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  • 1.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden.
    Sandberg, Lovisa
    Bergvall, Tomas
    Watson, Sarah
    Noren, G. Niklas
    vigiRank for statistical signal detection in pharmacovigilance: First results from prospective real-world use2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, no 8, p. 1006-1010Article in journal (Refereed)
    Abstract [en]

    Purpose: vigiRank is a data-driven predictive model for emerging safety signals. In addition to disproportionate reporting patterns, it also accounts for the completeness, recency, and geographic spread of individual case reporting, as well as the availability of case narratives. Previous retrospective analysis suggested that vigiRank performed better than disproportionality analysis alone. The purpose of the present analysis was to evaluate its prospective performance. Methods: The evaluation of vigiRank was based on real-world signal detection in VigiBase. In May 2014, vigiRank scores were computed for pairs of new drugs and WHO Adverse Reaction Terminology critical terms with at most 30 reports from at least 2 countries. Initial manual assessments were performed in order of descending score, selecting a subset of drug-adverse drug reaction pairs for in-depth expert assessment. The primary performance metric was the proportion of initial assessments that were decided signals during in-depth assessment. As comparator, the historical performance for disproportionality-guided signal detection in VigiBase was computed from a corresponding cohort of drug-adverse drug reaction pairs assessed between 2009 and 2013. During this period, the requirement for initial manual assessment was a positive lower endpoint of the 95% credibility interval of the Information Component measure of disproportionality, observed for the first time. Results: 194 initial assessments suggested by vigiRank's ordering eventually resulted in 6 (3.1%) signals. Disproportionality analysis yielded 19 signals from 1592 initial assessments (1.2%; P <.05). Conclusions: Combining multiple strength-of-evidence aspects as in vigiRank significantly outperformed disproportionality analysis alone in real-world pharmacovigilance signal detection, for VigiBase.

  • 2.
    Cooper, Callum J.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Koonjan, Shazeeda
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Anders S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Enhancing Whole Phage Therapy and Their Derived Antimicrobial Enzymes through Complex Formulation2018In: Pharmaceuticals, ISSN 1424-8247, E-ISSN 1424-8247, Vol. 11, no 2, article id UNSP 34Article, review/survey (Refereed)
    Abstract [en]

    The resurgence of research into phage biology and therapy is, in part, due to the increasing need for novel agents to treat multidrug-resistant infections. Despite a long clinical history in Eastern Europe and initial success within the food industry, commercialized phage products have yet to enter other sectors. This relative lack of success is, in part, due to the inherent biological limitations of whole phages. These include (but are not limited to) reaching target sites at sufficiently high concentrations to establish an infection which produces enough progeny phages to reduce the bacterial population in a clinically meaningful manner and the limited host range of some phages. Conversely, parallels can be drawn between antimicrobial enzymes derived from phages and conventional antibiotics. In the current article the biological limitations of whole phage-based therapeutics and their derived antimicrobial enzymes will be discussed. In addition, the ability of more complex formulations to address these issues, in the context of medical and non-medical applications, will also be included.

  • 3. Dobchev, D. A.
    et al.
    Mäger, I.
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Tulp, I.
    Karelson, G.
    Tamm, T.
    Tamm, K.
    Jänes, J.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Karelson, M.
    Prediction of Cell-Penetrating Peptides using Artificial Neural Networks2010In: Current Computer-Aided Drug Design, ISSN 1573-4099, Vol. 6, no 2, p. 79-89Article in journal (Refereed)
    Abstract [en]

    An investigation of cell-penetrating peptides (CPPs) by using combination of Artificial Neural Networks (ANN) and Principle Component Analysis (PCA) revealed that the penetration capability (penetrating/non-penetrating) of 101 examined peptides can be predicted with accuracy of 80%-100%. The inputs of the ANN are the main characteristics classifying the penetration. These molecular characteristics (descriptors) were calculated for each peptide and they provide bio-chemical insights for the criteria of penetration. Deeper analysis of the PCA results also showed clear clusterization of the peptides according to their molecular features.

