seizure-related disability, mortality, comorbidities, stigma, and costs. In the past decade, important advances have been made in the understanding of the pathophysiological mechanisms of the disease and factors affecting its prognosis. These advances have translated into new conceptual and operational definitions of epilepsy in addition to revised criteria and terminology for its diagnosis and classification. Although the number of available antiepileptic drugs has increased substantially during the past 20 years, about a third of patients remain resistant to medical treatment. Despite improved effectiveness of surgical procedures, with more than half of operated patients achieving long-term freedom from seizures, epilepsy surgery is still done in a small subset of drug-resistant patients. The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research. Concerted actions to address these challenges are urgently needed. © 2015 Elsevier Ltd.


Soussi T.,Karolinska Institutet | Soussi T.,University Pierre and Marie Curie
Advances in Cancer Research | Year: 2011

TP53 mutations are the most frequent genetic alterations found in human cancer. For more than 20. years, TP53 mutation databases have collected over 30,000 somatic mutations from various types of cancer. Analyses of these mutations have led to many types of studies and have improved our knowledge about the TP53 protein and its function. The recent advances in sequencing methodologies and the various cancer genome sequencing projects will lead to a profound shift in database curation and data management. In this paper, we will review the current status of the TP53 mutation database, its application to various fields of research, and how data quality and curation can be improved. We will also discuss how the genetic data will be stored and handled in the future and the consequences for database management. © 2011 Elsevier Inc.


Friberg L.,Karolinska Institutet
Journal of the American College of Cardiology | Year: 2014

Objectives The aim of this study was to examine mortality and liver disease among patients exposed to dronedarone. Background There has been concern about the safety of dronedarone, especially for patients with heart failure and permanent atrial fibrillation (AF). There have also been suspicions about liver toxicity. Methods All 174,995 patients with a diagnosis of AF during 2010 to 2012 were identified in the Swedish Patient Register. Of these, 4,856 patients had received dronedarone according to the Swedish Drug Register, and 170,139 patients who had not were used as a control population. Mean follow-up was 1.6 years, with a minimal follow-up of 6 months. Results Patients prescribed dronedarone were younger (age 65.5 years vs. 75.7 years, p < 0.0001) and healthier than control patients. The annual mortality rate among patients who received dronedarone was 1.3% compared with 14.0% in the control population. There were no sudden cardiac deaths and no deaths related to liver failure among patients who received treatment with dronedarone. After propensity score matching and adjustment for cofactors, patients who received dronedarone had lower mortality than other AF patients (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.33 to 0.51). Dronedarone patients with heart failure had lower mortality than other heart failure patients (HR: 0.40; 95% CI: 0.30 to 0.53). They also had lower mortality than expected from the general population (standardized mortality ratio: 0.67; 95% CI: 0.55 to 0.78), which indicates the selection of low-risk patients. The risk of liver disease was not increased (HR: 0.57; 95% CI: 0.34 to 0.92). Conclusions Dronedarone, as prescribed to AF patients in Sweden, has not exposed patients to increased risks of death or liver disease. © 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.


Esser C.,Leibniz Research Institute for Environmental Medicine | Rannug A.,Karolinska Institutet
Pharmacological Reviews | Year: 2015

The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim–basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views—namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Zelenin P.V.,Karolinska Institutet
Journal of Neurophysiology | Year: 2011

Most vertebrates are capable of two forms of locomotion, forward and backward, strongly differing in the patterns of motor coordination. Basic mechanisms generating these patterns are located in the spinal cord; they are activated and regulated by supraspinal commands. In the lamprey, these commands are transmitted by reticulospinal (RS) neurons. The aim of this study was to reveal groups of RS neurons controlling different aspects of forward (FS) and backward (BS) swimming in the lamprey. Activity of individual larger RS neurons in intact lampreys was recorded during FS and BS by chronically implanted electrodes. It was found that among the neurons activated during locomotion, 27% were active only during FS, 3% only during BS, and 70% during both FS and BS. In a portion of RS neurons, their mean firing frequency was correlated with frequency of body undulations during FS (8%), during BS (34%), or during both FS and BS (22%), suggesting their involvement in control of locomotion intensity. RS activity was phasically modulated by the locomotor rhythm during FS (20% of neurons), during BS (29%), or during both FS and BS (16%). The majority of RS neurons responding to vestibular stimulation (and presumably involved in control of body orientation) were active mainly during FS. This explains the absence of stabilization of the body orientation observed during BS. We discuss possible functions of different groups of RS neurons, i.e., activation of the spinal locomotor CPG, inversion of the direction of propagation of locomotor waves, and postural control. © 2011 the American Physiological Society.


D'Onofrio B.M.,Indiana University | Lahey B.B.,University of Chicago | Turkheimer E.,University of Virginia | Lichtenstein P.,Karolinska Institutet
American Journal of Public Health | Year: 2013

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene- environment interactions). In this context, we stress the critical need for researchers to use familybased, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.


Feychting M.,Karolinska Institutet
American Journal of Epidemiology | Year: 2013

Research on an association between extremely low frequency (ELF) magnetic fields and breast cancer has been conducted since the 1980s, based on the hypothesis that ELF fields suppress melatonin production and melatonin protects against breast cancer development. In this issue of the Journal, Li et al. (Am J Epidemiol. 2013;178(7):1038-1045) present a well-designed study on occupational exposure to ELF fields and breast cancer that adds to the already large pool of data that has not supported the hypothesis. Over time, the quality and statistical power of studies within this research area have increased considerably, and advances in exposure assessment have reduced exposure misclassification. The evidence is consistently negative. A World Health Organization health risk assessment concluded in 2005 that the evidence from experimental and epidemiologic studies is sufficient to give confidence that ELF magnetic fields do not cause breast cancer. The new study adds even more confidence to this conclusion. We should now focus our time and research resources on more promising hypotheses, the results of which could make a difference for public health and advance science. Further epidemiologic studies on ELF fields and breast cancer are likely to have little new knowledge to add. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


Ljungman P.,Karolinska University Hospital | Ljungman P.,Karolinska Institutet
Clinical Microbiology and Infection | Year: 2012

Vaccination of immunocompromised patients is challenging both regarding efficacy and safety. True efficacy data are lacking so existing recommendations are based on immune responses and safety data. Inactivated vaccines can generally be used without risk but the patients who are most at risk for infectious morbidity and mortality as a result of their severely immunosuppressed state are also those least likely to respond to vaccination. However, vaccination against pneumococci, Haemophilus influenzae and influenza are generally recommended. Live vaccines must be used with care because the risk for vaccine-associated disease exists. © 2012 The Author. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.


Lane R.M.,Isis Pharmaceuticals | Darreh-Shori T.,Karolinska Institutet
Journal of Alzheimer's disease : JAD | Year: 2015

Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.


Astorga-Wells J.,Karolinska Institutet
Molecular & cellular proteomics : MCP | Year: 2011

A membrane cell for hydrogen and deuterium exchange on-line with mass spectrometry has been developed to monitor protein-protein interactions and protein conformations. It consists of two channels separated by a semipermeable membrane, where one channel carries the protein sample and the other deuterium oxide. The membrane allows transfer of deuterium oxide into the sample flow. The labeling time is controlled via the flow rate in the sample channel. This cell was validated against three models commonly used in hydrogen-deuterium exchange mass spectrometry: monitoring of folded and unfolded states in a protein, mapping the protein secondary structure at the peptide level, and detection of protein and antibody interactions. The system avoids the conventionally used sample dilution and handling, allowing for potential automation.


Lerner M.,Karolinska Institutet
PloS one | Year: 2012

The pro-apoptotic p53 target Noxa is a BH3-only protein that antagonizes the function of selected anti-apoptotic Bcl-2 family members. While much is known regarding the transcriptional regulation of Noxa, its posttranscriptional regulation remains relatively unstudied. In this study, we therefore investigated whether Noxa is regulated by microRNAs. Using a screen combining luciferase reporters, bioinformatic target prediction analysis and microRNA expression profiling, we identified miR-200c as a negative regulator of Noxa expression. MiR-200c was shown to repress basal expression of Noxa, as well as Noxa expression induced by various stimuli, including proteasomal inhibition. Luciferase reporter experiments furthermore defined one miR-200c target site in the Noxa 3'UTR that is essential for this direct regulation. In spite of the miR-200c:Noxa interaction, miR-200c overexpression led to increased sensitivity to the clinically used proteasomal inhibitor bortezomib in several cell lines. This apparently contradictory finding was reconciled by the fact that in cells devoid of Noxa expression, miR-200c overexpression had an even more pronounced positive effect on apoptosis induced by proteasomal inhibition. Together, our data define miR-200c as a potentiator of bortezomib-induced cell death. At the same time, we show that miR-200c is a novel negative regulator of the pro-apoptotic Bcl-2 family member Noxa.


Grunewald J.,Karolinska Institutet | Grunewald J.,Karolinska University Hospital
Seminars in Respiratory and Critical Care Medicine | Year: 2010

Sarcoidosis develops in genetically predisposed individuals that are exposed to unknown antigens. There is a statistically significant increased risk for the disease among family members of sarcoidosis patients, and the disease differs in different ethnic groups. It is a genetically complex disease, with many genes contributing, both as risk factors but also with an influence on the disease course. The strongest genetic associations with sarcoidosis are found within the major histocompatibility complex (MHC) [human leukocyte antigen (HLA) in humans]region on chromosome six. This region includes, besides the HLA-class I and class-II genes, a large number of genes important for the immune response and inflammation. The well studied associations between sarcoidosis and HLA-class II molecules indicate specific antigen presentation for T helper cells, which is in agreement with the characteristic finding of lung-accumulated CD4+ T helper cells expressing a limited set of T cell receptors. Strong associations between distinct HLA-DRB1 alleles and the disease phenotype and course have been described, especially so in patient subgroups. Although a large number of genes are associated with sarcoidosis, this review focuses on gene associations and their influence on the disease phenotype, including the disease course. Copyright © 2010 by Thieme Medical Publishers, Inc.


Jonsson B.,Lakemedelsverket Medicinal Products Agency | Bergh J.,Karolinska Institutet
Nature Reviews Clinical Oncology | Year: 2012

Between January 2001 and January 2012, 48 new medicinal products for cancer treatment were licensed within the EU, and 77 new indications were granted for products already licensed. In some cases, a major improvement to existing therapies was achieved, for example, trastuzumab in breast cancer. In other cases, new fields for effective drug therapy opened up, such as in chronic myeloid leukemia, and renal-cell carcinoma. In most cases, however, the benefit-risk balance was considered to be only borderline favorable. Based on our assessment of advice procedures for marketing authorization, 'need for speed' seems to be the guiding principle in anticancer drug development. Although, for drugs that make a difference, early licensure is of obvious importance to patients, this is less evident in the case of borderline drugs. Without proper incentives and with hurdles inside and outside companies, a change in drug development cannot be expected; drugs improving benefit-risk modestly over available therapies will be brought forward towards licensure. In this Perspectives article, we discuss some hurdles to biomarker-driven drug development and provide some suggestions to overcome them. © 2012 Macmillan Publishers Limited. All rights reserved.


Shorvon S.,University College London | Tomson T.,Karolinska Institutet | Tomson T.,Karolinska University Hospital
The Lancet | Year: 2011

Sudden unexpected death in epilepsy (SUDEP) refers to the sudden death of a seemingly healthy individual with epilepsy, usually occurring during, or immediately after, a tonic-clonic seizure. The frequency of SUDEP varies depending on the severity of the epilepsy, but overall the risk of sudden death is more than 20 times higher than that in the general population. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. Data from a pooled analysis of risk factors indicate that the higher the frequency of tonic-clonic seizures, the higher the risk of SUDEP; furthermore, risk of SUDEP is also elevated in male patients, patients with long-duration epilepsy, and those on antiepileptic polytherapy. SUDEP usually occurs when the seizures are not witnessed and often at night. In this Seminar, we provide advice to clinicians on ways to minimise the risk of SUDEP, information to pass on to patients, and medicolegal aspects of these deaths. © 2011 Elsevier Ltd.


Oberg M.,Karolinska Institutet | Jaakkola M.S.,University of Oulu | Woodward A.,University of Auckland | Peruga A.,World Health Organization | Pruss-Ustun A.,World Health Organization
The Lancet | Year: 2011

Exposure to second-hand smoke is common in many countries but the magnitude of the problem worldwide is poorly described. We aimed to estimate the worldwide exposure to second-hand smoke and its burden of disease in children and adult non-smokers in 2004. The burden of disease from second-hand smoke was estimated as deaths and disability-adjusted life-years (DALYs) for children and adult non-smokers. The calculations were based on disease-specific relative risk estimates and area-specific estimates of the proportion of people exposed to second-hand smoke, by comparative risk assessment methods, with data from 192 countries during 2004. Worldwide, 40 of children, 33 of male non-smokers, and 35 of female non-smokers were exposed to second-hand smoke in 2004. This exposure was estimated to have caused 379 000 deaths from ischaemic heart disease, 165 000 from lower respiratory infections, 36 900 from asthma, and 21 400 from lung cancer. 603 000 deaths were attributable to second-hand smoke in 2004, which was about 1·0 of worldwide mortality. 47 of deaths from second-hand smoke occurred in women, 28 in children, and 26 in men. DALYs lost because of exposure to second-hand smoke amounted to 10·9 million, which was about 0·7 of total worldwide burden of diseases in DALYs in 2004. 61 of DALYs were in children. The largest disease burdens were from lower respiratory infections in children younger than 5 years (5 939 000), ischaemic heart disease in adults (2 836 000), and asthma in adults (1 246 000) and children (651 000). These estimates of worldwide burden of disease attributable to second-hand smoke suggest that substantial health gains could be made by extending effective public health and clinical interventions to reduce passive smoking worldwide. Swedish National Board of Health and Welfare and Bloomberg Philanthropies. © 2011 Elsevier Ltd.


Gonzalez H.,Danderyd Hospital | Olsson T.,Karolinska Institutet | Borg K.,Danderyd Hospital
The Lancet Neurology | Year: 2010

Postpolio syndrome is characterised by the exacerbation of existing or new health problems, most often muscle weakness and fatigability, general fatigue, and pain, after a period of stability subsequent to acute polio infection. Diagnosis is based on the presence of a lower motor neuron disorder that is supported by neurophysiological findings, with exclusion of other disorders as causes of the new symptoms. The muscle-related effects of postpolio syndrome are possibly associated with an ongoing process of denervation and reinnervation, reaching a point at which denervation is no longer compensated for by reinnervation. The cause of this denervation is unknown, but an inflammatory process is possible. Rehabilitation in patients with postpolio syndrome should take a multiprofessional and multidisciplinary approach, with an emphasis on physiotherapy, including enhanced or individually modified physical activity, and muscle training. Patients with postpolio syndrome should be advised to avoid both inactivity and overuse of weak muscles. Evaluation of the need for orthoses and assistive devices is often required. © 2010 Elsevier Ltd. All rights reserved.


Mellstedt H.,Karolinska Institutet
Annals of Oncology | Year: 2013

Biopharmaceuticals are complex protein molecule drugs produced by living organisms. Biopharmaceuticals as anti-neoplastic monoclonal antibodies are a major breakthrough in oncology. When the patent of innovator biopharmaceuticals expires, copies will be introduced. These copies are after approval by European Medicines Agency (EMA) within EU called biosimilars and have their own regulatory pathways which differ from the chemical generics approval process. The main reason is that identical copies of chemical molecules via chemical syntheses can be produced but copies of innovator biopharmaceuticals will only be similar. An extensive comparability exercise has to be carried out between the reference product and the biosimilar before approval. However, still there might be differences between the innovator anti-neoplastic monoclonal antibody and the biosimilar anti-neoplastic antibody which cannot be detected until extended clinical studies have been carried out. Moreover, all indications for an anti-neoplastic biosimilar antibody may not have been tested for at the time of approval but extrapolated based on the indications of the reference monoclonal antibody. The limited information on biosimilar anti-neoplastic monoclonal antibodies at approval may still be justified taking into account tha the aim is to reduce price. However, the risk-benefit ratio for biosimilar anti-neoplastic monoclonal antibodies should be carefully evaluated, considering that anti-neoplastic monoclona antibody therapy has a curative intent, price reduction so far within EU of biosimilars is modest and that in the end only part of the total costs for cancer health care is related to biopharmaceuticals. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Shapiro E.,Weizmann Institute of Science | Biezuner T.,Weizmann Institute of Science | Linnarsson S.,Karolinska Institutet
Nature Reviews Genetics | Year: 2013

The unabated progress in next-generation sequencing technologies is fostering a wave of new genomics, epigenomics, transcriptomics and proteomics technologies. These sequencing-based technologies are increasingly being targeted to individual cells, which will allow many new and longstanding questions to be addressed. For example, single-cell genomics will help to uncover cell lineage relationships; single-cell transcriptomics will supplant the coarse notion of marker-based cell types; and single-cell epigenomics and proteomics will allow the functional states of individual cells to be analysed. These technologies will become integrated within a decade or so, enabling high-throughput, multi-dimensional analyses of individual cells that will produce detailed knowledge of the cell lineage trees of higher organisms, including humans. Such studies will have important implications for both basic biological research and medicine. © 2013 Macmillan Publishers Limited. All rights reserved.