  • 4.
    Elmongy, Hatem
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Damanhour University, Egypt.
    Ahmed, Hytham
    Wahbi, Abdel-Aziz
    Amini, Ahmad
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abdel-Rehim, Mohamed
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Determination of metoprolol enantiomers in human plasma and saliva samples utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry2016In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 30, no 8, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    A sensitive, accurate and reliable bioanalytical method for the enantioselective determination of metoprolol in plasma and saliva samples utilizing liquid chromatography-electrospray ionization tandem mass spectrometry was developed and validated. Human plasma and saliva samples were pretreated by microextraction by packed sorbent (MEPS) prior to analysis. A new MEPS syringe form with two inputs was used. Metoprolol enantiomers and internal standard pentycaine (IS) were eluted from MEPS sorbent using isopropanol after removal of matrix interferences using aliquots of 5% methanol in water. Complete separation of metoprolol enantiomers was achieved on a Cellulose-SB column (150x4.6mm, 5m) using isocratic elution with mobile phase 0.1% ammonium hydroxide in hexane-isopropanol (80:20, v/v) with a flow rate of 0.8mL/min. A post-column solvent-assisted ionization was applied to enhance metoprolol ionization signal in positive mode monitoring (+ES) using 0.5% formic acid in isopropanol at a flow rate of 0.2mL/min. The total chromatographic run time was 10min for each injection. The detection of metoprolol in plasma and saliva samples was performed using triple quadrupole tandem mass spectrometer in +ES under the following mass transitions: m/z 268.0872.09 for metoprolol and m/z 303.3154.3 for IS. The linearity range was 2.5-500ng/mL for both R- and S-metoprolol in plasma and saliva. The limits of detection and quantitation for both enantiomers were 0.5 and 2.5ng/mL respectively, in both matrices (plasma and saliva). The intra- and inter-day precisions were presented in terms of RSD values for replicate analysis of quality control samples and were <5%; the accuracy of determinations varied from 96 to 99%. The method was able to determine the therapeutic levels of metoprolol enantiomers in both human plasma and saliva samples successfully, which can aid in therapeutic drug monitoring in clinical laboratories.

  • 5.
    Ezzat, Kariem
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    EL Andaloussi, Samir
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Abdo, Rania
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Peptide-based matrices as drug delivery vehicles2010In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 16, no 9, p. 1167-1178Article, review/survey (Refereed)
    Abstract [en]

    Peptides, polypeptides and proteins have been extensively studied for their various structural and functional roles in living organisms. However, breakthrough discoveries in the last decades identified some peptide-based matrices that posses the ability to traverse biological membranes, and many peptides, polypeptides and even complete proteins have been shown to have such properties. Hence, these matrices have been successfully used for the intracellular delivery of many therapeutic cargos including small molecules, proteins, peptides, oligonucleutides, plasmids and nanoparticles both in vitro and in vivo. Being neither toxic nor carcinogenic and meanwhile efficient in delivery, they are recognized as very promising vectors to overcome the shortcomings of the available technologies. The characteristics of these peptide-based matrices and their applications in drug delivery are here briefly illustrated together with current challenges and future prospects.

  • 6.
    Forrest, Mia
    Stockholm University, Faculty of Social Sciences, Department of Social Anthropology.
    Swedish Obesity Specialists: Obesity and its Treatment at a Specialist Clinic in Stockholm2009Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Swedish Obesity Specialists examines how obesity is conceptualized as a medical condition by the staff working at an obesity clinic in Stockholm Sweden. Through eight weeks of participant observations and eight semi-structured interviews this thesis answers the question of how specialist working in the field of obesity construct obesity as a medical site. The thesis aims at understanding how obesity is becoming an issue for medicine, further how obesity’s entry into medicine creates new understandings of the body and medical treatments. Through the theoretical concepts of global assemblages and bio-power I argue that obesity as a disease is defined through seemingly objective criteria aimed at defining a population of sufferers, simultaneously for obesity to be viewed as disease scientifically valid treatments on an individual level must be put into place. By viewing obesity’s entry into medicine as a process of shared consensus, this thesis examines the relationship between global levels of knowledge production and their application and negotiation at one clinic treating obesity. Here expert knowledge and governance are integrated to create both treatment and an idea of what obesity as a medical condition is. In this thesis I argue that the application of expert knowledge and global criteria leads to unexpected views on what can be conceived as medical treatment. Further the thesis discusses how the body of the patient becomes reinterpreted once obesity becomes a medical condition.