Djalali A.,Karolinska Institutet
Prehospital and disaster medicine | Year: 2013

Hospitals are expected to continue to provide medical care during disasters. However, they often fail to function under these circumstances. Vulnerability to disasters has been shown to be related to the socioeconomic level of a country. This study compares hospital preparedness, as measured by functional capacity, between Iran and Sweden. Hospital affiliation and size, and type of hazards, were compared between Iran and Sweden. The functional capacity was evaluated and calculated using the Hospital Safety Index (HSI) from the World Health Organization. The level and value of each element was determined, in consensus, by a group of evaluators. The sum of the elements for each sub-module led to a total sum, in turn, categorizing the functional capacity into one of three categories: A) functional; B) at risk; or C) inadequate. The Swedish hospitals (n = 4) were all level A, while the Iranian hospitals (n = 5) were all categorized as level B, with respect to functional capacity. A lack of contingency plans and the availability of resources were weaknesses of hospital preparedness. There was no association between the level of hospital preparedness and hospital affiliation or size for either country. The results suggest that the level of hospital preparedness, as measured by functional capacity, is related to the socioeconomic level of the country. The challenge is therefore to enhance hospital preparedness in countries with a weaker economy, since all hospitals need to be prepared for a disaster. There is also room for improvement in more affluent countries.


Norman M.,Karolinska Institutet
Seminars in Perinatology | Year: 2010

Hypertension is a major risk factor for ischemic heart disease and stroke, which are leading causes of morbidity and death worldwide. Besides the contributions from genes and adult life-style, this review highlights that adult hypertension is likely to be a legacy of preterm birth. This knowledge has important health implications for the new and rapidly growing population of young people born very preterm. Increased awareness among both families and professionals about preterm birth being a perinatal risk factor for adult hypertension is needed. Measurement of blood pressure in children and young people born preterm is also recommended, all to detect and treat hypertension in young people born preterm long before end organ damage occurs. © 2010 Elsevier Inc.


Rao B.,University of Dundee | Lain S.,Karolinska Institutet | Thompson A.M.,University of Dundee
British Journal of Cancer | Year: 2013

Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic effect of p53 can protect normal cells from the toxicity of S-or M-phase poisons. Here, we have reviewed existing cyclotherapy regimens using two well-known p53 activators, nutlin-3 and actinomycin D. We have highlighted an exemplar clinical perspective for cyclotherapy in breast cancer. The recent development of novel stapled peptides as activators of p53 without the corresponding cytotoxicity holds great promise for cyclotherapy to enhance the therapeutic window of existing chemotherapy drugs. © 2013 Cancer Research UK.


Stenvinkel P.,Karolinska Institutet
Journal of Internal Medicine | Year: 2010

The epidemics of cardiovascular disease, obesity, diabetes, HIV and cancer have all received much attention from the public, media and policymakers. By contrast, chronic kidney disease (CKD) has remained largely a 'silent' epidemic. This is unfortunate because early diagnosis of renal disease based on proteinuria and/or reduced estimated glomerular filtration rate could enable early intervention to reduce the high risks of cardiovascular events, end-stage renal disease (ESRD) and death that are associated with CKD. Given the global increase in the incidence of the leading causes of CKD - hypertension, obesity and diabetes mellitus - better disease management and prevention planning are needed, as effective strategies are available to slow the progression of CKD and reduce cardiovascular risk. CKD may be regarded as a clinical model of accelerated vascular disease and premature ageing, and the risk-factor profile changes during the progression from mild/moderate CKD to ESRD. Although many randomized controlled trials in patients with mild to moderate CKD have shown beneficial effects of interventions aimed at preventing the progression of CKD, most trials have been unable to demonstrate a beneficial effect of interventions aimed at improving outcome in ESRD. Thus, novel treatment strategies are needed in this high-risk patient group. © 2010 The Association for the Publication of the Journal of Internal Medicine.


Norhammar A.,Karolinska University Hospital | Schenck-Gustafsson K.,Karolinska University Hospital | Schenck-Gustafsson K.,Karolinska Institutet
Diabetologia | Year: 2013

Cardiovascular disease is the leading cause of death in both men and women. This is also true for patients with diabetes. In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed. Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities. However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes. Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors. This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes. Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular. The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed. © 2012 Springer-Verlag.


Wiza C.,Institute of Clinical Biochemistry and Pathobiochemistry | Nascimento E.B.M.,Karolinska Institutet | Ouwens D.M.,Institute of Clinical Biochemistry and Pathobiochemistry
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt-and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt-and mTOR-signaling network in health and disease. © 2012 the American Physiological Society.


Samuelsson B.,Karolinska Institutet
The Journal of biological chemistry | Year: 2012

The role of basic science in the development of health care has received more and more attention. In my own area of research involving the so-called eicosanoids, there are many examples of how studies of structure and function of small molecules, as well as proteins and genes, have led to new therapeutic agents for treatment of a variety of diseases. In most of the cases, the discoveries have resulted in the recognition of novel therapeutic targets amenable to modulation by small molecules. However, there are also examples in which the molecular mechanisms of actions of drugs, discovered by phenotypic screening, have been elucidated. The majority of the examples in this article consist of approved drugs; however, in some cases, ongoing developments of potential therapeutics are cited.


Andersson E.R.,Karolinska Institutet
Cellular and Molecular Life Sciences | Year: 2012

Endocytosis is increasingly understood to play crucial roles in most signaling pathways, from determining which signaling components are activated, to how the signal is subsequently transduced and/or terminated. Whether a receptor-ligand complex is internalized via a clathrin-dependent or clathrin-independent endocytic route, and the complexes' subsequent trafficking through specific endocytic compartments, to then be recycled or degraded, has profound effects on signaling output. This review discusses the roles of endocytosis in three markedly different signaling pathways: the Wnt, Notch, and Eph/Ephrin pathways. These offer fundamentally different signaling systems: (1) diffusible ligands inducing signaling in one cell, (2) membrane-tethered ligands inducing signaling in a contacting receptor cell, and (3) bi-directional receptor-ligand signaling in two contacting cells. In each of these systems, endocytosis controls signaling in fascinating ways, and comparison of their similarities and dissimilarities will help to expand our understanding of endocytic control of signal transduction across multiple signaling pathways. © 2011 Springer Basel AG.


Dantuma N.P.,Karolinska Institutet | Hoppe T.,University of Cologne
Trends in Cell Biology | Year: 2012

The AAA (ATPases associated with various cellular activities) family member Cdc48/p97 is best known for its role in ubiquitin-dependent proteasomal degradation of aberrant endoplasmic reticulum (ER) proteins, a process known as ER-associated degradation (ERAD). However, recent studies have also defined Cdc48/p97 as a central player in various chromatin-associated processes linked to cell cycle progression, DNA replication, transcription, and the DNA damage response. Notwithstanding the apparent differences in location and function, the role of Cdc48/p97 in ubiquitin-dependent extraction from chromatin (UDEC) bears striking similarities with its action in ERAD. Here, we discuss recent data that expand our current model of the role of Cdc48/p97 as a ubiquitin-selective segregase in the nuclear chromatin environment. © 2012 Elsevier Ltd.


van Vollenhoven R.F.,Karolinska Institutet | van Vollenhoven R.F.,Clinical Trials Unit
Autoimmunity Reviews | Year: 2012

Rituximab (Rituxan, Mabthera) is a monoclonal therapeutic anti-CD20 antibody approved for use in lymphoma and rheumatoid arthritis but not for use in systemic lupus erythematosus (SLE). Nonetheless, over the past decade many reports based on case series and observational studies have suggested benefits in selected groups of SLE patients with this monoclonal. It is also clear that off-label use of rituximab in SLE is not uncommon in many countries in the world. However, two randomized controlled clinical trials of rituximab failed to demonstrate a benefit for this agent, raising important questions on how to assess the potential role of rituximab in SLE. In this article I will review the available data and provide some comments that may be of use for the practicing clinician. © 2011.


Westerblad H.,Karolinska Institutet | Allen D.G.,University of Sydney
Antioxidants and Redox Signaling | Year: 2011

Reactive oxygen and nitrogen species (ROS/RNS) are involved in numerous aspects of cellular signaling. Classically ROS/RNS have been associated with cellular dysfunction and disease, but it is now clear that they are also of integral importance under normal conditions. In this review, we discuss ROS/RNS effects in skeletal muscle, with special focus on changes in contractile function. The review deals with the tentative roles of ROS/RNS for acute changes that can occur during strenuous exercise resulting in muscle fatigue, for the recovery from fatigue, and for the effects of training/overtraining. We also discuss two groups of inherited diseases; muscle dystrophies, where recent data suggest that ROS/RNS may be of unexpectedly large importance, and mitochondrial myopathies, where the role of ROS seems more limited than originally thought. © 2011 Mary Ann Liebert, Inc.


The IntelliMaze allows automated behavioral analysis of group housed laboratory mice while individually assigned protocols can be applied concomitantly for different operant conditioning components. Here we evaluate the effect of additional component availability (enrichment) on behavioral and cognitive performance of mice in the IntelliCage, by focusing on aspects that had previously been found to consistently differ between three strains, in four European laboratories. Enrichment decreased the activity level in the IntelliCages and enhanced spatial learning performance. However, it did not alter strain differences, except for activity during the initial experimental phase. Our results from non-enriched IntelliCages proved consistent between laboratories, but overall laboratory-consistency for data collected using different IntelliCage set-ups, did not hold for activity levels during the initial adaptation phase. Our results suggest that the multiple conditioning in spatially and cognitively enriched environments are feasible without affecting external validity for a specific task, provided animals have adapted to such an IntelliMaze.


Nordberg A.,Karolinska Institutet
Alzheimer's Research and Therapy | Year: 2011

Abstract. Recent progress in molecular imaging has provided new important knowledge for further understanding the time course of early pathological disease processes in Alzheimer's disease (AD). Positron emission tomography (PET) amyloid beta (A) tracers such as Pittsburgh Compound B detect increasing deposition of fibrillar A in the brain at the prodromal stages of AD, while the levels of fibrillar A appear more stable at high levels in clinical AD. There is a need for PET ligands to visualize smaller forms of A, oligomeric forms, in the brain and to understand how they interact with synaptic activity and neurodegeneration. The inflammatory markers presently under development might provide further insight into the disease mechanism as well as imaging tracers for tau. Biomarkers measuring functional changes in the brain such as regional cerebral glucose metabolism and neurotransmitter activity seem to strongly correlate with clinical symptoms of cognitive decline. Molecular imaging biomarkers will have a clinical implication in AD not only for early detection of AD but for selecting patients for certain drug therapies and to test disease-modifying drugs. PET fibrillar A imaging together with cerebrospinal fluid biomarkers are promising as biomarkers for early recognition of subjects at risk for AD, for identifying patients for certain therapy and for quantifying anti-amyloid effects. Functional biomarkers such as regional cerebral glucose metabolism together with measurement of the brain volumes provide valuable information about disease progression and outcome of drug treatment. © 2011 BioMed Central Ltd.


Bolte S.,Karolinska Institutet
Developmental Medicine and Child Neurology | Year: 2014

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder of multifactorial origin. Today, ASD is generally not curable, although it is treatable to a varying degree to prevent worse outcomes. Some reports indicate the possibility of major improvements or even recovery in ASD. However, these studies are based on scientific shortcomings, and the lack of a clear definition of 'cure' in ASD further compromises interpretation of research findings. The development of animal models and decreasing costs of genome sequencing provide new options for treatment research and individualized medicine in ASD. This article briefly reviews several issues related to the question whether there is recovery from ASD, starting with a short overview of the presumed aetiologies. © 2014 Mac Keith Press.


Rising A.,Karolinska Institutet | Rising A.,Swedish University of Agricultural Sciences
Acta Biomaterialia | Year: 2014

Recent biotechnological progress has enabled the production of spider silk proteins, spidroins, in heterologous hosts. Matrices based on recombinant spidroins support stem cell growth and are well tolerated when implanted in living tissue, thus the material is highly attractive for use in regenerative medicine. However, the matrices made are far from natural silk in terms of mechanical properties and are either spontaneously assembled, which results in heterogeneous products, or spun from harsh solvents with the concomitant risk of harmful remnants in the final products. If we could mimic the spider's aqueous silk spinning process we would likely obtain a material that had reproducible and better characteristics and that more easily could be transferred to clinical practice. Herein, the knowledge of the spiders' silk production system and the prerequisites for artificial spinning and assembly of recombinant proteins are reviewed and discussed in a biomedical context. © 2013 Acta Materialia Inc.


Context can be defined as all factors that are not part of a quality improvement intervention itself. More research indicates which aspects are 'conditions for improvement', which influence improvement success. However, little is known about which conditions are most important, whether these are different for different quality interventions or whether some become less or more important at different times in carrying out an improvement. Knowing more about these conditions could help speed up and spread improvements and develop the science. This paper proposes ways to build knowledge about the conditions needed for different changes, and to create conditional-attribution explanations to provide qualified generalisations. It describes theory-based, non-experimental research designs. It also suggests that 'practical improvers' can make their changes more effective by reflecting on and revising their own 'assumption-theories' about the conditions which will help and hinder the improvements they aim to implement.


This study explores how moral reasoning is expressed in matching health care with the problems older persons experience in their everyday life. Narrative data were collected from older persons who had applied for home modification services and from professionals involved in these services in Sweden. A theoretical framework, based on theories on the anthropology of morals, was applied to explore how the participants made conclusions about "what should be done." Moral reasoning was found to be guided by ideologies related to the historical and cultural context of the Swedish welfare state. Different interpretations of how these values should be expressed in specific situations led to different conclusions about what should be done. The study highlights the importance of understanding how values are enacted rather than what values different social agents have in order to understand how health care services can be designed and provided to support older persons' everyday life. © 2013 by the American Anthropological Association.


In this issue of Science Signaling, Mills et al. show that the amino acid L-arginine increases the concentration of the second messenger c-di-GMP in Salmonella enterica serovar Typhimurium through a specific diguanylate cyclase, leading to increased production of the exopolysaccharide cellulose, which is an extracellular matrix component of environmental and host-associated biofilms. Copyright 2015 by the American Association for the Advancement of Science; All rights reserved.


Hjern A.,Karolinska Institutet
Scandinavian Journal of Public Health | Year: 2012

In an increasingly globalized world more people have the possibility to settle in a country other than the one in which they were born. To the new country migrants bring their lifestyle and other important risk factors and protective factors for health. If the immigrants are refugees, a period of uncertainty awaits them before their life in a new country can begin. As newcomers to Swedish society, they often end up in low-status neighborhoods, are reduced to heavy and low-wage jobs and often also continue to be socially vulnerable as a result of discrimination. Immigrants in Sweden of non-European background report three to four times as often as Swedishborn people that they suffer from poor or very poor health. Male immigrants smoke more than Swedishborn men, while alcohol-related diseases are less common among many immigrant groups. The incidence of a number of specific public health problems, such as allergic diseases and diabetes, varies widely across different immigrant groups. The particular background of refugees makes them especially susceptible to psychiatric morbidity, a susceptibility that is further increased by the stresses that occur during the asylum process. Adult undocumented migrants and asylum seekers have limited access to health and medical care in Sweden. © 2012 the Nordic Societies of Public Health.


Anderstam B.,Karolinska Institutet
Scandinavian journal of clinical and laboratory investigation | Year: 2013

The consumption of fructose has increased dramatically during the last few decades and parallels the epidemics of obesity, metabolic syndrome, diabetes and chronic kidney disease (CKD). Fructose occurs naturally e.g. in fruit and in honey (rich in this monosaccharide) and as sucrose (table sugar). The effects of fructose have been attributed to the transient increases in serum uric acid levels during its metabolism. Recent research, also in CKD patients, has linked fructose to dysmetabolism of lipids, glucose and oxidative radicals. However, a general consensus of the potentially harmful effects of fructose is lacking. We improved a sensitive inulin assay for fructose measurement in serum and plasma and tested its accuracy in an acute experiment following consumption of pure fructose in controls. In addition, fructose and uric acid were analyzed postprandially during 240 min in six maintenance hemodialysis (HD) patients and nine healthy subjects consuming 190 ml cream/75 g sucrose in a fasting state. Whereas the fructose levels reached a maximum level after 60 min in controls they had not even started to decrease at 240 min in HD-patients. Likewise, while uric acid levels remained stable in controls they increased by 10% in HD patients at 240 min following the meal. In conclusion, a glucose and fat rich meal is associated with delayed absorption and/or metabolism of fructose in HD patients as well as increased serum uric acid levels.