  • 7. Franke, Andreas G.
    et al.
    Gränsmark, Patrik
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI).
    Agricola, Alexandra
    Schühle, Kai
    Ronnmel, Thilo
    Sebastian, Alexandra
    Balló, Harald E.
    Gorbulev, Stanislav
    Gerdes, Christer
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI).
    Frank, Björn
    Ruckes, Christian
    Tüscher, Oliver
    Lieb, Klaus
    Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no 3, p. 248-260Article in journal (Refereed)
    Abstract [en]

    Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2 x 200 mg modafinil, 2 x 20 mg methylphenidate, and 2 x 200 mg caffeine or placebo in a 4 x 4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

  • 8. Freimann, Krista
    et al.
    Kurrikoff, Kaido
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Galanin receptors as a potential target for neurological disease2015In: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, Vol. 19, no 12, p. 1665-1676Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Galanin is a 29/30 amino acid long neuropeptide that is widely expressed in the brains of many mammals. Galanin exerts its biological activities through three different G protein-coupled receptors, GalR1, GalR2 and GalR3. The widespread distribution of galanin and its receptors in the CNS and the various physiological and pharmacological effects of galanin make the galanin receptors attractive drug targets.

    AREAS COVERED: This review provides an overview of the role of galanin and its receptors in the CNS, the involvement of the galaninergic system in various neurological diseases and the development of new galanin receptor-specific ligands.

    EXPERT OPINION: Recent advances and novel approaches in migrating the directions of subtype-selective ligand development and chemical modifications of the peptide backbone highlight the importance of the galanin neurochemical system as a potential target for drug development.

  • 9. Hammarström, Lars G. J.
    et al.
    Harmel, Robert K.
    Granath, Mikael
    Ringom, Rune
    Gravenfors, Ylva
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Svensson, Per H.
    Wennman, David
    Lundin, Göran
    Roddis, Ylva
    Kitambi, Satish S.
    Bernlind, Alexandra
    Lehmann, Fredrik
    Ernfors, Patrik
    The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 18, p. 8577-8592Article in journal (Refereed)
    Abstract [en]

    Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

  • 10. Homann, Manijeh Vafa
    et al.
    Emami, S. Noushin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Yman, Victor
    Stenström, Christine
    Sondén, Klara
    Ramström, Hanna
    Karlsson, Mattias
    Asghar, Muhammad
    Färnert, Anna
    Detection of Malaria Parasites After Treatment in Travelers: A 12-months Longitudinal Study and Statistical Modelling Analysis2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 25, p. 66-72Article in journal (Refereed)
    Abstract [en]

    The rapid clearance of malaria parasite DNA from circulation has widely been accepted as a fact without being systemically investigated. We assessed the persistence of parasite DNA in travelers treated for Plasmodium falciparum malaria in a malaria-free area. Venous blood was collected at the time of admission and prospectively up to one year. DNA and RNA were extracted and analyzed using species-specific and gametocyte-specific real-time PCR as well as merozoite surface protein 2 (msp2)-PCR. In 31 successfully treated individuals, asexual parasites were seen by microscopy until two days after treatment, whereas parasite DNA was detected by msp2- and species-specific PCR up to days 31 and 42, respectively. Statistical modelling predicted 26% (+/- 0.05 SE) species-specific PCR positivity until day 40 and estimated 48 days for all samples to become PCR negative. Gametocytes were detected by microscopy and PCR latest two days after treatment. C-T values correlated well with microscopy-defined parasite densities before but not after treatment started. These results reveal that PCR positivity can persist several weeks after treatment without evidence of viable sexual or asexual parasites, indicating that PCR may overestimate parasite prevalence after treatment.