Theander S.S.,Lund University | Wetterberg L.,Karolinska Institutet
Schizophrenia Research | Year: 2010

The aim was to perform a bibliometric study, and compare the quantity of publications on schizophrenia with the total medical literature in Medline during 57years, 1950-2006.The annual additions of literature to Medline are continually increasing and form the Medline growth curve. Comparisons of the number of publications on schizophrenia, or any other disease, to this curve, may be used to estimate the research activity. Methods for the identification of relevant references to papers on schizophrenia were evaluated and three different samples were operationally defined, retrieved and counted.During 1950-2006, 16.28 million references were added to Medline. Nearly 68. 000, 0.42%, references were related to schizophrenia. The percentage of papers on schizophrenia among the psychiatric literature decreased from 5.2 to 2.6%. The present study indicates that the number of references on schizophrenia in Medline has followed the general increase of medical publications. This pattern differs compared to some other research fields such as dementia, HIV, and peptic ulcer.Samples of references on schizophrenia may be retrieved in Medline by operational definitions of search methods. The quantity of schizophrenia research during 57years has kept pace with the total medical literature. One interpretation of the results is that more resources are needed to enhance research activities on schizophrenia. © 2009 Elsevier B.V.


Larsson M.,Orebro University | Larsson M.,Karolinska Institutet
Animal Cognition | Year: 2014

It has been suggested that the basic building blocks of music mimic sounds of moving humans, and because the brain was primed to exploit such sounds, they eventually became incorporated in human culture. However, that raises further questions. Why do genetically close, culturally well-developed apes lack musical abilities? Did our switch to bipedalism influence the origins of music? Four hypotheses are raised: (1) Human locomotion and ventilation can mask critical sounds in the environment. (2) Synchronization of locomotion reduces that problem. (3) Predictable sounds of locomotion may stimulate the evolution of synchronized behavior. (4) Bipedal gait and the associated sounds of locomotion influenced the evolution of human rhythmic abilities. Theoretical models and research data suggest that noise of locomotion and ventilation may mask critical auditory information. People often synchronize steps subconsciously. Human locomotion is likely to produce more predictable sounds than those of non-human primates. Predictable locomotion sounds may have improved our capacity of entrainment to external rhythms and to feel the beat in music. A sense of rhythm could aid the brain in distinguishing among sounds arising from discrete sources and also help individuals to synchronize their movements with one another. Synchronization of group movement may improve perception by providing periods of relative silence and by facilitating auditory processing. The adaptive value of such skills to early ancestors may have been keener detection of prey or stalkers and enhanced communication. Bipedal walking may have influenced the development of entrainment in humans and thereby the evolution of rhythmic abilities. © 2013 The Author(s).


Giske C.G.,Karolinska University Hospital | Giske C.G.,Karolinska Institutet
Clinical Microbiology and Infection | Year: 2015

Recently there has been a renewed interest in reviving older antimicrobial agents, particularly those with activity against multidrug-resistant Gram-negative bacilli. Because many such antimicrobials are not licensed in all countries, there is a paucity of international surveillance data, and none of these agents is part of any antimicrobial resistance surveillance on the level of the EU. Some of the agents are used in lower urinary tract infection, whereas most available supranational surveillance data pertain to severe infections such as bloodstream infections. Among old antimicrobial agents, the most interesting compounds from a clinical perspective are the two intravenous agents colistin and temocillin, the two oral agents pivmecillinam and nitrofurantoin, and fosfomycin, which is available both for intravenous and oral use. The most interesting target microorganisms are Enterobacteriaceae, although colistin also has good activity against Pseudomonas aeruginosa and Acinetobacter species. Recent European surveillance data point to approximately 5% resistance to colistin in general among Klebsiella pneumoniae, whereas resistance in carbapenemase-producing Enterobacteriaceae may be up to 15% to 20% in some settings. Temocillin is stable against many extended-spectrum β-lactamase-producing Enterobacteriaceae and some carbapenemase producers, but low-level resistance is not uncommon in extended-spectrum β-lactamase producers, and high-level resistance is always seen with OXA-48 group carbapenemases. Fosfomycin resistance is rare in areas with limited use but increasing is in countries with higher usage. Resistance levels to mecillinam and nitrofurantoin are generally low in EU countries, but clinical data supporting treatment efficacy of multidrug-resistant strains are few. Systematic surveillance of the above-mentioned agents will be important, particularly for those agents used in severe infections. © 2015 European Society of Clinical Microbiology and Infectious Diseases.


Abrams G.D.,Stanford University | Renstrom P.A.,Karolinska Institutet | Safran M.R.,Stanford University
British Journal of Sports Medicine | Year: 2012

Tennis is a popular sport with tens of millions of players participating worldwide. This popularity was one factor leading to the reappearance of tennis as a medal sport at the 1988 Summer Olympics in Seoul, South Korea. The volume of play, combined with the physical demands of the sports, can lead to injuries of the musculoskeletal system. Overall, injury incidence and prevalence in tennis has been reported in a number of investigations. The sport creates specific demands on the musculoskeletal system, with acute injuries, such as ankle sprains, being more frequent in the lower extremity while chronic overuse injuries, such as lateral epicondylitis, are more common in the upper extremity in the recreational player and shoulder pain more common in the high-level player. This review discusses the epidemiology of injuries frequently experienced in tennis players and examines some of these injuries' correlation with the development of osteoarthritis. In addition, player-specific factors, such as age, sex, volume of play, skill level, racquet properties and grip positions as well as the effect of playing surface on the incidence and prevalence of injury is reported. Finally, recommendations on standardisation of future epidemiological studies on tennis injuries are made in order to be able to more easily compare results of future investigations.


Torring O.,Karolinska Institutet
Therapeutic Advances in Musculoskeletal Disease | Year: 2015

Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor κB ligand and is a very potent antiresorptive drug. Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has been proven in a large prospective, randomized multicenter study of 7808 postmenopausal women with osteoporosis [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes somewhat greater increases in bone mineral density (BMD) than the class of bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass and bone strength in the spine, ultradistal and diaphysis of the radius, proximal tibia and the hip. Recently long-term treatment with denosumab has been shown to cause a continued almost linear increase in total hip and femoral neck BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ from the bisphosphonate group in which the rate of improvement of BMD diminishes and for some drugs becomes negative after 3–4 years when the process of secondary mineralization flattens out. This unique property of an antiresorptive drug points towards mechanisms of action which differ from the bisphosphonate group. Both types of antiresorptives decrease cortical porosity but contrary to bisphosphonates the reduction in cortical porosity continues with denosumab which, in addition, also seems to cause a slight continuous modeling-based formation of new bone despite suppression of bone remodeling. The net effect is an increase in cortical thickening and bone mass, and increased strength of cortical bone. This may contribute substantially to the significant further reduction of the nonvertebral fracture risk which was found in the long-term denosumab arm of the FREEDOM extension trial during years 4–7. © The Author(s), 2015


Romling U.,Karolinska Institutet | Galperin M.Y.,U.S. National Center for Biotechnology Information
Trends in Microbiology | Year: 2015

Recent studies of bacterial cellulose biosynthesis, including structural characterization of a functional cellulose synthase complex, provided the first mechanistic insight into this fascinating process. In most studied bacteria, just two subunits, BcsA and BcsB, are necessary and sufficient for the formation of the polysaccharide chain in vitro. Other subunits - which differ among various taxa - affect the enzymatic activity and product yield in vivo by modulating (i) the expression of the biosynthesis apparatus, (ii) the export of the nascent β-D-glucan polymer to the cell surface, and (iii) the organization of cellulose fibers into a higher-order structure. These auxiliary subunits play key roles in determining the quantity and structure of resulting biofilms, which is particularly important for the interactions of bacteria with higher organisms - leading to rhizosphere colonization and modulating the virulence of cellulose-producing bacterial pathogens inside and outside of host cells. We review the organization of four principal types of cellulose synthase operon found in various bacterial genomes, identify additional bcs genes that encode components of the cellulose biosynthesis and secretion machinery, and propose a unified nomenclature for these genes and subunits. We also discuss the role of cellulose as a key component of biofilms and in the choice between acute infection and persistence in the host. © 2015 Elsevier Ltd.


Aspenstrom P.,Karolinska Institutet
Small GTPases | Year: 2014

BAR proteins comprise a heterogeneous group of multi- domain proteins with diverse biological functions. The common denominator is the Bin-Amphiphysin-Rvs (BAR) domain that not only confers targeting to lipid bilayers, but also provides scaffolding to mold lipid membranes into concave or convex surfaces. This function of BAR proteins is an important determinant in the dynamic reconstruction of membrane vesicles, as well as of the plasma membrane. Several BAR proteins function as linkers between cytoskeletal regulation and membrane dynamics. These links are provided by direct interactions between BAR proteins and actinnucleation-promoting factors of the Wiskott-Aldrich syndrome protein family and the Diaphanous-related formins. The Rho GTPases are key factors for orchestration of this intricate interplay. This review describes how BAR proteins regulate the activity of Rho GTPases, as well as how Rho GTPases regulate the function of BAR proteins. This mutual collaboration is a central factor in the regulation of vital cellular processes, such as cell migration, cytokinesis, intracellular transport, endocytosis, and exocytosis. © 2014 Taylor & Francis Group, LLC.


Nedelcu R.G.,Karolinska Institutet | Persson A.S.K.,Nobel Biocare
Journal of Prosthetic Dentistry | Year: 2014

Statement of problem. Intraoral scanners may use proprietary acquisition and manufacturing processes. However, limited information is available regarding their accuracy, their precision, and the influence that refraction or coating may have on their output.Purpose. The purpose of the study was to evaluate the scanning accuracy and precision of 4 intraoral scanners and to assess the influence of different test materials and coating thicknesses.Material and methods. Models were fabricated in 3 materials (polymethyl methacrylate [Telio CAD], titanium, and zirconia) and reference scanned with an industrial optical scanner. The models were scanned with intraoral scanners (3M Lava COS, Cerec AC/Bluecam, E4D, and iTero). A thick layer of coating was applied and scanned (3M Lava COS). Further evaluation on a gypsum cast was undertaken for the E4D system. Data were evaluated by using 3-dimensional analysis with "3D compare" software commands (3D compare analysis) regarding standard, mean, and maximum deviations, with subsequent statistical analysis.Results. The 3M Lava COS, Cerec AC/Bluecam, and iTero generally displayed similar results regarding deviations. Maximum deviations, however, increased by several factors for the noncoating scanners (iTero and E4D). Statistical significance was found regarding material properties for noncoating scanners (P<.05). iTero displayed consistent material-specific, localized errors on the translucent material (Telio CAD). E4D showed the largest deviations. Scans of the gypsum cast displayed specific localized areas with greater deviations. Excessive coating was nonsignificant.Conclusions. Significant differences were found between the coating and noncoating scanners, and specific scanning errors for the system with parallel confocal microscopy were found for certain model materials. Specific areas of sizable deviations for the system with laser triangulation technology can be explained by the scanner design and noncoating technology. Excessive coating had no negative effect. © 2014 Editorial Council for the Journal of Prosthetic Dentistry.


Buschges A.,University of Cologne | Scholz H.,University of Cologne | El Manira A.,Karolinska Institutet
Current Biology | Year: 2011

Motor behaviour results from information processing across multiple neural networks acting at all levels from initial selection of the behaviour to its final generation. Understanding how motor behaviour is produced requires identifying the constituent neurons of these networks, their cellular properties, and their pattern of synaptic connectivity. Neural networks have been traditionally studied with neurophysiological and neuroanatomical approaches. These approaches have been highly successful in particularly suitable 'model' preparations, typically ones in which the numbers of neurons in the networks were relatively small, neural network composition was unvarying across individual animals, and the preparations continued to produce fictive motor patterns in vitro. However, analysing networks without these characteristics, and analysing the complete ensemble of networks that cooperatively generate behaviours, is difficult with these approaches. Recently developed molecular and neurogenetic tools provide additional avenues for analysing motor networks by allowing individual or groups of neurons within networks to be manipulated in novel ways and allowing experiments to be performed not only in vitro but also in vivo. We review here some of the new insights into motor network function that these advances have provided and indicate how these advances might bridge gaps in our understanding of motor control. To these ends, we first review motor neural network organisation highlighting cross-phylum principles. We then use prominent examples from the field to show how neurogenetic approaches can complement classical physiological studies, and identify additional areas where these approaches could be advantageously applied. © 2011 Elsevier Ltd. All rights reserved.


Haeggstrom J.Z.,Karolinska Institutet | Funk C.D.,Queens University
Chemical Reviews | Year: 2011

Lipoxygenase reactions are catalyzed by nonheme iron-containing dioxygenases, which introduce molecular oxygen into polyunsaturated fatty acids with one or more cis,cis-1,4-pentadiene moieties in the structure.5 9 Please also consult previous reviews. The iron is subsequently oxidized by electron transfer to the peroxy radical, generating a peroxy-anion, which subsequently is protonated to give the hydroperoxide and active enzyme. The hydrogen abstraction and insertion of oxygen occur on opposite sides of the substrate. Plant lipoxygenases have been extensively studied, and soybean lipoxygenase was purified and crystallized already in 1947. An S chirality of the hydroperoxide product was long believed to be a hallmark for a lipoxygenase-catalyzed reaction. However, it is now well established that lipoxygenases can also remove a pro-R hydrogen from the substrate with antarafacial insertion of oxygen to generate products with R chirality.


Antai D.,Karolinska Institutet
International Journal of Infectious Diseases | Year: 2012

Background: This study aimed to simultaneously examine the association between multiple dimensions of gender inequities and full childhood immunization. Methods: A multilevel logistic regression analysis was performed on nationally representative sample data from the 2008 Nigeria Demographic and Health Survey, which included 33385 women aged 15-49 years who had a total of 28647 live-born children; 24910 of these children were included in this study. Results: A total of 4283 (17%) children had received full immunization. Children of women whose spouse did not contribute to household earnings had a higher likelihood of receiving full childhood immunization (odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.02-3.77), and children of women who lacked decision-making autonomy had a lower likelihood of receiving full childhood immunization (OR 0.74, 95% CI 0.60-0.91). The likelihood of receiving full childhood immunization was higher among female children (OR 1.28, 95% CI 1.06-1.54), Yoruba children (OR 2.45, 95% CI 1.19-4.26), and children resident in communities with low illiteracy (OR 1.82, 95% CI 1.06-3.12), but lower for children of birth order 5 or above (OR 0.64, 95% CI 0.45-0.96), children of women aged ≤24 years (OR 0.66, 95% CI 0.50-0.87) and 25-34 years (OR 0.79, 95% CI 0.63-0.99), children of women with no education (OR 0.33, 95% CI 0.21-0.54) and primary education (OR 0.66, 95% CI 0.45-0.97), as well as children of women resident in communities with high unemployment (OR 0.34, 95% CI 0.20-0.57). Conclusions: The woman being the sole provider for her family (i.e., having a spouse who did not contribute to household earnings) was associated with a higher likelihood of fully immunizing the child, and the woman lacking decision-making autonomy was associated with a lower likelihood of fully immunizing the child. These findings draw attention to the need for interventions aimed at promoting women's employment and earning possibilities, whilst changing gender-discriminatory attitudes within relationships, communities, and society in general. © 2011 International Society for Infectious Diseases.


Fredholm B.B.,Karolinska Institutet
Journal of Molecular Medicine | Year: 2014

This minireview briefly summarizes the evidence that adenosine, acting on four G-protein coupled receptors, can play physiological roles, but is also critically involved in pathological processes. The factors that decide which of these is the more important in a specific cell or organ are briefly summarized. The fact that drugs that target adenosine receptors in disease will also hit the physiological processes will make drug development more tricky. © 2013 Springer-Verlag Berlin Heidelberg.


Johnsson P.,Karolinska Institutet | Morris K.V.,University of New South Wales | Morris K.V.,Scripps Research Institute
Cell Research | Year: 2014

New findings bring to light a previously unappreciated mechanism involved in the regulation of the oncoprotein MYC. Interesting observations find that the long noncoding RNA (lncRNA) PVT1 is active in controlling levels of MYC through regulation of MYC protein stability. © 2014 IBCB, SIBS, CAS.


We assessed if histidine-rich-protein-2 (HRP2) based rapid diagnostic test (RDT) remains an efficient tool for Plasmodium falciparum case detection among fever patients in Zanzibar and if primary health care workers continue to adhere to RDT results in the new epidemiological context of low malaria transmission. Further, we evaluated the performance of RDT within the newly adopted integrated management of childhood illness (IMCI) algorithm in Zanzibar. We enrolled 3890 patients aged ≥ 2 months with uncomplicated febrile illness in this health facility based observational study conducted in 12 primary health care facilities in Zanzibar, between May-July 2010. One patient had an inconclusive RDT result. Overall 121/3889 (3.1%) patients were RDT positive. The highest RDT positivity rate, 32/528 (6.1%), was found in children aged 5-14 years. RDT sensitivity and specificity against PCR was 76.5% (95% CI 69.0-83.9%) and 99.9% (95% CI 99.7-100%), and against blood smear microscopy 78.6% (95% CI 70.8-85.1%) and 99.7% (95% CI 99.6-99.9%), respectively. All RDT positive, but only 3/3768 RDT negative patients received anti-malarial treatment. Adherence to RDT results was thus 3887/3889 (99.9%). RDT performed well in the IMCI algorithm with equally high adherence among children <5 years as compared with other age groups. The sensitivity of HRP-2 based RDT in the hands of health care workers compared with both PCR and microscopy for P. falciparum case detection was relatively low, whereas adherence to test results with anti-malarial treatment was excellent. Moreover, the results provide evidence that RDT can be reliably integrated in IMCI as a tool for improved childhood fever management. However, the relatively low RDT sensitivity highlights the need for improved quality control of RDT use in primary health care facilities, but also for more sensitive point-of-care malaria diagnostic tools in the new epidemiological context of low malaria transmission in Zanzibar. ClinicalTrials.gov NCT01002066.


Innocenti G.M.,Karolinska Institutet | Vercelli A.,University of Turin | Caminiti R.,University of Rome La Sapienza
Cerebral Cortex | Year: 2014

In primates, different cortical areas send axons of different diameters into comparable tracts, notably the corpus callosum (Tomasi S, Caminiti R, Innocenti GM. 2012. Areal differences in diameter and length of corticofugal projections. Cereb Cortex. 22:1463-1472). We now explored if an area also sends axons of different diameters to different targets. We find that the parietal area PEc sends thicker axons to area 4 and 6, and thinner ones to the cingulate region (area 24). Areas 4 and 9, each sends axons of different diameters to the nucleus caudatus, to different levels of the internal capsule, and to the thalamus. The internal capsule receives the thickest axon, followed by thalamus and nucleus caudatus. The 2 areas (4 and 9) differ in the diameter and length of axons to corresponding targets. We calculated how diameter determines conduction velocity of the axons and together with pathway length determines transmission delays between different brain sites. We propose that projections from and within the cerebral cortex consist of a complex system of lines of communication with different geometrical and time computing properties. © The Author 2013.


Larsson S.C.,Karolinska Institutet
Current Opinion in Lipidology | Year: 2013

PURPOSE OF REVIEW: This review summarizes current epidemiologic evidence regarding the associations of dietary fat and other nutrients with risk of stroke. RECENT FINDINGS: Recent epidemiologic studies show no association of total fat intake or absolute intakes of saturated, monounsaturated, or polyunsaturated fat with risk of stroke. Data on long-chain omega-3 polyunsaturated fatty acids in relation to stroke risk are inconclusive but may favor fewer strokes in women. Insufficient evidence exists for trans fatty acids, other fatty acids, and dietary cholesterol intake. Present evidence indicates that high dietary magnesium and potassium intakes may lower the risk of stroke, whereas a high sodium (salt) intake and a low dietary vitamin D intake likely increase stroke risk. Calcium does not prevent stroke in populations with moderate-to-high calcium intakes but might play a role in populations with low calcium intakes. Supplementation with single vitamins likely has no protective effect on stroke in well nourished populations. SUMMARY: Available epidemiologic evidence indicates that diets high in magnesium and potassium may play a role in the prevention of stroke, whereas a high sodium intake is a risk factor. It remains unclear whether specific fatty acids, dietary cholesterol, and combinations of vitamins affect the risk of stroke. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Unintentional Childhood Injuries pose a major public health challenge in Africa and Uganda. Previous estimates of the problem may have underestimated the childhood problem. We set to determine unintentional childhood injury pattern, odds, and outcomes at the National Paediatric Emergency unit in Kampala city using surveillance data. Incident proportions, odds and proportional rates were calculated and used to determine unintentional injury patterns across childhood (1-12 years). A total of 556 cases recorded between January and May 2008 were analyzed: majority had been transported to hospital by mothers using mini-buses, private cars, and motorcycles. Median distance from injury location to hospital was 5 km. Homes, roads, and schools were leading injury locations. Males constituted 60% of the cases. Play and daily living activities were commonest injury time activities. Falls, burns and traffic accounted for 70.5% of unintentional childhood injuries. Burns, open wounds, fractures were commonest injury types. Motorcycles, buses and passenger-cars caused most crashes. Play grounds, furniture, stairs and trees were commonest source of falls. Most burn injuries were caused by liquids, fires and hot objects. 43.8% of cases were admitted. 30% were discharged without disability; 10%, were disabled; 1%, died. Injury odds and proportional incidence rates varied with age, place and cause. Poisoning and drowning were rare. Local pediatric injury priorities should include home, road and school safety. Unintentional injuries are common causes of hospital visit by children under 13 years especially boys. Homes, roads and educational facilities are commonest unintentional injury sites. Significant age and gender differences exist in intentional injury causation, characteristics and outcomes. In its current form, our surveillance system seems inefficient in capturing poisoning and drowning. The local prevention priorities could include home, road and school safety; especially dissemination and uptake of proven interventions. Burns should be focus of domestic injury prevention among under-fives. Commercial passenger motorcycles require better regulation and control.


Jakobsson L.,Karolinska Institutet | van Meeteren L.A.,University Utrecht
Experimental Cell Research | Year: 2013

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor Β (TGF-Β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-Β family in the mouse. © 2013 Elsevier Inc.


Gondor A.,Karolinska Institutet
Seminars in Cancer Biology | Year: 2013

The genome is dynamically organized in the nuclear space in a manner that reflects and influences nuclear functions. Developmental processes that govern the formation and maintenance of epigenetic memories are also tightly linked to adaptive changes in the physical and functional landscape of the nuclear architecture. Biological and biophysical principles governing the three-dimensional folding of chromatin are therefore central to our understanding of epigenetic regulation during adaptive responses and in complex diseases, such as cancer. Accumulating evidence points to the direction that global alterations in nuclear architecture and chromatin folding conspire with unstable epigenetic states of the primary chromatin fiber to drive the phenotypic plasticity of cancer cells. © 2013 Elsevier Ltd.


Cao Y.,Karolinska Institutet | Cao Y.,Linkoping University
Trends in Endocrinology and Metabolism | Year: 2013

Erythropoietin (EPO) is a frequently prescribed drug for treatment of cancer-related and chemotherapy-induced anemia in cancer patients. Paradoxically, recent preclinical and clinical studies indicate that EPO could potentially accelerate tumor growth and jeopardize survival in cancer patients. In this review I critically discuss the current knowledge and broad biological functions of EPO in association with tumor growth, invasion, and angiogenesis. The emphasis is focused on discussing the complex interplay between EPO and other tumor-derived factors in angiogenesis, tumor growth, invasion, and metastasis. Understanding the multifarious functions of EPO and its reciprocal relation with other signaling pathways is crucial for developing more effective agents for cancer therapy and for minimizing risks for cancer patients. © 2012 Elsevier Ltd.


Prostate cancer is one of the most heritable cancers in men, and recent genome-wide association studies have revealed numerous genetic variants associated with disease. The risk variants identified using case-control designs that compared unaffected individuals with all types of patients with prostate cancer show little or no ability to discriminate between indolent and fatal forms of this disease. This suggests different genetic components are involved in the initiation as compared with the prognosis of prostate cancer. Future studies contrasting patients with more and less aggressive disease, and exploring association with disease progression and prognosis, should be more effective in detecting genetic risk factors for prostate cancer outcome. © 2010 BioMed Central Ltd.


Klinge B.,Karolinska Institutet
European journal of oral implantology | Year: 2012

The aim of this narrative review was to explore and discuss marginal bone loss around transmucosal oral implants and the related incidence of this biologic complication. Treatment with osseointegrated implants is most often successful and improves the quality of life for the patient. At present only limited data are available to evaluate long-term technical and biological complications. When peri-implant tissue destruction occurs, little is known about the initiating process. Possible factors of relevance for the initiation and progression of peri-implantitis are discussed. Periodontitis, smoking and a variety of local factors are among the most plausible putative reported risk factors. Also, oral hygiene and the inability to clean the reconstruction were reported. The unit for reporting incidence of peri-implant bone loss varies in different studies between implants and patients. Since there seems to be a clustering effect, and implants in the same mouth cannot be considered independent from each other, it is recommended to use the patient as a unit. The different cut-off values for clinical parameters reported in different studies will exert a significant influence on the magnitude of the reported incidence of peri-implantitis. It is suggested that the composite variables including bone loss > or =2 mm, compared to initial radiographs at delivery of the prosthetic device, in combination with bleeding on probing should be interpreted as a 'red flag' for the clinician to critically evaluate if any intervention is indicated in the individual case. Until more solid scientific evidence has been made available, it is likely that the academic controversy in relation to peri-implant bone loss and peri-implantitis will continue.


Richardson J.,Royal Infirmary | Lnnqvist P.A.,Karolinska Institutet | Naja Z.,Makassed General Hospital
British Journal of Anaesthesia | Year: 2011

SummaryParavertebral nerve blocks (PVBs) can provide excellent intraoperative anaesthetic and postoperative analgesic conditions with less adverse effects and fewer contraindications than central neural blocks. Most published data are related to unilateral PVB, but its potential as a bilateral technique has been demonstrated. Bilateral PVB has been used successfully in the thoracic, abdominal, and pelvic regions, sometimes obviating the need for general anaesthesia. We have reviewed the use of bilateral PVB in association with surgery and chronic pain therapy. This covers 12 published studies with a total of 538 patients, and with varied methods and outcome measures. Despite the need for relatively large doses of local anaesthetics, there are no reports of systemic toxicity. The incidence of complications such as pneumothorax and hypotension is low. More studies on the use of bilateral PVB are required. © The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Kumar R.,Banaras Hindu University | Nylen S.,Karolinska Institutet
Frontiers in Immunology | Year: 2012

Visceral leishmaniasis (VL), commonly known as kala-azar, is caused by Leishmania donovani and Leishmania infantum (Leishmania chagasi in the Americas). These Leishmania species infect macrophages throughout the viscera, and parasites are typically found in the spleen, liver, and bone marrow. Patients with active disease typically exhibit marked immunosuppression, lack reactivity to the Leishmania skin test (LST), a delayed type hyper-sensitivity test, and their peripheral blood mononuclear cells (PBMC) fail to respond when stimulated with leishmanial antigens in vitro. However, most people infected with visceralizing species of Leishmania never develop disease. Understanding immune failure and the underlying immune mechanism that lead to disease as well as control of infection are key questions for research in this field. In this review, we discuss immunological events described in human and experimental VL and how these can affect the outcome of infection. © 2012 Kumar and Nylén.


Aims: While past research has shown that school performance is associated with some specific health outcomes in adulthood, few studies have taken a general approach to the link between school performance and adult disease. The aim of the present study was therefore to investigate sixth grade school performance in relation to disease-specific hospital care in adulthood and, moreover, to examine whether other conditions in childhood could account for any such associations. Methods: The data used was the Stockholm Birth Cohort, consisting of 14,294 individuals born in 1953. Associations between school performance and disease-specific hospital care were analysed by means of Cox regression. Results: Poor school performance was shown to be linked to a variety of diseases in adulthood, e.g. drug dependence, stomach ulcer, cerebrovascular diseases, and accidents. Some differences according to gender were found. Most associations, but not all, were explained by the simultaneous inclusion of various family-related and individual factors (e.g. social class, cognitive ability, and behavioural problems). Conclusions: In sum, the results of this study suggest that poor school performance may be an essential part of risk clustering in childhood with important implications for the individual's health career. © 2013 the Nordic Societies of Public Health.


Bjorksten B.,Karolinska Institutet
Vaccine | Year: 2012

Numerous epidemiological studies suggest that there is an inverse relationship between "immunologically mediated diseases of affluence", such as allergy, diabetes and inflammatory bowel disease on one hand and few infections encountered in early childhood, on the other hand. Careful analysis of the epidemiological, clinical and animal studies taken together, however, suggests that the protection is mediated by broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life, rather than by infections. Microbial exposure has little relationship with "hygiene" in the usual meaning of the word and the term "hygiene hypothesis" is therefore misleading. A better term would be "microbial deprivation hypothesis". The suggestion that childhood infections would protect against allergic disease led to unfortunate speculations that vaccinations would increase the risk for allergies and diabetes. Numerous epidemiological studies have therefore been conducted, searching for a possible relationship between various childhood vaccinations on one hand and allergy on the other hand. It is reasonable from these studies to conclude that vaccinations against infectious agents neither significantly increase, nor reduce the likelihood of immunologically mediated diseases. It is established that the postnatal maturation of immune regulation is largely driven by exposure to microbes. Germ free animals manifest excessive immune responses when immunised and they do not develop normal immune regulatory function. The gut is by far the largest source of microbial exposure, as the human gut microbiome contains up to 1014 bacteria, i.e. ten times the number of cells in the human body. Several studies in recent years have shown differences in the composition of the gut microbiota between allergic and non-allergic individuals and between infants living in countries with a low and a high prevalence of immune mediated diseases. The administration of probiotic bacteria to pregnant mothers and postnatal to their infants has immune modulatory effects. So far, however, probiotic bacteria do not seem to significantly enhance immune responses to vaccines. The potential to improve vaccine responses by modifying the gut microbiota in infants and the possibility to employ probiotic bacteria as adjuvants and/or delivery vehicles, is currently explored in several laboratories. Although to date few clinical results have been reported, experimental studies have shown some encouraging results. © 2011 Elsevier Ltd.


Antai D.,Karolinska Institutet
Journal of Epidemiology | Year: 2011

Background: Each ethnic group has its own cultural values and practices that widen inequalities in child health and survival among ethnic groups. This study seeks to examine the mediatory effects of ethnicity and socioeconomic position on under-5 mortality in Nigeria. Methods: Using multilevel logistic regression analysis of a nationally representative sample drawn from 7620 females age 15 to 49 years in the 2003 Nigeria Demographic and Health Survey, the risk of death in children younger than 5 years (under-5 deaths) was estimated using odds ratios with 95% confidence intervals for 6029 children nested within 2735 mothers who were in turn nested within 365 communities. Results: The prevalence of under-5 death was highest among children of Hausa/Fulani/Kanuri mothers and lowest among children of Yoruba mothers. The risk of under-5 death was significantly lower among children of mothers from the Igbo and other ethnic groups, as compared with children of Hausa/Fulani/Kanuri mothers, after adjustment for individual-and community-level factors. Much of the disparity in under-5 mortality with respect to maternal ethnicity was explained by differences in physician-provided community prenatal care. Conclusions: Ethnic differences in the risk of under-5 death were attributed to differences among ethnic groups in socioeconomic characteristics (maternal education and to differences in the maternal childbearing age and short birthspacing practices. These findings emphasize the need for community-based initiatives aimed at increasing maternal education and maternal health care services within communities. © 2010 by the Japan Epidemiological Association.


Winnersjo R.,Karolinska Institutet
Journal of injury & violence research | Year: 2012

Violence is a major public health problem. Both clinical and population based studies shows that violence against men and women has physical and psychological health consequences. However, elsewhere and in Sweden little is known of the effect of individual socioeconomic position (SEP) on the relation between violence and health outcomes. This study aimed to assess the effect of individual SEP on the relation between violence and three health outcomes (general health, pain and anxiety) among women in Stockholm County. The study used data from the Stockholm Public Health Survey, a cross-sectional survey carried out in 2006 for the Stockholm County Council by Statistic Sweden. 34 704 respondents answered the survey, the response rate was sixth one percent. Analyses were carried out using descriptive statistics and logistic regression analysis in SPSS v.17.0. Individual SEP increased the odds of reporting poor health outcomes among victimized women in Stockholm County. Regarding self-reported health women in low-SEP who reported victimization in the past twelve months had odds of 2,36 (95% CI 1.48-3.77) for the age group 18-29 years and 3.78 (95% CI 2.53-5.64) for the age group 30-44 years compared with women in high-SEP and non-victim. For pain the odds was 2,41 (95% CI 1,56-3,73) for the age group 18-29 years and 2,98 (95% CI 1,99-4,46) for women aged 30-44 years. Regarding anxiety the age group 18-29 years had odds of 2,53 (95% CI 1,58-4,03) and for the age group 30-44 years had odds of 3,87 (95% CI 2,55-5,87). Results showed that individual SEP (measured by occupation) matters to the relationship between violence and health outcomes such as general self-reported health, pain and anxiety. Women in lower SEP and experienced victimization in the past twelve months had increased odds of reporting poorer self-rated health, pain and anxiety compared to those in higher SEP with no experience of victimization. However, further exploration of the relationship between poverty, individual SEP is needed using other Swedish population samples.