  • 11. Iaccarino, Leonardo
    et al.
    Chiotis, Konstantinos
    Alongi, Pierpaolo
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital Huddinge, Sweden.
    Wall, Anders
    Cerami, Chiara
    Bettinardi, Valentino
    Gianolli, Luigi
    Nordbereg, Agneta
    Perani, Daniela
    A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 59, no 2, p. 603-614Article in journal (Refereed)
    Abstract [en]

    Assessments of brain glucose metabolism (F-18-FDG-PET) and cerebral amyloid burden (C-11-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of F-18-FDGPET and C-11-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for F-18-FDG-PET and of standardized uptake value ratio semiquantification for C-11-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57 +/- 7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, F-18-FDG-PET and C-11-PiB-PET. F-18-FDG-PET, compared to C-11-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both F-18-FDG-PET and C-11-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

  • 12. Johansson-Pajala, Rose-Marie
    et al.
    Martin, Lene
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Jorsäter Blomgren, Kerstin
    Nurses' self-reported medication competence in relation to their pharmacovigilant activities in clinical practice.2015In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 21, no 1, p. 145-152Article in journal (Refereed)
    Abstract [en]

    RATIONALE, AIMS AND OBJECTIVES: Adverse drug reactions (ADRs) represent a major health problem and previous studies show that nurses can have an active role in promoting medication safety. The aim of this study was to describe and evaluate nurses' self-reported competence and pharmacovigilant activities in clinical practice and also to explore the impact of age, education, workplace and nursing experience on these matters.

    METHODS: This cross-sectional study was based on a questionnaire covering areas related to nurses' medication competence, including knowledge, assessment and information retrieval, and pharmacovigilant activities within these areas, for example, the detection and assessment of ADRs. A 45-item questionnaire was 2013 sent out to 296 nurses in different settings and counties in Sweden. They were selected on the basis of having applied to a university course including pharmacovigilance during 2008-2011. One hundred twenty-four had participated in the courses (exposed) and 172 had applied to the courses but not participated (unexposed).

    RESULTS: Completed questionnaires were obtained from 75 exposed (60%) and 93 unexposed (54%) nurses. Overall nurses rated themselves high in medication competence but low in pharmacovigilant activities. Significant (P ≤ 0.001) differences between groups were observed regarding medication competence. The exposure of completed dedicated courses in pharmacovigilance was the strongest factor for self-reported medication competence when adjusted for age, other education, workplace and experience. No significant differences between the groups were found regarding the number of pharmacovigilant activities during the 6 months prior to answering the questionnaire.

    CONCLUSION: Dedicated university courses improved nurses' self-reported competence in pharmacovigilance but did not increase the number of related activities. Education per se seems to be not sufficient to generate pharmacovigilant activities among nurses.

  • 13. Juhlin, Kristina
    et al.
    Ye, Xiaofei
    Stockholm University, Faculty of Science, Department of Mathematics. Third Military Medical University, China.
    Star, Kristina
    Norén, G. Niklas
    Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre.
    Outlier removal to uncover patterns in adverse drug reaction surveillance - a simple unmasking strategy2013In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 22, no 10, p. 1119-1129Article in journal (Refereed)
    Abstract [en]