Li D.,Karolinska Institutet
Journal of Investigative Dermatology | Year: 2015

Wound healing is a basic biological process restoring the integrity of the skin. The role of microRNAs during this process remains largely unexplored. By using an in vivo human skin wound healing model, we show here that the expression of miR-31 is gradually upregulated in wound edge keratinocytes in the inflammatory (1 day after injury) through the proliferative phase (7 days after injury) in comparison with intact skin. In human primary keratinocytes, overexpression of miR-31 promoted cell proliferation and migration, whereas inhibition of miR-31 had the opposite effects. Moreover, we identified epithelial membrane protein 1 (EMP-1) as a direct target of miR-31 in keratinocytes. The expression of EMP-1 in the skin was negatively correlated with the level of miR-31 during wound healing. Silencing of EMP-1 mimicked the effects of overexpression of miR-31 on keratinocyte proliferation and migration, indicating that EMP-1 is a critical target mediating the functions of miR-31 in keratinocytes. Finally, we demonstrated that transforming growth factor-β2, which is highly expressed in skin wounds, upregulated miR-31 expression in keratinocytes. Collectively, we identify miR-31 as a key regulator for promoting keratinocyte proliferation and migration during wound healing.Journal of Investigative Dermatology advance online publication, 12 March 2015; doi:10.1038/jid.2015.48. © 2015 The Society for Investigative Dermatology, Inc


Ehrenborg E.,Karolinska University Hospital | Skogsberg J.,Karolinska Institutet
Atherosclerosis | Year: 2013

Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD). Specific human PPARD gene variants show no clear association with CVD but interactions between variants and lifestyle factors might influence disease risk. During recent years, development of specific and potent PPARD agonists has also made it possible to study the effects of PPARD activation in humans. PPARD agonists seem to exert beneficial effects on dyslipidemia and insulin-resistant syndromes but safety issues have been raised due to the role that PPARD plays in cell proliferation. Thus, large long term outcome as well as detailed safety and tolerability studies are needed to evaluate whether PPARD agonists could be used to treat CVD in humans. © 2013 Elsevier Ireland Ltd.


Kimsey I.J.,Duke University | Petzold K.,Karolinska Institutet | Sathyamoorthy B.,Duke University | Stein Z.W.,University of Michigan | Al-Hashimi H.M.,Duke University
Nature | Year: 2015

Rare tautomeric and anionic nucleobases are believed to have fundamental biological roles, but their prevalence and functional importance has remained elusive because they exist transiently, in low abundance, and involve subtle movements of protons that are difficult to visualize. Using NMR relaxation dispersion, we show here that wobble dG.dT and rG.rU mispairs in DNA and RNA duplexes exist in dynamic equilibrium with short-lived, low-populated Watson-Crick-like mispairs that are stabilized by rare enolic or anionic bases. These mispairs can evade Watson-Crick fidelity checkpoints and form with probabilities (10-3 to 10-5) that strongly imply a universal role in replication and translation errors. Our results indicate that rare tautomeric and anionic bases are widespread in nucleic acids, expanding their structural and functional complexity beyond that attainable with canonical bases. © 2015 Macmillan Publishers Limited All rights reserved.


Betsholtz C.,Uppsala University | Betsholtz C.,Karolinska Institutet
Nature Genetics | Year: 2015

How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma. © 2015 Nature America, Inc. All rights reserved.


Falck-Ytter T.,Karolinska Institutet | Falck-Ytter T.,Uppsala University
Journal of Neurophysiology | Year: 2012

In support for the direct-matching hypothesis, Ambrosini et al. (2011) recently reported that goal-directed saccades during action observation were modulated by manipulations of basic motor information. This finding indicates that motor programs, activated by low-level visual descriptions of others' actions, are involved in predicting other people's action goals. Here, I put this result into a broader context, review alternative interpretations, and suggest strategies for future studies. © 2012 the American Physiological Society.


Barros R.P.A.,University of Houston | Gustafsson J.-A.,University of Houston | Gustafsson J.-A.,Karolinska Institutet
Cell Metabolism | Year: 2011

The metabolic syndrome has reached pandemic level worldwide, and evidence is that estradiol plays a key role in its development. The discovery of the second estrogen receptor, ERβ, in tissues previously not considered targets of estradiol was a breakthrough in endocrinology. In the present review, we discuss how the presence of ERβ and the previously described ERα in tissues involved in glucose and lipid homeostasis (brain, skeletal muscle, adipose tissue, pancreas, liver, and heart) may have important implications to risk factors associated with the metabolic syndrome. Imbalance of ERα/ERβ ratio in this "metabolic network" may lead to the metabolic syndrome. © 2011 Elsevier Inc.


Kasuga K.,Karolinska Institutet
Methods in Molecular Biology | Year: 2013

Major histocompatibility complexes (MHC) are expressed on antigen-presenting cells (APC) that display peptide antigens. This is a crucial step to activate a T-cell response. Since immunogenic ligand of MHC is closely related with autoimmunity, inflammatory diseases, and cancer, comprehensive analysis of MHC ligands (the so-called Ligandome) is essential to unveil disease pathogenesis. Recently, immunotherapies such as vaccination have been focused on as new therapies of cancer, HIV, and infectious diseases. Therefore, the importance of comprehensive analysis of MHC ligands is increasing. Mass spectrometry has been the core technology of ligand identification since the 1990s. The sensitivity of mass spectrometers has been improved dramatically in recent years; thus, it enables to identify MHC ligands in clinical materials. This chapter lays out the workflow of MHC ligand identification in clinical materials, especially human bronchoalveolar (BAL) cells. MHC-ligand complexes are enriched by immunoaffinity extraction and captured ligand peptides are identified by LC-MS/MS. MHC class II ligand in BAL cells is described in this text; however, this approach is applicable to MHC class I and other clinical materials such as tissues. © Springer Science+Business Media New York 2013.


Sederholm M.,Karolinska Institutet
Journal of Electrocardiology | Year: 2014

The continuous change of the ST and QRS vectorcardiograms reflect the underlying ischemic event, and can be used as a tool in the management of the acute event. It also reflects reperfusion, and can guide the clinician on when and how to intervene. Continuous vectorcardiography has proven to add prognostic information, both in the acute phase (can be used already in the ambulance during transportation to CCU) and after discharge from hospital. This paper reviews the origin of continous vectorcardiography as a monitoring device in AMI, including the follow-up research until today. © 2014 Published by Elsevier Inc.


Kimby E.,Karolinska Institutet
Blood | Year: 2015

In this issue of Blood, Mir et al present data on the prognostic role of cytokines, chemokines, and their ligands measured in serum in patients with follicular lymphoma (FL).1 This lymphoma has a variable course, and reliable markers for predicting outcome are needed.


Emsley P.,University of Oxford | Lohkamp B.,Karolinska Institutet | Scott W.G.,University of California at Santa Cruz | Cowtan K.,University of York
Acta Crystallographica Section D: Biological Crystallography | Year: 2010

Coot is a molecular-graphics application for model building and validation of biological macromolecules. The program displays electron-density maps and atomic models and allows model manipulations such as idealization, real-space refinement, manual rotation/translation, rigid-body fitting, ligand search, solvation, mutations, rotamers and Ramachandran idealization. Furthermore, tools are provided for model validation as well as interfaces to external programs for refinement, validation and graphics. The software is designed to be easy to learn for novice users, which is achieved by ensuring that tools for common tasks are discoverable through familiar user-interface elements (menus and toolbars) or by intuitive behaviour (mouse controls). Recent developments have focused on providing tools for expert users, with customisable key bindings, extensions and an extensive scripting interface. The software is under rapid development, but has already achieved very widespread use within the crystallographic community. The current state of the software is presented, with a description of the facilities available and of some of the underlying methods employed.


Innocenti G.M.,Karolinska Institutet | Vercelli A.,University of Turin
Frontiers in Neuroanatomy | Year: 2010

The search for the fundamental building block of the cerebral cortex has highlighted three structures, perpendicular to the cortical surface: (i) columns of neurons with radially invariant response properties, e.g., receptive field position, sensory modality, stimulus orientation or direction, frequency tuning etc., (ii) minicolumns of radially aligned cell bodies and (iii) bundles, constituted by the apical dendrites of pyramidal neurons with cell bodies in different layers. The latter were described in detail, and sometimes quantitatively, in several species and areas. It was recently suggested that the dendritic bundles consist of apical dendrites belonging to neurons projecting their axons to specific targets. We review the concept above and suggest that another structural and computational unit of cerebral cortex is the cortical output unit, i.e., an assembly of bundles of apical dendrites and their parent cell bodies including each of the outputs to distant cortical or subcortical structures, of a given cortical locus (area or part of an area). This somato-dendritic assembly receives inputs some of which are common to the whole assembly and determine its radially invariant response properties, others are specific to one or more dendritic bundles, and determine the specific response signature of neurons in the different cortical layers and projecting to different targets. © 2010 Innocenti and Vercelli.


High sample complexity is one of the major challenges in mass spectrometry-based proteomics today. Despite massive improvement in instrumentation, sample prefractionation is still needed to reduce sample complexity and improve proteome coverage. Isoelectric focusing (IEF) has been traditionally used as a first-dimension protein separation technique in two-dimensional gel electrophoresis-based proteomics. Recently, peptide IEF has emerged as appealing alternative for anion exchange chromatography in multidimensional LC-MS/MS workflows. The rationale behind using narrow-range peptide isoelectric focusing as a prefractionation method prior to ms/ms is to reduce the complexity induced by tryptic digestion. This is done by selectively analyzing a sub-fraction of peptides with an acidic pI. The pI range is chosen as it has previously been shown that 96 % of human proteins have at least one tryptic peptide between pH 3.4 and 4.9. This ensures high proteome coverage while reducing the number of peptides with 2/3. In addition the focusing precision is optimal in this range. Therefore, by analyzing this sub-fraction of peptides the complexity of the sample can be reduced without significant loss of proteome coverage. As the theoretical pI of peptides can be calculated, the pI of the identified peptides can be used to validate the peptide sequence (identified peptides with pI outside the pH range 3.4-4.9 are more likely to be false positives). In addition, this approach is compatible with iTRAQ labelling as the different iTRAQ labels migrate similarly in IEF. © Springer Science+Business Media New York 2013.


Burglin T.R.,Karolinska Institutet
Sub-Cellular Biochemistry | Year: 2011

The homeodomain is a protein domain of about 60 amino acids that is encoded by homeobox genes. The homeodomain is a DNA binding domain, and hence homeodomain proteins are essentially transcription factors (TFs). They have been shown to play major roles in many developmental processes of animals, as well as fungi and plants. A primary function of homeodomain proteins is to regulate the expression of other genes in development and differentiation. Thousands of homeobox genes have been identified, and they can be grouped into many different classes. Often other conserved protein domains are found linked to a homeodomain. Several particular types of homeobox genes are organized into chromosomal clusters. The best-known cluster, the HOX cluster, is found in all bilaterian animals. Tetrapods contain four HOX clusters that arose through duplication in early vertebrate evolution. The genes in these clusters are called Hox genes. Lower chordates, insects and nematodes tend to have only one HOX cluster. Of particular interest is that many of the HOX cluster genes function in the process of pattern formation along the anterior-posterior body axis. Many other types of homeodomain proteins play roles in the determination of cell fates and cell differentiation. Homeobox genes thus perform key roles for all aspects of the development of an organism. © Springer Science+Business Media B.V. 2011.


Franco R.,University of Barcelona | Franco R.,CIBER ISCIII | Fernandez-Suarez D.,Karolinska Institutet
Progress in Neurobiology | Year: 2015

Macrophages are important players in the fight against viral, bacterial, fungal and parasitic infections. From a resting state they may undertake two activation pathways, the classical known as M1, or the alternative known as M2. M1 markers are mostly mediators of pro-inflammatory responses whereas M2 markers emerge for resolution and cleanup. Microglia exerts in the central nervous system (CNS) a function similar to that of macrophages in the periphery. Microglia activation and proliferation occurs in almost any single pathology affecting the CNS. Often microglia activation has been considered detrimental and drugs able to stop microglia activation were considered for the treatment of a variety of diseases. Cumulative evidence shows that microglia may undergo the alternative activation pathway, express M2-type markers and contribute to neuroprotection. This review focuses on details about the role of M2 microglia and in the approaches available for its identification. Approaches to drive the M2 phenotype and data on its potential in CNS diseases are also reviewed. © 2015 Elsevier Ltd.


Fernandez de la Cruz L.,Karolinska Institutet
Molecular Psychiatry | Year: 2016

The risk of death by suicide in individuals with obsessive–compulsive disorder (OCD) is largely unknown. Previous studies have been small and methodologically flawed. We analyzed data from the Swedish national registers to estimate the risk of suicide in OCD and identify the risk and protective factors associated with suicidal behavior in this group. We used a matched case–cohort design to estimate the risk of deaths by suicide and attempted suicide in individuals diagnosed with OCD, compared with matched general population controls (1:10). Cox regression models were used to study predictors of suicidal behavior. We identified 36 788 OCD patients in the Swedish National Patient Register between 1969 and 2013. Of these, 545 had died by suicide and 4297 had attempted suicide. In unadjusted models, individuals with OCD had an increased risk of both dying by suicide (odds ratio (OR)=9.83 (95% confidence interval (CI), 8.72–11.08)) and attempting suicide (OR=5.45 (95% CI, 5.24–5.67)), compared with matched controls. After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial for both death by suicide and attempted suicide. Within the OCD cohort, a previous suicide attempt was the strongest predictor of death by suicide. Having a comorbid personality or substance use disorder also increased the risk of suicide. Being a woman, higher parental education and having a comorbid anxiety disorder were protective factors. We conclude that patients with OCD are at a substantial risk of suicide. Importantly, this risk remains substantial after adjusting for psychiatric comorbidities. Suicide risk should be carefully monitored in patients with OCD.Molecular Psychiatry advance online publication, 19 July 2016; doi:10.1038/mp.2016.115. © 2016 The Author(s)


Vonderschen K.,Karolinska Institutet | Wagner H.,RWTH Aachen
Trends in Neurosciences | Year: 2014

Interaural time differences (ITDs) represent an important cue in sound localization and auditory scene analysis. To assess this cue the auditory system internally delays binaural inputs to compensate for the outer delay, before neurons in the brainstem detect the coincident arrival of the inputs from the two ears. Different origins of internal delays have been controversially discussed and have given rise to conflicting interpretations of the ITD representation ensuing from coincidence detection. Yet, recent findings indicate that ITD representations undergo substantial transformations or remodeling after the detection step. Here we treat the detection step separately from remodeling, and explain why a similar representation of ITD across species may exist in the forebrain despite differences in detection and representation in the midbrain. © 2014 Elsevier Ltd.


Blanchart A.,Karolinska Institutet
Oncogene | Year: 2016

Although genome alterations driving glioma by fueling cell malignancy have largely been resolved, less is known of the impact of tumor environment on disease progression. Here, we demonstrate functional GABAA receptor-activated currents in human glioblastoma cells and show the existence of a continuous GABA signaling within the tumor cell mass that significantly affects tumor growth and survival expectancy in mouse models. Endogenous GABA released by tumor cells, attenuates proliferation of the glioma cells with enriched expression of stem/progenitor markers and with competence to seed growth of new tumors. Our results suggest that GABA levels rapidly increase in tumors impeding further growth. Thus, shunting chloride ions by a maintained local GABAA receptor activity within glioma cells has a significant impact on tumor development by attenuating proliferation, reducing tumor growth and prolonging survival, a mechanism that may have important impact on therapy resistance and recurrence following tumor resection.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.245. © 2016 Macmillan Publishers Limited


Stenvinkel P.,Karolinska Institutet
Journal of Renal Nutrition | Year: 2011

Although hyperadiponectinemia is a common phenomenon in chronic kidney disease and is considered to have similar beneficial effects on metabolic risk in this patient group, many recent studies in general population have unexpectedly shown that high, rather than low, concentrations predict mortality. However, the apparent unfavorable effect of high adiponectin might not necessarily be exclusively or partially related to a direct effect of adiponectin, but rather it could be a consequence of a concurrent process of wasting (or pathogenic pathways linked to the wasting process) which may increase adiponectin levels. It is also possible that elevated circulating adiponectin levels mirror a state of volume and salt overload because natriuretic peptides and high salt intake were recently shown to stimulate secretion of adiponectin. Until nutritional and pharmacological treatment strategies that increase adiponectin in uremic patients can be advocated nephrologists have an important task to unravel the observed paradoxes. © 2011 National Kidney Foundation, Inc.


Orrevall Y.,Karolinska Institutet
Nutrition | Year: 2015

For patients with cancer at the end of life the goal of nutritional care is to optimize quality of life and comfort. Food and drink should be served as requested by the patient but without exerting pressure. For patients who have developed cachexia and are potentially candidates to receive artificial nutrition, discussions between the patient, family and health care team are needed to set the goals of nutritional care, considering both the risk of adverse effects of the treatment and ethical issues. The premise for a benefit from parenteral nutrition is that survival of the tumor spread exceeds that of starvation (usually by about 2-3 months). © 2015 Elsevier Inc.


Hukasova E.,Karolinska Institutet
Journal of visualized experiments : JoVE | Year: 2012

Förster resonance energy transfer (FRET)-based reporters(1) allow the assessment of endogenous kinase and phosphatase activities in living cells. Such probes typically consist of variants of CFP and YFP, intervened by a phosphorylatable sequence and a phospho-binding domain. Upon phosphorylation, the probe changes conformation, which results in a change of the distance or orientation between CFP and YFP, leading to a change in FRET efficiency (Fig 1). Several probes have been published during the last decade, monitoring the activity balance of multiple kinases and phosphatases, including reporters of PKA(2), PKB(3), PKC(4), PKD(5), ERK(6), JNK(7), Cdk(18), Aurora B(9) and Plk1(9). Given the modular design, additional probes are likely to emerge in the near future(10). Progression through the cell cycle is affected by stress signaling pathways( 11). Notably, the cell cycle is regulated differently during unperturbed growth compared to when cells are recovering from stress(12).Time-lapse imaging of cells through the cell cycle therefore requires particular caution. This becomes a problem particularly when employing ratiometric imaging, since two images with a high signal to noise ratio are required to correctly interpret the results. Ratiometric FRET imaging of cell cycle dependent changes in kinase and phosphatase activities has predominately been restricted to sub-sections of the cell cycle(8,9,13,14). Here, we discuss a method to monitor FRET-based probes using ratiometric imaging throughout the human cell cycle. The method relies on equipment that is available to many researchers in life sciences and does not require expert knowledge of microscopy or image processing.


Sandhu K.S.,Karolinska Institutet
Epigenetics | Year: 2010

Genomically imprinted genes show parentally fixed mono-allelic expression and are important for the mammalian development. Dysregulation of genomic imprinting leads to several complex pathological conditions. Though the genetic and epigenetic regulation of imprinted genes has been well studied, their protein aspects are largely ignored. Here, we systematically studied a sub-network centered on proteins encoded by imprinted genes within human interactome. Using concepts of network biology, we uncover a highly connected, transitive and central network module of imprinted gene-products and their interacting partners (IGPN). The network is enriched in development, metabolism and cell cycle related functions and its malfunctioning ascribes error intolerance to human interactome network. Further, detailed analysis revealed that its higher centrality is determined by 'date' interactions among the proteins belonging to different functional classes than the 'party' interactions within the same functional class. Interestingly, a significant proportion of this network genetically associates with disease phenotypes. Moreover, the network comprises of gene-sets that are upregulated in leukemia, psychosis, obesity/diabetes and downregulated in autism. We conclude that imprinted gene-products are part of a functionally and topologically important module of human interactome and errors in this sub-network are intolerant to otherwise robust human interactome. The findings might also shed light on how imprinted genes, which are rather very few, coordinate at protein level to pleiotropically regulate growth and metabolism during embryonic and post-natal development. © 2010 Landes Bioscience.


Soderberg-Naucler C.,Karolinska Institutet
Expert Review of Anti-Infective Therapy | Year: 2014

Human cytomegalovirus is a common virus that establishes latency and persistence after a primary infection in 50-90% of populations worldwide. In otherwise healthy persons, the infection is generally mild or asymptomatic, although it may cause mononucleosis, prolonged episodes of fever, and hepatitis. However, in AIDS patients and transplant recipients who are immunosuppressed, severe, life-threatening infections may develop. CMV is also the most common congenital infection and may cause birth defects and deafness. Emerging evidence shows a high prevalence of this virus in patients with chronic inflammatory diseases or tumours of different origin, such as breast, colon, and prostate cancer, neuroblastoma, medulloblastoma, and glioblastoma. Several drugs are available to treat CMV infections. This review will highlight the possibility of using anti-CMV therapy to improve outcome not only in patients with acute CMV infections but also in patients with inflammatory diseases and cancer. © 2014 Informa UK Ltd.


Johannessen Landmark C.,Oslo University College | Johannessen S.I.,University of Oslo | Tomson T.,Karolinska Institutet
Advanced Drug Delivery Reviews | Year: 2012

Antiepileptic drugs (AEDs) are the mainstay in the treatment of epilepsy, one of the most common serious chronic neurological disorders. AEDs display extensive pharmacological variability between and within patients, and a major determinant of differences in response to treatment is pharmacokinetic variability. Host factors affecting AED delivery may be defined as the pharmacokinetic characteristics that determine the AED delivery to the site of action, the epileptic focus. Individual differences may occur in absorption, distribution, metabolism and excretion. These differences can be determined by genetic factors including gender and ethnicity, but the pharmacokinetics of AEDs can also be affected by age, specific physiological states in life, such as pregnancy, or pathological conditions including hepatic and renal insufficiency. Pharmacokinetic interactions with other drugs are another important source of variability in response to AEDs. Pharmacokinetic characteristics of the presently available AEDs are discussed in this review as well as their clinical implications. © 2011 Elsevier B.V.


Treuter E.,Karolinska Institutet | Venteclef N.,French Institute of Health and Medical Research
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

Nuclear receptors (NRs) exert crucial functions in controlling metabolism and inflammation by both positively and negatively regulating gene expression. Recent evidence suggests that the transcriptional activities of many NRs can be modulated and even re-directed through post-translational modification by small ubiquitin-related modifiers (SUMO). SUMOylation triggers a plethora of diverse molecular events that can alter both the fate and function of modified NRs at the nongenomic, genomic, and epigenomic level. However, it is the intriguing link of SUMOylation to transcriptional repression, and in particular to transrepression, that has emerged as a common underlying mechanism that impacts on biological processes controlled by NRs. It further appears that the cell-type-specific SUMOylation status of NRs can be regulated by ligands and by signal-dependent crosstalk of post-translational modifications. Given the causal role of altered NR signaling in the development and pathogenesis of human diseases, it is likely that aberrant SUMO conjugation, deconjugation, or interpretation contributes to these alterations. Here, we review the current progress made in both the study and understanding of the molecular mechanisms and consequences of NR SUMOylation and also discuss the physiological and pharmacological implications with a particular focus on transrepression pathways that link metabolism and inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. © 2010 Elsevier B.V.


Bonn S.E.,Karolinska Institutet
Journal of medical Internet research | Year: 2012

Increased use of the Internet provides new opportunities for collecting data in large studies. The aim of our new Web-based questionnaire, Active-Q, is to assess total physical activity and inactivity in adults. Active-Q assesses habitual activity during the past year via questions in four different domains: (1) daily occupation, (2) transportation to and from daily occupation, (3) leisure time activities, and (4) sporting activities. The objective of our study is to validate Active-Q's energy expenditure estimates using the doubly labeled water (DLW) method, and to assess the reproducibility of Active-Q by comparing the results of the questionnaire completed by the same group on two occasions. The validity and reproducibility of Active-Q were assessed in a group of 37 individuals, aged 20 to 65 years. Active-Q was distributed via email to the participants. The total energy expenditure of the participants was assessed using DLW for 11 consecutive days. The median time to complete Active-Q was 6.1 minutes. The majority of participants (27/37, 73%) reported that the questionnaire was "easy" or "very easy" to answer. On average, Active-Q overestimated the total daily energy expenditure by 440 kJ compared with the DLW. The Spearman correlation between the two methods was r = 0.52 (P < .001). The intraclass correlation coefficient for total energy expenditure between the results of Active-Q completed on two occasions was 0.83 (95% CI 0.73-0.93). Active-Q is a valid and reproducible method of assessing total energy expenditure. It is also a user-friendly method and suitable for Web-based data collection in large epidemiological studies.


Lal M.,Karolinska Institutet | Caplan M.,Yale University
Physiology | Year: 2011

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process. Several enzymes capable of releasing domains of integral membrane proteins have been described. Transmembrane protein proteo-lytic cleavage is regulated and involved not only in degrading membrane spanning segments but also in generating messengers that elicit biological responses. This review examines the role of the released functional protein domain in signaling mechanisms regulating an array of cellular and physiological processes. © 2011 Int. Union Physiol. Sci./Am. Physiol. Soc.


Grossniklaus H.E.,Emory University | Kang S.J.,Emory University | Berglin L.,Karolinska Institutet
Progress in Retinal and Eye Research | Year: 2010

There have been numerous types of animal models of choroidal neovascularization (CNV) and retinal neovascularization (RNV). Understanding the pathobiology of CNV and RNV is important when evaluating and utilizing these models. Both CNV and RNV are dynamic processes. A break or defect in Bruchs' membrane is necessary for CNV to develop. This may be induced with a laser, mechanically via surgery, or in the setting of transgenic mice. Some of the transgenic mouse models spontaneously develop RNV and/or retinal angiomatous proliferation (RAP)-like lesions. The pathogenesis of RNV is well-known and is generally related to ischemic retinopathy. Models of oxygen-induced retinopathy (OIR) closely resemble retinopathy of prematurity (ROP). The streptozotocin (STZ) rat model develops features similar to diabetic retinopathy. This review summarizes general categories and specific examples of animal models of CNV and RNV. There are no perfect models of CNV or RNV and individual investigators are encouraged to choose the model that best suits their needs. © 2010 Elsevier Ltd.


Whitington T.,Karolinska Institutet
Nature Genetics | Year: 2016

Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Soussi T.,Karolinska Institutet | Soussi T.,University Pierre and Marie Curie
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2011

Tumor sequencing projects have been initiated over the last decade with the promising goal of identifying novel cancer genes and potential therapeutic targets. One of the unexpected findings of these projects was the discovery that cancer genomes contain thousands of passenger mutations that are irrelevant to tumor development and are coselected by a small number of driver mutations that constitute the true selection power in cancer progression. Although often discarded and considered to be irrelevant, the value of passenger mutations should not be underestimated, as they are the most important markers of the exposure to various carcinogens and are essential to assess the etiology of individual tumors.Over the last century, the history of cancer epidemiology evolved in different stages and concepts from occupational observational studies beginning in the 18th century, in vitro and in vivo experimental analyses and cancer gene analyses, such as Ha-ras or TP53. Mutation spectra of passenger mutations from various types of cancers not only confirm the findings of molecular epidemiology analysis, but also reveal novel profiles that will extend this knowledge to single tumors in all types of cancer. © 2011 Elsevier B.V.


Klingberg T.,Karolinska Institutet
Trends in Cognitive Sciences | Year: 2014

Theories view childhood development as being either driven by structural maturation of the brain or being driven by skill-learning. It is hypothesized here that working memory (WM) development during childhood is partly driven by training effects in the environment, and that similar neural mechanisms underlie training-induced plasticity and childhood development. In particular, the functional connectivity of a fronto-parietal network is suggested to be associated with WM capacity. The striatum, dopamine receptor D2 (DRD2) activity, and corticostriatal white-matter tracts, on the other hand, seem to be more important for plasticity and change of WM capacity during both training and development. In this view, the development of WM capacity during childhood partly involves the same mechanisms as skill-learning. © 2014 Elsevier Ltd.


McInerney G.M.,Karolinska Institutet
DNA and Cell Biology | Year: 2015

RNA stress granules (SGs) represent a cell-intrinsic antiviral defense mechanism. The assembly of SGs in response to viral infection is coordinated by the cellular protein G3BP, which is targeted by many viruses to block SG formation. We recently showed that proteins containing the short linear motif Phe-Gly-Asp-Phe (FGDF), bind G3BP in a hydrophobic groove on the surface of the nuclear transport factor-2-like domain. Binding in this manner blocks the ability of G3BP to form SGs and allows efficient replication of viruses carrying this motif. Copyright © Mary Ann Liebert, Inc. 2015.


Zaravinos A.,Karolinska Institutet
Journal of Oncology | Year: 2015

The epithelial to mesenchymal transition (EMT) is a powerful process in tumor invasion, metastasis, and tumorigenesis and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells. It is now well known that miRNAs are important regulators of malignant transformation and metastasis. The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated. The metastasis suppressive role of the miR-200 members is strongly associated with a pathologic EMT. This review describes the most recent advances regarding the influence of miRNAs in EMT and the control they exert in major signaling pathways in various cancers. The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed. Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways. The link between cancer stem cells and EMT is also reported and the most recent developments regarding clinical trials that are currently using anti-miRNA constructs are further discussed. © 2015 Apostolos Zaravinos.


Tomson T.,Karolinska Institutet | Battino D.,Neurological Institute Carlo Besta Foundation
The Lancet Neurology | Year: 2012

Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed. © 2012 Elsevier Ltd.


Cao Y.,Karolinska Institutet
International Journal of Developmental Biology | Year: 2011

The tumor vasculature is an increasingly attractive target for development of anticancer drugs. The fundamental principle for antiangiogenic cancer therapy is based on the inhibitory effect of chemical compounds, proteins or nucleotides on tumor angiogenesis. Indeed, in almost all preclinical tumor models, antiangiogenic monotherapy with different agents shows potent effects on suppression of tumor growth. However, antiangiogenic monotherapy has barely produced any clinical benefits in cancer patients. Although in combination with chemotherapy some antiangiogenic drugs demonstrate survival improvement in patients with certain types of cancers, the overall benefits by addition of antiangiogenic drugs (ADs) to chemotherapy remain modest. The disparity of AD responses between preclinical models and clinical cancer patients has raised important issues, which include: 1) Are current animal tumor models appropriate for assessing the therapeutic efficacy of ADs for clinical development? 2) What are the key differences between mouse tumor models and human cancer patients? 3) Are anti-VEGF drugs off target in cancer patients? 4) What are alternative options for improvement of the clinical benefits of ADs? In this short review, I discuss these critical issues in relation to the clinical practice of ADs. © 2011 UBC Press.


Bohm-Starke N.,Karolinska Institutet
Acta Obstetricia et Gynecologica Scandinavica | Year: 2010

Vulvodynia in young women is a significant clinical challenge. This overview focuses on localized provoked vulvodynia (LPV) with regard to medical and physical predictors of the condition. Several causative factors have been proposed and one major conceptual issue is the role of inflammation. Trauma to the vestibular mucosa causes an initial inflammatory response which may result in peripheral and central pain sensitization. In women with LPV, evidence of mucosal nerve fiber proliferation and enhanced systemic pain perception has been found. A dysfunction of the pelvic floor muscles is common and many patients also suffer from other bodily pain. In general, the level of scientific quality in published studies on vulvodynia is low. Further research on epidemiology, etiology and conduction of clinical trials with high evidence grade is desired. © 2010 Informa Healthcare.


Chen J.-F.,Boston University | Eltzschig H.K.,Aurora University | Fredholm B.B.,Karolinska Institutet
Nature Reviews Drug Discovery | Year: 2013

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors-either directly or indirectly-have now entered the clinic. However, only one adenosine receptor-specific agent-the adenosine A 2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)-has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.


Strom O.,Karolinska Institutet | Landfeldt E.,OptumInsight
Osteoporosis International | Year: 2012

Summary Automatic generic substitution of alendronate products, used to reduce drug costs, and medication persistence was studied retrospectively between 2006 and 2009. During this period the number of, and the rate of substitution between, alendronate products increased while persistence decreased. Patient preferences should be considered when designing and evaluating generic policies. Introduction Automatic generic substitution (AGS) was implemented in Sweden in 2002. The objective of this study was to investigate the association between AGS and persistence with alendronate treatment of primary osteoporosis in Sweden. Methods An open historical cohort of women and men (n= 36,433) was identified in the Swedish Prescribed Drug Register through filled prescriptions for alendronate or risedronate between 2005 and 2009. Co-morbidity data was extracted from the National Patient Register. The association between AGS and medication persistence was investigated using non-parametric and parametric survival analysis. Results Between 2006 and 2009, the number of alendronate products increased from 15 to 25, the proportion of prescriptions constituting a substitution increased from 10.8% to 45.2%, and the proportion of patients persisting with alendronate treatment for 12 months fell from 66.9% to 51.7%. Patients starting alendronate treatment in 2006 had lower risk of stopping treatment compared with those starting in 2007 (HR 1.34, 95% CI 1.29-1.39), 2008 (HR 1.49, 95% CI 1.43-1.55), and 2009 (HR 1.50, 95% CI 1.40-1.60). No difference was observed in persistence with proprietary risedronate during the same period. Individuals who had their alendronate product substituted at the first prescription refill had significantly higher probability of discontinuation (HR 1.25, 95% CI 1.20-1.30). Conclusion AGS causes increased product substitution which appears to be associated with reduced treatment persistence. Poor health outcomes and associated costs due to forgone drug exposure should be taken into account in the design and evaluation of policies implemented to encourage utilisation of generic medicines. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011.


Roukos D.H.,University of Ioannina | Ku C.-S.,Karolinska Institutet
Annals of Surgical Oncology | Year: 2012

Revolutionary sequencing technologies have changed biomedical research and life science exponentially. Revealing the whole landscape of causal somatic and inherited mutations underlying individual patient's cancer sample by whole-genome sequencing (WGS) and wholeexome sequencing (WES) can lead to not only a new mutations- based taxonomy of solid tumors (Stratton, Science 331:1553-1558, 2011). But also shapes a roadmap for precision medicine (Roychowdhury et al., Sci Transl Med 3:111 ra121, 2011; Roukos, Expert Rev Mol Diagn 12:215-218, 2012; Mirnezami et al., N Engl J Med 366:489-491, 2012). This inevitable approach for personalized diagnostics in concert with free-falling genome sequencing costs raises now the question of applying next-generation sequencing (NGS) technology in the clinic. In the pragmatic clinical world and in contrast to innovative research, is NGS-based clinical evidence sufficient for decision-making on tailoring the best available treatment to the individual cancer patient?. © Society of Surgical Oncology 2012.