    PurposeThis study aimed to develop an algorithm for uncovering associations masked by extreme reporting rates, characterize the occurrence of masking by influential outliers in two spontaneous reporting databases and evaluate the impact of outlier removal on disproportionality analysis. MethodsWe propose an algorithm that identifies influential outliers and carries out parallel analysis after their omission. It considers masking of drugs as well as of adverse drug reactions (ADRs), uses a direct measure of the masking effect and makes no assumptions regarding the number of outliers per drug or ADR. The occurrence of masking is characterized in the WHO Global Individual Case Safety Report database, VigiBase and a regional collection of reports from Shanghai, China. ResultsFor WHO-ART critical terms such as myocardial infarction, rhabdomyolysis and hypoglycaemia outlier removal led to a 25-50% increase in the number of Statistics of Disproportionate Reporting (SDR) and gains in time to detection of 1-2years, while keeping the rate of spurious SDRs from the parallel analysis at 1%. Twenty-three per cent of VigiBase and 18% of Shanghai SRS reports listed an influential outlier. Twenty-seven per cent of the ADRs and 5% of the drugs in VigiBase, and 2% of the ADRs and 3% of the drugs in Shanghai SRS were involved in an outlier. The overall increase in the number of SDRs for both datasets was 3%. ConclusionMasking by outliers has substantial impact on specific ADRs including, in VigiBase, rhabdomyolysis, myocardial infarction and hypoglycaemia. It is a local phenomenon involving a fair number of reports but yielding a limited number of additional SDRs.

  • 14. Kratz, Felix
    et al.
    Senter, Peter
    Steinhagen, Henning
    Kurrikoff, Kaido
    Suhorutsenko, Julia
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Cell-Penetrating Peptides in Cancer Targeting2012In: Drug Delivery in Oncology: From Basic Research to Cancer Therapy / [ed] Felix Kratz, Peter Senter, Henning Steinhagen, Wiley-VCH Verlagsgesellschaft, 2012, p. 1189-1217Chapter in book (Refereed)
  • 15.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Alvarez-Salas, Elena
    Grigoleit, Jan-Sebastian
    Well-being and immune response: a multi-system perspective2016In: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 29, p. 34-41Article in journal (Refereed)
    Abstract [en]

    Whereas it is well-established that inflammation and other immune responses can change how we feel, most people are still surprised to hear that, conversely, well-being and its violations also affect our immune system. Here we show that those effects are highly adaptive and bear potential for both research and therapeutic applications. The studies discussed in this review demonstrate that immunity is tuned by ones emotions, personality, and social status as well as by other life style variables like sleep, nutrition, obesity, or exercise. We further provide a short excursion on the effects of stress and depression on immunity and discuss acute experimental endotoxemia as a model to study the effects of well-being on the innate immune response in humans.

  • 16. Lindh, Martin
    et al.
    Karlen, Anders
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Karolinska Institutet, Sweden.
    Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 5, p. 1571-1576Article in journal (Refereed)
    Abstract [en]

    Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

  • 17. Lundborg, Magnus
    et al.
    Wennberg, Christian L.
    Narangifard, Ali
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Norlen, Lars
    Predicting drug permeability through skin using molecular dynamics simulation2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 283, p. 269-279Article in journal (Refereed)
    Abstract [en]

    Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.

  • 18. Malina, Tamás
    et al.
    Krecsák, László
    Westerström, Alexander
    Stockholm University, Faculty of Science, Department of Physics.
    Szeman-Nágy, Gábor
    Gyémánt, Gyöengyi
    M-Hamvas, Márta
    Rowan, Edward G.
    Harvey, Alan L.
    Warrell, David A.
    Pál, Balázs
    Rusznák, Zoltán
    Vasas, Gábor
    Individual variability of venom from the European adder (Vipera berus berus) from one locality in Eastern Hungary2017In: Toxicon, ISSN 0041-0101, E-ISSN 1879-3150, Vol. 135, p. 59-70Article in journal (Refereed)
    Abstract [en]