Stackelberg O.,Karolinska Institutet
Circulation | Year: 2014

BACKGROUND: Studies investigating the role of alcohol consumption in the development of abdominal aortic aneurysm (AAA) are scarce. We aimed to examine associations between total alcohol consumption and specific alcoholic beverages and the hazard of AAA.METHODS AND RESULTS: The study population was made up of 44 715 men from the Cohort of Swedish Men and 35 569 women from the Swedish Mammography Cohort who were 46 to 84 years of age at baseline in 1998. Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals for the associations between alcohol consumption, assessed through a food frequency questionnaire, and AAA, identified by means of linkage to the Swedish Inpatient Register and the Swedish Vascular Registry (Swedvasc). Over the 14-year follow-up until December 2011 (1 019 954 person-years), AAAs occurred in 1020 men and 194 women. Compared with the consumption of 1 glass of alcohol per week (12 g of ethanol), the hazard ratio of AAA among men who consumed 10 glasses per week was 0.80 (95% confidence interval, 0.68-0.94). The corresponding hazard ratio among women who consumed 5 glasses per week was 0.57 (95% confidence interval, 0.40-0.82). Among participants free from cardiovascular disease, total alcohol consumption did not seem to be associated with hazard of the disease. The most commonly consumed alcoholic beverages, beer among men and wine among women, were inversely associated, whereas no association was observed for liquor.CONCLUSIONS: Moderate alcohol consumption, specifically wine and beer, was associated with a lower hazard of abdominal aortic aneurysm. The associations between higher doses of alcohol and risk of the disease remain unknown. © 2014 American Heart Association, Inc.


Jensen L.D.,Karolinska Institutet | Cao Y.,Linkoping University
Cell Cycle | Year: 2013

Circadian rhythms control multiple physiological and pathological processes, including embryonic development in mammals and development of various human diseases. We have recently, in a developing zebrafish embryonic model, discovered that the circadian oscillation controls developmental angiogenesis. Disruption of crucial circadian regulatory genes, including Bmal1 and Period2, results in marked impairment or enhancement of vascular development in zebrafish. At the molecular level, we show that the circadian regulator Bmal1 directly targets the promoter region of the vegf gene in zebrafish, leading to an elevated expression of VEGF. These findings can reasonably be extended to developmental angiogenesis in mammals and even pathological angiogenesis in humans. Thus, our findings, for the first time, shed new light on mechanisms that underlie circadian clock-regulated angiogenesis. © 2013 Landes Bioscience.


Beck O.,Karolinska Institutet
Journal of analytical toxicology | Year: 2012

It has recently been demonstrated that amphetamine, methadone and tetrahydrocannabinol are detectable in exhaled breath following intake. Exhaled breath, therefore, constitutes a new possible matrix for drugs-of-abuse testing. The present work aims to further explore this possibility by a study on patients treated for acute intoxication with abused drugs. Fifty-nine patients (44 males, age range 24-74) were included in the study, and breath, plasma and urine samples were collected following recovery, together with interview data. Analyses of breath and plasma samples were conducted with liquid chromatography-mass spectrometry methods. Urine was screened using immunochemical reagents and positive findings confirmed with liquid chromatography-mass spectrometry methods. The following analytes were investigated: methadone, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, codeine, 6-acetylmorphine, diazepam, oxazepam, morphine, benzoylecgonine, cocaine, buprenorphine and tetrahydrocannabinol. In 53 of the studied cases, recent intake of an abused substance prior to admission was reported. In 35 of these (66%), the breath analysis gave a positive finding. Identifications were based on correct chromatographic retention time and product ion ratios obtained in selected reaction monitoring mode. Generally, data from breath, plasma, urine and self-report were in agreement. Detected substances in breath included amphetamine, methamphetamine, buprenorphine, 6-acetylmorphine, morphine, codeine, methadone, tetrahydrocannabinol, diazepam, oxazepam and cocaine. Problem analytes with low detection rates were benzodiazepines and tetrahydrocannabinol. This study gives further support to the possibility of developing exhaled breath into a new matrix for drugs-of-abuse testing by extending the number of analytes that are documented to be detectable in breath.


Cnattingius S.,Karolinska Institutet
International journal of obesity (2005) | Year: 2012

Rates of high birth weight infants, overweight and obese children and adults are increasing. The associations between birth weight and adult weight may have consequences for the obesity epidemic across generations. We examined the association between mothers' birth weight for gestational age and adult body mass index (BMI) and these factors' joint effect on risk of having a large-for-gestational-age (LGA) offspring (>+2 s.d. above the mean). A cohort of 162 676 mothers and their first-born offspring with birth information recorded on mothers and offspring in the nation-wide Swedish Medical Birth Register 1973-2006. Compared with mothers with appropriate birth weight for gestational age (AGA; -1 to +1 s.d.), mothers born LGA had increased risks of overweight (BMI 25.0-29.9; odds ratio (OR), 1.50; 95% CI 1.39-1.61), obesity class I (BMI 30.0-34.9; OR 1.77; 95% CI 1.59-1.98), obesity class II (BMI 35.0-39.9; OR 2.77; 95% CI 2.37-3.24) and obesity class III (BMI ≥40.0; OR 2.04; 95% CI 1.49-2.80). In each stratum of mother's birth weight for gestational age, risk of having an LGA offspring increased with mother's BMI. The risk of an LGA offspring was highest among women with a high (≥30) BMI who also had a high birth weight for gestational age (>+1 s.d.). In these groups, the ORs for LGA offspring ranged from 5 to 14 when compared with mothers born AGA with normal BMI (≤24.9). However, the strongest increase in risk by BMI was seen among mothers born SGA: the OR of having an LGA offspring was 13 times as high among SGA mothers with BMI ≥35.0 compared with the OR among SGA mothers with normal BMI (ORs=4.61 and 0.35, respectively). Prenatal conditions are important for the obesity epidemic. Prevention of LGA births may contribute to curtail the intergenerational vicious cycle of obesity.


Pietroiusti A.,University of Rome Tor Vergata | Campagnolo L.,University of Rome Tor Vergata | Fadeel B.,Karolinska Institutet
Small | Year: 2013

Engineered nanomaterials may exert adverse effects on human health which, in turn, may be linked to their propensity to cross biological barriers in the body. Here, available evidence is discussed, based on in vivo studies for interactions of commercially relevant nanoparticles with critical internal barriers. The internal barriers in focus in this review are the blood-brain barrier, protecting the brain, the blood-testis barrier, protecting the male germ line, and the placenta, protecting the developing fetus. The route of exposure (pulmonary, gastro-intestinal, intravenous, intraperitoneal, dermal), and, hence, the portal of entry of nanoparticles into the body, is of critical importance. Different physico-chemical properties, not only size, may determine the ability of nanoparticles to breach biological barriers; the situation is further compounded by the formation of a so-called corona of biomolecules on the surfaces of nanoparticles, the composition of which may vary depending on the route of exposure and the translocation of nanoparticles from one biological compartment to another. The relevance of nanoparticle interactions with internal biological barriers for their impact on the organs protected by these barriers is also discussed. Evidence derived from in vivo (animal) studies on the interactions of nanoparticles with critical internal barriers is discussed. Different physico-chemical properties of nanomaterials may determine their ability to breach biological barriers and the situation is further compounded by the formation of a so-called corona of biomolecules on the surfaces of nanoparticles, the composition of which may vary depending on the route of exposure and the translocation of nanoparticles from one biological compartment to another. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Lamb G.D.,La Trobe University | Westerblad H.,Karolinska Institutet
Journal of Physiology | Year: 2011

Reactive oxygen and nitrogen species (ROS/RNS) are important for skeletal muscle function under both physiological and pathological conditions. ROS/RNS induce long-term and acute effects and the latter are the focus of the present review. Upon repeated muscle activation both oxygen and nitrogen free radicals likely increase and acutely affect contractile function. Although fluorescent indicators often detect only modest increases in ROS during repeated activation, there are numerous studies showing that manipulations of ROS can affect muscle fatigue development and recovery. Exposure of intact muscle fibres to the oxidant hydrogen peroxide (H 2O 2) affects mainly the myofibrillar function, where an initial increase in Ca 2+ sensitivity is followed by a decrease. Experiments on skinned fibres show that these effects can be attributed to H 2O 2 interacting with glutathione and myoglobin, respectively. The primary RNS, nitric oxide (NO •), may also acutely affect myofibrillar function and decrease the Ca 2+ sensitivity. H 2O 2 can oxidize the sarcoplasmic reticulum Ca 2+ release channels. This oxidation has a large stimulatory effect on Ca 2+-induced Ca 2+ release of isolated channels, whereas it has little or no effect on the physiological, action potential-induced Ca 2+ release in skinned and intact muscle fibres. Thus, acute effects of ROS/RNS on muscle function are likely to be mediated by changes in myofibrillar Ca 2+ sensitivity, which can contribute to the development of muscle fatigue or alternatively help counter it. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


Lin C.-Y.,University of Houston | Gustafsson J.-A.,University of Houston | Gustafsson J.-A.,Karolinska Institutet
Nature Reviews Cancer | Year: 2015

Members of the nuclear receptor superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are nuclear receptor family members that function in cholesterol transport, glucose metabolism and the modulation of inflammatory responses. There is now accumulating evidence to support the involvement of LXRs in a variety of malignancies and the potential efficacy of their ligands in these diseases. This Review summarizes the discovery and characterization of LXRs and their ligands, their effects and mechanisms in preclinical cancer models, and the future directions of basic and translational LXR research in cancer therapeutics. © 2015 Macmillan Publishers Limited. All rights reserved.


Bellavia A.,Karolinska Institutet
American Journal of Epidemiology | Year: 2014

The association between long sleep duration and death is not fully understood. Long sleep is associated with low physical activity, which is a strong predictor of death. Our aim was to investigate the association between sleep duration and death across categories of total physical activity in a large prospective cohort of Swedish men and women. We followed a population-based cohort of 70,973 participants (37,846 men and 33,127 women), aged 45-83 years, from January 1998 to December 2012. Sleep duration and physical activity levels were assessed through a questionnaire. We evaluated the association of interest in terms of mortality rates by estimating hazard ratios with Cox regression and in terms of survival by evaluating 15th survival percentile differences with Laplace regression. During 15 years of follow-up, we recorded 14,575 deaths (8,436 men and 6,139 women). We observed a significant interaction between sleep duration and physical activity in predicting death (P < 0.001). Long sleep duration (>8 hours) was associated with increased mortality risk (hazard ratio = 1.24; 95% confidence interval: 1.11, 1.39) and shorter survival (15th percentile difference = -20 months; 95% confidence interval: -30, -11) among only those with low physical activity. The association between long sleep duration and death might be partly explained by comorbidity with low physical activity. © The Author 2013.


Luijsterburg M.S.,Karolinska Institutet | Van Attikum H.,Leiden University
Molecular Oncology | Year: 2011

The integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management. © 2011 Federation of European Biochemical Societies.


Persson J.,Karolinska Institutet
Current Opinion in Anaesthesiology | Year: 2010

Purpose of review: Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the last few years prompting an update. Interesting recent publications will be highlighted against a background of established knowledge. Recent findings: In the field of anesthesia, particularly in pediatrics, some contributions have been made concerning intramuscular versus intravenous induction. The need for anticholinergic adjuvants has also been clarified. Neuroapoptosis has been observed in animals and its implications for human subjects are discussed in a general context of neurotoxicity. The most important developments, however, are in the treatment of pain. Neurological and urological side effects strongly question long-term use. Other potentially beneficial effects have also been reported, such as anti-inflammatory and antidepressive effects. There are also indications that ketamine may attenuate postoperative delirium in coronary by-pass patients. Summary: More questions have arisen than have been answered. Some have very grave implications. The issue of neuroapoptosis must be clarified. The long-term effects must be further investigated. On the bright side the effects on postoperative delirium, as well as the anti-inflammatory and antidepressive effects, might open new vistas for an old drug. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Polderman T.J.C.,VU University Amsterdam | Benyamin B.,University of Queensland | De Leeuw C.A.,VU University Amsterdam | De Leeuw C.A.,Radboud University Nijmegen | And 5 more authors.
Nature Genetics | Year: 2015

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool. © 2015 Nature America, Inc. All rights reserved.


Larsson S.C.,Karolinska Institutet
American Journal of Gastroenterology | Year: 2016

OBJECTIVES:Diets that induce a high glycemic response might increase the risk of biliary tract cancer (BTC). We evaluated the hypothesis that diets with high glycemic load (GL) and high glycemic index (GI), which are measures of the glycemic effect of foods, are associated with an increased incidence of BTC.METHODS:We used data from a population-based prospective study of 76,014 Swedish adults (age 45−83 years; 57% men) who were free of cancer and had completed a food-frequency questionnaire in the autumn of 1997. Incident cancer cases were ascertained by linkage with the Swedish Cancer Registry. Data were analyzed using Cox proportional hazards regression models.RESULTS:During a mean follow-up of 13.3 years (1,010,777 person-years), we identified 140 extrahepatic BTC cases (including 77 gallbladder cancers) and 23 intrahepatic BTC cases. A high dietary GL was associated with an increased risk of BTC. The multivariable relative risks for the highest versus lowest quartile of dietary GL were 1.63 (95% confidence interval (95% CI), 1.01–2.63) for extrahepatic BTC, 2.14 (95% CI, 1.06–4.33) for gallbladder cancer, and 3.46 (95% CI, 1.22–9.84) for intrahepatic BTC. Dietary GI was statistically significantly positively associated with risk of extrahepatic BTC and gallbladder cancer. We observed no statistically significant association between carbohydrate intake and BTC risk, although all associations were positive.CONCLUSION:Although these data do not prove a causal relationship, they are consistent with the hypothesis that high-GL and high-GI diets are associated with an increased risk of BTC.Am J Gastroenterol advance online publication, 29 March 2016; doi:10.1038/ajg.2016.101. © 2016 American College of Gastroenterology


Persson K.E.M.,Karolinska Institutet
Acta Tropica | Year: 2010

Malaria is a disease that kills several million people every year. P. falciparum merozoites invade new erythrocytes every 48. h, causing fever, anemia and cerebral malaria. Effective immunity against malaria develops slowly and only after repeated exposure. Antibodies are an important part of this immunity. However, the antigens that mediate immunity by inducing functionally imperative antibodies have not yet been identified. This review gives an overview of the erythrocyte invasion process, which has been described to include several different antigens. Invasion inhibitory antibodies can inhibit merozoite penetration of new erythrocytes, and different methods for measurement of the presence of functionally important antibodies have been employed. ELISA, Invasion inhibition assays and ADCI are some of the methods discussed. © 2009 Elsevier B.V.


Ost L.-G.,Karolinska Institutet | Ost L.-G.,University of Stockholm
Behaviour Research and Therapy | Year: 2014

Acceptance and Commitment therapy (ACT) has attracted a lot of interest during the last 10-15 years with a strong increase of the number of randomized controlled trials (RCTs). The present review and meta-analysis includes 60 RCTs (4234 participants) on psychiatric disorders, somatic disorders, and stress at work. The mean effect size across all comparisons was small (0.42). Compared to the Öst (2008) meta-analysis there was no significant improvement in methodological quality and deterioration in effect size (from 0.68). When ACT was compared to various forms of cognitive or behavioral treatments a small and non-significant effect size of 0.16 was obtained. An evidence-base evaluation showed that ACT is not yet well-established for any disorder. It is probably efficacious for chronic pain and tinnitus, possibly efficacious for depression, psychotic symptoms, OCD, mixed anxiety, drug abuse, and stress at work, and experimental for the remaining disorders. © 2014 Elsevier Ltd. All rights reserved.


Cao Y.,Karolinska Institutet
Nature Reviews Clinical Oncology | Year: 2010

Antiangiogenic cancer therapy is based on agents that target blood vessels of the tumor to inhibit its growth. However, experience from the clinic demonstrates that survival benefits following antiangiogenic therapy do not always correlate with tumor size and growth inhibition. Emerging evidence shows that delivery of antiangiogenic drugs might induce systemic alterations of the vasculature that modulate the function of various tissues and organs. Normalization of tissues and organs by antiangiogenic therapy may be an important mechanism underlying the survival benefits seen in patients with cancer who suffer cancer-associated systemic syndromes. This new concept has been validated in preclinical tumor models, and responses in patients have positively correlated with clinical benefits. © 2010 Macmillan Publishers Limited. All rights reserved.


Percipalle P.,Karolinska Institutet
Nucleus (Austin, Tex.) | Year: 2013

Actin is a key player for nuclear structure and function regulating both chromosome organization and gene activity. In the cell nucleus actin interacts with many different proteins. Among these proteins several studies have identified classical nuclear factors involved in chromatin structure and function, transcription and RNA processing as well as proteins that are normally involved in controlling the actin cytoskeleton. These discoveries have raised the possibility that nuclear actin performs its multi task activities through tight interactions with different sets of proteins. This high degree of promiscuity in the spectrum of protein-to-protein interactions correlates well with the conformational plasticity of actin and the ability to undergo regulated changes in its polymerization states. Several of the factors involved in controlling head-to-tail actin polymerization have been shown to be in the nucleus where they seem to regulate gene activity. By focusing on the multiple tasks performed by actin and actin-binding proteins, possible models of how actin dynamics controls the different phases of the RNA polymerase II transcription cycle are being identified.