    We have revealed intra-population variability among venom samples from several individual European adders (Vipera berus berus) within a defined population in Eastern Hungary. Individual differences in venom pattern were noticed, both gender-specific and age-related, by one-dimensional electrophoresis. Gelatin zymography demonstrated that these individual venoms have different degradation profiles indicating varying protease activity in the specimens from adders of different ages and genders. Some specimens shared a conserved region of substrate degradation, while others had lower or extremely low protease activity. Phospholipase A(2) activity of venoms was similar but not identical. Interspecimen diversity of the venom phospholipase A(2)-spectra (based on the components' molecular masses) was detected by MALDI-TOF MS. The lethal toxicity of venoms (LD50) also showed differences among individual snakes. Extracted venom samples had varying neuromuscular paralysing effect on chick biventer cervicis nerve-muscle preparations. The paralysing effect of venom was lost when calcium in the physiological salt solution was replaced by strontium; indicating that the block of twitch responses to nerve stimulation is associated with the activity of a phospholipase-dependent neurotoxin. In contrast to the studied V.b. berus venoms from different geographical regions so far, this is the first V.b berus population discovered to have predominantly neurotoxic neuromuscular activity. The relevance of varying venom yields is also discussed. This study demonstrates that individual venom variation among V.b. berus living in particular area of Eastern Hungary might contribute to a wider range of clinical manifestations of V.b. hems envenoming than elsewhere in Europe.

  • 19. Mann, Anita
    et al.
    Thakur, Garima
    Shukla, Vasundhara
    Singh, Anand Kamal
    Khanduri, Richa
    Naik, Rangeetha
    Jiang, Yang
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kalra, Namita
    Dwarakanath, B. S.
    Langel, Ulo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ganguli, Munia
    Differences in DNA Condensation and Release by Lysine and Arginine Homopeptides Govern Their DNA Delivery Efficiencies2011In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 8, no 5, p. 1729-1741Article in journal (Refereed)
    Abstract [en]

    Designing of nanocarriers that can efficiently deliver therapeutic DNA payload and allow its smooth intracellular release for transgene expression is still a major constraint. The optimization of DNA nanocarriers requires thorough understanding of the chemical and structural characteristics of the vector-nucleic acid complexes and its correlation with the cellular entry, intracellular state and transfection efficiency. L-Lysine and L-arginine based cationic peptides alone or in conjugation with other vectors are known to be putative DNA delivery agents. Here we have used L-lysine and L-arginine homopeptides of three different lengths and probed their DNA condensation and release properties by using a multitude of biophysical techniques including fluorescence spectroscopy, gel electrophoresis and atomic force microscopy. Our results clearly showed that although both lysine and arginine based homopeptides condense DNA via electrostatic interactions, they follow different pattern of DNA condensation and release in vitro. While lysine homopeptides condense DNA to form both monomolecular and multimolecular complexes and show differential release of DNA in vitro depending on the peptide length, arginine homopeptides predominantly form multimolecular complexes and show complete DNA release for all peptide lengths. The cellular uptake of the complexes and their intracellular state (as observed through flow cytometry and fluorescence microscopy) seem to be controlled by the peptide chemistry. The difference in the transfection efficiency of lysine and arginine homopeptides has been rationalized in light of these observations.

  • 20.
    Miller, Frank
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Statistics.
    Zohar, Sarah
    Stallard, Nigel
    Madan, Jason
    Posch, Martin
    Hee, Siew Wan
    Pearce, Michael
    Vågerö, Mårten
    Day, Simon
    Approaches to sample size calculation for clinical trials in rare diseases2018In: Pharmaceutical statistics, ISSN 1539-1604, E-ISSN 1539-1612, Vol. 17, no 3, p. 214-230Article in journal (Refereed)
    Abstract [en]

    We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision-theoretic approach. These approaches are compared head-to-head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult-onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision-theoretic approach. These should therefore be discussed extensively.

  • 21. Pellè, Lucia
    et al.
    Carlsson, Henrik
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cipollini, Monica
    Bonotti, Alessandra
    Foddis, Rudy
    Cristaudo, Alfonso
    Romei, Cristina
    Elisei, Rossella
    Gemignani, Federica
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Landi, Stefano
    The polymorphism rs2480258 within CYP2E1 is associated with different rates of acrylamide metabolism in vivo in humans2018In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 92, no 6, p. 2137-2140Article in journal (Refereed)
    Abstract [en]

    In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. The goal of the present study was to further assess the role of rs2480258 by measuring the rate of AA > GA biotransformation in vivo. In blood samples from a cohort of 120 volunteers, the internal doses of AA and GA were assessed by AA and GA adducts to hemoglobin (Hb) measured by mass spectrometry. The rate of biotransformation was assessed by calculating the GA-Hb/AA-Hb ratio. To maximize the statistical power, 60 TT was compared to 60 CC-homozygotes and the results showed that TT homozygotes had a statistically significant reduced rate of biotransformation. Present results reinforced the notion that T-allele of rs2480258 is a marker of low functional activity of CYP2E1. Moreover, we studied the role of polymorphisms (SNPs) within glutathione-S-transferases (GSTs) enzymes and epoxide hydrolase (EPHX), verifying previous findings that SNPs within GSTs and EPHX influence the metabolism rate.

  • 22.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    28-Day dietary exposure of mice to a low total dose (7 mg/kg) of perfluorooctanesulfonate (PFOS) alters neither the cellular compositions of the thymus and spleen nor humoral immune responses: Does the route of administration play a pivotal role in PFOS-induced immunotoxicity?2010In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 267, no 03-jan, p. 132-139Article in journal (Refereed)
    Abstract [en]

    Short-term exposure of mice to high doses of perfluorooctanesulfonate (PFOS), an ubiquitous and highly persistent environmental contaminant, induces various metabolic changes and toxic effects, including immunotoxicity. However, extrapolation of these findings to the long-term, low-dose exposures to which humans are subject is highly problematic. In this connection, recent studies have concluded that sub-chronic (28-day) exposure of mice by oral gavage to doses of PFOS that result in serum levels comparable to those found in general human populations suppress adaptive immunity. Because of the potential impact of these findings on environmental research and monitoring, we have examined here whether sub-chronic dietary exposure (a major route of human exposure) to a similarly low-dose of PFOS also suppress adaptive immune responses. Dietary treatment of male B6C3F1 mice for 28 days with a dose of PFOS that resulted in a serum concentration of 11 mu g/ml (ppm) significantly reduced body weight gain and increased liver mass. However, this treatment did not alter the cellular compositions of the thymus and spleen; the number of splenic cells secreting IgM antibodies against sheep red blood cell (SRBC); serum levels of IgM and IgG antibodies specifically towards SRBC; or circulating levels of IgM antibodies against the T-cell-independent antigen trinitrophenyl conjugated to lipopolysaccharide (TNP-LPS). These findings indicate that such sub-chronic dietary exposure of mice to PFOS resulting in serum levels approximately 8-85-fold greater than those observed in occupationally exposed individuals does not exert adverse effects on adaptive immunity.

  • 23. Rahman, Inayat U.
    et al.
    Idrees, Muhammad
    Waqas, Mohammad
    Karim, Abdul
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    A study of the interaction between H-pylori mice passage strains and gastric epithelial cells2018In: Pakistan Journal of Pharmaceutical Sciences, ISSN 1011-601X, Vol. 31, no 3, p. 769-775Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylon (H. pylori) infections are very serious health problem that are further worsened by increasing/developing resistance to the current antibiotics. Therefore, new therapeutic agents are needed for H. pylori eradication. Use of a CD46 derived peptide (P3) as bactericidal agent against H. pylon has shown high activity rate in vivo and this study examines the changes in H. pylori features in response to effect of P3 treatment. AGS cells were infected with H. pylon wild type strain 67:21 and its mice passage strains (P3 treated and untreated strains) and further examined using immunoblotting assay, FACS and Urease activity analysis. Comparatively we found increased level of Urease alpha subunit A (UreA) and alkyl hydroperoxide reductase C (AhpC) proteins for P3 treated strain of H. pylori than its wild type or untreated strain after infection of AGS cells. Conclusion These results suggest that there might be a high rate of adherence to host cells for the P3 treated passage strain than untreated or wild type strain. Our findings also indicate that either adhesins are being changed or H pylon interaction to the host cells is affected after P3 treatment.