Zhu J.,Karolinska Institutet
Oncogene | Year: 2015

The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.260. © 2015 Macmillan Publishers Limited


Tannenbaum C.,University of Montreal | Johnell K.,Karolinska Institutet
Drugs and Aging | Year: 2014

Up to 50 % of heart failure patients suffer from lower urinary tract symptoms. Urinary incontinence has been associated with worse functional status in patients with heart failure, occurring three times more frequently in patients with New York Heart Association Class III and IV symptoms compared with those with milder disease. The association between heart failure and urinary symptoms may be directly attributable to worsening heart failure pathophysiology; however, medications used to treat heart failure may also indirectly provoke or exacerbate urinary symptoms. This type of drug-disease interaction, in which the treatment for heart failure precipitates incontinence, and removal of medications to relieve incontinence worsens heart failure, can be termed therapeutic competition. The mechanisms by which heart failure medication such as diuretics, angiotensin-converting enzyme (ACE) inhibitors and β-blockers aggravate lower urinary tract symptoms are discussed. Initiation of a prescribing cascade, whereby antimuscarinic agents or β3-agonists are added to treat symptoms of urinary urgency and incontinence, is best avoided. Recommendations and practical tips are provided that outline more judicious management of heart failure patients with lower urinary tract symptoms. Compelling strategies to improve urinary outcomes include titrating diuretics, switching ACE inhibitors, treating lower urinary tract infections, appropriate fluid management, daily weighing, and uptake of pelvic floor muscle exercises. © 2013 The Author(s).


Jakobsson J.G.,Karolinska Institutet
Pharmaceuticals | Year: 2014

Day surgery, coming to and leaving the hospital on the same day as surgery as well as ambulatory surgery, leaving hospital within twenty-three hours is increasingly being adopted. There are several potential benefits associated with the avoidance of in-hospital care. Early discharge demands a rapid recovery and low incidence and intensity of surgery and anaesthesia related side-effects; such as pain, nausea and fatigue. Patients must be fit enough and symptom intensity so low that self-care is feasible in order to secure quality of care. Preventive multi-modal analgesia has become the gold standard. Administering paracetamol, NSIADs prior to start of surgery and decreasing the noxious influx by the use of local anaesthetics by peripheral block or infiltration in surgical field prior to incision and at wound closure in combination with intra-operative fast acting opioid analgesics, e.g., remifentanil, have become standard of care. Single preoperative 0.1 mg/kg dose dexamethasone has a combined action, anti-emetic and provides enhanced analgesia. Additional α-2-agonists and/or gabapentin or pregabalin may be used in addition to facilitate the pain management if patients are at risk for more pronounced pain. Paracetamol, NSAIDs and rescue oral opioid is the basic concept for self-care during the first 3-5 days after common day/ambulatory surgical procedures. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Bluhm G.,Karolinska Institutet
Noise & health | Year: 2011

In Sweden, as in many other European countries, traffic noise is an important environmental health issue. At present, almost two million people are exposed to average noise levels exceeding the outdoor national guideline value (55 dB(A)). Despite efforts to reduce the noise burden, noise-related health effects, such as annoyance and sleep disturbances, are increasing. The scientific interest regarding more serious health effects related to the cardiovascular system is growing, and several experimental and epidemiological studies have been performed or are ongoing. Most of the studies on cardiovascular outcomes have been related to noise from road or aircraft traffic. Few studies have included railway noise. The outcomes under study include morning saliva cortisol, treatment for hypertension, self-reported hypertension, and myocardial infarction. The Swedish studies on road traffic noise support the hypothesis of an association between long-term noise exposure and cardiovascular disease. However, the magnitude of effect varies between the studies and has been shown to depend on factors such as sex, number of years at residence, and noise annoyance. Two national studies have been performed on the cardiovascular effects of aircraft noise exposure. The first one, a cross-sectional study assessing self-reported hypertension, has shown a 30% risk increase per 5 dB(A) noise increase. The second one, which to our knowledge is the first longitudinal study assessing the cumulative incidence of hypertension, found a relative risk (RR) of 1.10 (95% CI 1.01 - 1.19) per 5 dB(A) noise increase. No associations have been found between railway noise and cardiovascular diseases. The findings regarding noise-related health effects and their economic consequences should be taken into account in future noise abatement policies and community planning.


Gajecki M.,Karolinska Institutet
Addiction science & clinical practice | Year: 2014

Brief interventions via the internet have been shown to reduce university students' alcohol intake. This study tested two smartphone applications (apps) targeting drinking choices on party occasions, with the goal of reducing problematic alcohol intake among Swedish university students. Students were recruited via e-mails sent to student union members at two universities. Those who gave informed consent, had a smartphone, and showed risky alcohol consumption according to the Alcohol Use Disorders Identification Test (AUDIT) were randomized into three groups. Group 1 had access to the Swedish government alcohol monopoly's app, Promillekoll, offering real-time estimated blood alcohol concentration (eBAC) calculation; Group 2 had access to a web-based app, PartyPlanner, developed by the research group, offering real-time eBAC calculation with planning and follow-up functions; and Group 3 participants were controls. Follow-up was conducted at 7 weeks. Among 28574 students offered participation, 4823 agreed to join; 415 were excluded due to incomplete data, and 1932 fulfilled eligibility criteria for randomization. Attrition was 22.7-39.3 percent, higher among heavier drinkers and highest in Group 2. Self-reported app use was higher in Group 1 (74%) compared to Group 2 (41%). Per-protocol analyses revealed only one significant time-by-group interaction, where Group 1 participants increased the frequency of their drinking occasions compared to controls (p = 0.001). Secondary analyses by gender showed a significant difference among men in Group 1 for frequency of drinking occasions per week (p = 0.001), but not among women. Among all participants, 29 percent showed high-risk drinking, over the recommended weekly drinking levels of 9 (women) and 14 (men) standard glasses. Smartphone apps can make brief interventions available to large numbers of university students. The apps studied using eBAC calculation did not, however, seem to affect alcohol consumption among university students and one app may have led to a negative effect among men. Future research should: 1) explore ways to increase user retention, 2) include apps facilitating technical manipulation for evaluation of added components, 3) explore the effects of adapting app content to possible gender differences, and 4) offer additional interventions to high-risk users. clinicaltrials.gov: NCT01958398.


Javed F.,Karolinska Institutet | Romanos G.E.,University of Rochester
Journal of Dentistry | Year: 2010

Objectives: To assess the role of primary stability for successful immediate loading (IL) of dental implants. Data: Original articles studying the role of primary stability for successful immediate loading of dental implants were included. The reference lists of potentially relevant review articles were also sought. Sources: The MEDLINE-PubMed databases were searched for appropriate articles addressing the objectives of the present study. Databases were searched from 1979 up to and including April 2010. The search was performed using a variety of keywords in different combinations. Articles published only in English language were included. Letters to the Editor, historical reviews and unpublished articles were not sought. Conclusions: There is a significant biological response by the hard and soft tissues to IL of dental implants. Within the limitations of the present literature review, it is evident that the core issue to observe during IL is the establishment of a good implant primary stability. There is sufficient evidence to suggest that the degree of achieved primary stability during IL protocols is dependent on several factors including bone density and quality, implant shape, design and surface characteristics and surgical technique. Further research is required in situations, such as poor bone quality and quantity and multiple implants or augmentation procedures, which may challenge the attainment of primary stability during IL.


Klingberg T.,Karolinska Institutet
Trends in Cognitive Sciences | Year: 2010

Working memory (WM) capacity predicts performance in a wide range of cognitive tasks. Although WM capacity has been viewed as a constant trait, recent studies suggest that it can be improved by adaptive and extended training. This training is associated with changes in brain activity in frontal and parietal cortex and basal ganglia, as well as changes in dopamine receptor density. Transfer of the training effects to non-trained WM tasks is consistent with the notion of training-induced plasticity in a common neural network for WM. The observed training effects suggest that WM training could be used as a remediating intervention for individuals for whom low WM capacity is a limiting factor for academic performance or in everyday life. © 2010 Elsevier Ltd.


Palazon A.,University of Cambridge | Goldrath A.W.,University of California at San Diego | Nizet V.,University of California at San Diego | Johnson R.S.,University of Cambridge | Johnson R.S.,Karolinska Institutet
Immunity | Year: 2014

The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity todriving Tcell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity. Hypoxia-inducible factor (HIF) transcription factors can be triggered by hypoxia and by other factors associated with pathological stress. Johnson and colleagues review the role of HIF and other key players in the hypoxic response in the control of innate and adaptive immunity. © 2014 Elsevier Inc.


Lennartsson A.,Karolinska Institutet
Genome Biology | Year: 2016

A new study shows how a single cytokine, interleukin-4, regulates hematopoietic lineage choice by activating the JAK3-STAT6 pathway, which causes dendritic-cell-specific DNA demethylation. Please see related Research article: http://www.genomebiology.com/2016/17/1/4 © 2016 Lennartsson.


Falhammar H.,Karolinska University Hospital | Falhammar H.,Karolinska Institutet
Endocrine | Year: 2014

Adrenal incidentalomas (AI) are an escalating clinical issue due to the increasing use of imaging techniques. Occasional patients with AIs have been reported who have subsequently been diagnosed with congenital adrenal hyperplasia (CAH) due to CYP21A2 mutations (21-hydroxylase deficiency) or carrier status. The objective of this investigation was to describe a larger cohort of patients with AI suspected to be caused by 21-hydroxylase deficiency or carrier status. All patients with AI and suspected CYP21A2 mutations during the last decade at a single center in Stockholm, Sweden, were included. Nine patients were identified (54 ± 19-year-old at presentation). Two-thirds were females and two-thirds were from Sweden, while one-third was from the Middle East. Almost all (8/9) had children, but two had experienced fertility problems. Four of six women had symptoms of hyperandrogenism, and three had previously been diagnosed with polycystic ovary syndrome. The majority (7/9) had multiple AIs. In two cases, the initial suspicion had been adrenal cortical cancer, but increased urinary pregnanetriol had lead to the diagnosis of CAH. Basal serum 17-hydroxyprogesterone was 10 (1.75-338) nmol/L. Seven was diagnosed with CAH (six non-classic, one simple virilizing). Two patients were considered to be carriers. However, in four patients, no CYP21A2 mutation was found and thus no confirmation of the diagnosis could be achieved. Patient presented with multiple AIs with hyperandrogenism or a Middle East origin screening for CAH or carrier status may be indicated. © 2014 Springer Science+Business Media.


Sodergren M.,Karolinska Institutet
Maturitas | Year: 2013

With ageing populations a major challenge is to maintain physical and cognitive function, quality of life and independence. The literature does not only indicate important gender differences in lifestyle behaviours, but also how these behaviours might affect health outcomes. The current review has a male perspective when exploring lifestyle predictors of healthy ageing, such as physical activity and sedentary behaviours, smoking, diet and alcohol consumption. This review shows that not only do men with healthy lifestyles survive longer, but also with good health and disability is postponed and compressed into fewer years at the end of life. It is also clear that physical activity and smoking in midlife and late adulthood impact and predict healthy ageing in men. However, healthy ageing has no clear phenotypic definition and more research is needed to establish the impact on dietary and sedentary behaviours on healthy ageing in men. Adoption of healthier lifestyles could result in postponement of age associated diseases and/or the slowing down of the ageing process. Consequently, this allows independent living for a longer period of time and would reduce the burden to social and health care sectors. © 2013 Elsevier Ireland Ltd.


Levin B.R.,Emory University | Concepcion-Acevedo J.,Emory University | Udekwu K.I.,Karolinska Institutet
Current Opinion in Microbiology | Year: 2014

We postulate that phenotypic resistance to antibiotics, persistence, is not an evolved (selected-for) character but rather like mutation, an inadvertent product of different kinds of errors and glitches. The rate of generation of these errors is augmented by exposure to these drugs. The genes that have been identified as contributing to the production of persisters are analogous to the so-called mutator genes; they modulate the rate at which these errors occur and/or are corrected. In theory, these phenotypically resistant bacteria can retard the rate of microbiological cure by antibiotic treatment. © 2014 Elsevier Ltd.


A number of studies have explored the relationships of apolipoprotein E (APOE) genotype and education with dementia over the last decade. However, observations concerning the possible modifying effect of education on the APOE-dementia association are limited. The objective of this study was to test the hypothesis that education may decrease the risk of APOE ε4 on dementia. Pooled data from 3 major population-based studies in Northern Europe were used in this study, with a total of 3436 participants aged 65 and older derived from the Kungsholmen project and the Gothenburg Birth Cohort studies in Sweden, and the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) project in Finland. The main outcome measure was dementia, which was diagnosed in 219 persons according to standard criteria. APOE ε4 was associated with increased risk of dementia independent of the effect of education (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.9-3.4 for 1 ε4 carrier and OR, 3.7; 95% CI, 1.8-7.2 for 2 ε4 carriers). High education (8 years and more) was related to a lower dementia risk (OR, 0.5; 95% CI, 0.3-0.6). An interaction between education and APOE ε4 was observed. Compared with those with less education and no ε4, the odds of dementia among persons with low education who carried any ε4 allele was 2.7 (95% CI, 1.9-3.9), and 1.2 (0.7-1.8) if they had higher education. This study suggests that genetic (APOE ε4) and environmental (education) factors are not only independently but also interactively related to dementia risk and that high education may buffer the negative effect of APOE ε4 on dementia occurrence. Copyright © 2012 Elsevier Inc. All rights reserved.


Agahi N.,Karolinska Institutet | Shaw B.A.,University at Albany
Preventive Medicine | Year: 2013

Objective: To examine how trajectories of smoking observed over a 34-year period, were associated with the progression of mobility impairment, musculoskeletal pain, and symptoms of psychological distress from midlife to old age. Method: The Swedish Level of Living Survey (LNU) and the Swedish Panel Study of the Oldest Old (SWEOLD) were merged to create a nationally representative longitudinal sample of Swedish adults (aged 30-50 at baseline; n = 1060), with four observation periods, from 1968 through 2002. Five discrete smoking trajectory groups were treated as predictors of variation in health trajectories using multilevel regression. Results: At baseline, there were no differences in mobility impairment between smoking trajectory groups. Over time all smokers, particularly persistent and former heavy smokers, exhibited faster increases in mobility problems compared with persistent non-smokers. Additionally, all smoking groups reported more pain symptoms than the non-smokers, at baseline and over time, but most of these differences did not reach statistical significance. Persistent heavy smokers reported elevated levels of psychological distress at baseline and over time. Conclusion: Smokers, and even some former smokers, who survive into old age appear to be at increased risk for non-life-threatening conditions that can diminish quality of life and increase demands for services. © 2013 Elsevier Inc.


Nordberg A.,Karolinska Institutet
Neurodegenerative Diseases | Year: 2010

Amyloid imaging has provided evidence for early detection of amyloid (Aβ) load in prodromal Alzheimer's disease (AD). Several amyloid tracers have been developed for studies with positron emission tomography (PET). Early detection of at-risk subjects will be important in the future for a successful treatment of AD. The high Aβ load in the brain measured by PET in patients with mild cognitive impairment that later will convert to AD suggests early, significant, ongoing pathological processes prior to cognitive impairment. PET Aβ imaging will also be used for discrimination of AD from other dementia disorders, as well for the evaluation of anti-Aβ drugs. Copyright © 2010 S. Karger AG, Basel.


Andersson G.,Linkoping University | Andersson G.,Karolinska Institutet
Annual Review of Clinical Psychology | Year: 2016

During the past 15 years, much progress has been made in developing and testing Internet-delivered psychological treatments. In particular, therapist-guided Internet treatments have been found to be effective for a wide range of psychiatric and somatic conditions in well over 100 controlled trials. These treatments require (a) a secure web platform, (b) robust assessment procedures, (c) treatment contents that can be text based or offered in other formats, and (d) a therapist role that differs from that in face-to-face therapy. Studies suggest that guided Internet treatments can be as effective as face-to-face treatments, lead to sustained improvements, work in clinically representative conditions, and probably are cost-effective. Despite these research findings, Internet treatment is not yet disseminated in most places, and clinical psychologists should consider using modern information technology and evidence-based treatment programs as a complement to their other services, even though there will always be clients for whom face-to-face treatment is the best option. Copyright ©2016 by Annual Reviews. All rights reserved.


Andersson J.D.,Karolinska Institutet
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2013

The development of positron emission tomography radioligands for the GABAA/benzodiazepine receptor complex (GABAA receptor) labeled with 11C and 18F is examined. The review covers labeling strategies as well as brief biological evaluations of radioligands. In addition, we assess the special considerations that must be taken during a development program for radioligands targeting the GABAA receptor and explore some of the challenges that lie ahead. Copyright © 2013 John Wiley & Sons, Ltd.