  • 24.
    Regberg, Jakob
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Luis Daniel, Ferreira Vasconcelos
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Madani, Fatemeh
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Hällbrink, Mattias
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    pH-responsive PepFect cell-penetrating peptides2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 501, no 1-2, p. 32-38Article in journal (Refereed)
    Abstract [en]

    A series of cell-penetrating PepFect peptide analogues was developed by substitutions of the galanin-derived N-terminal sequence. Histidine modifications were incorporated in order to make the peptides pH-responsive. The peptides were all able to form non-covalent complexes with an oligonucleotide cargo by co-incubation in buffer. The complexes were characterized by dynamic light scattering and circular dichroism, and an assay to evaluate the peptide-cargo affinity was developed. Cellular bioactivity was studied in HeLa cells using a luciferase-based splice correction assay. In addition, the membrane interactions of the peptides in large unilammelar vesicles was studied using a calcein leakage assay. The effects of substitutions were found to be dependent of the non-modified, C-terminal sequence of the peptides; for analogues of PepFect 3 we observed an increase in membrane activity and bioactivity for histidine-containing analogues, whereas the same modifications introduced to PepFect 14 lead to a decreased bioactivity. Peptides modified with a leucine/histidine sequence were found to be pH responsive, complexes formed from these peptides were small at pH 7 and grew under acidic conditions. The most promising of the novel PepFect 3 analogues, PepFect 132 has a significantly higher bioactivity and membrane activity than the parent peptide PepFect 3.

  • 25.
    Skiöld, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Azimzadeh, Omid
    Merl-Pham, Juliane
    Naslund, Ingemar
    Wersall, Peter
    Lidbrink, Elisabet
    Tapio, Soile
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Unique proteomic signature for radiation sensitive patients; a comparative study between normo-sensitive and radiation sensitive breast cancer patients2015In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 776, p. 128-135Article in journal (Refereed)
    Abstract [en]

    Radiation therapy is a cornerstone of modern cancer treatment. Understanding the mechanisms behind normal tissue sensitivity is essential in order to minimize adverse side effects and yet to prevent local cancer reoccurrence. The aim of this study was to identify biomarkers of radiation sensitivity to enable personalized cancer treatment. To investigate the mechanisms behind radiation sensitivity a pilot study was made where eight radiation-sensitive and nine normo-sensitive patients were selected from a cohort of 2914 breast cancer patients, based on acute tissue reactions after radiation therapy. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 h incubation at 37 degrees C. The leukocytes of the two groups were isolated, pooled and protein expression profiles were investigated using isotope-coded protein labeling method (ICPL). First, leukocytes from the in vitro irradiated whole blood from normo-sensitive and extremely sensitive patients were compared to the non-irradiated controls. To validate this first study a second ICPL analysis comparing only the non-irradiated samples was conducted. Both approaches showed unique proteomic signatures separating the two groups at the basal level and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity supporting our previous study on oxidative stress response. This investigation provides unique characteristics of radiation sensitivity essential for individualized radiation therapy.

  • 26. Svensson, Fredrik
    et al.
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Karolinska Institutet, Sweden.
    Bender, Andreas
    Improving Screening Efficiency through Iterative Screening Using Docking and Conformal Prediction2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 3, p. 439-444Article in journal (Refereed)
    Abstract [en]

    High-throughput screening, where thousands of molecules rapidly can be assessed for activity against a protein, has been the dominating approach in drug discovery for many years. However, these methods are costly and require much time and effort. In order to suggest an improvement to this situation, in this study, we apply an iterative screening process, where an initial set of compounds are selected for screening based on molecular docking. The outcome of the initial screen is then used to classify the remaining compounds through a conformal predictor. The approach was retrospectively validated using 41 targets from the Directory of Useful Decoys, Enhanced (DUD-E), ensuring scaffold diversity among the active compounds. The results show that 57% of the remaining active compounds could be identified while only screening 9.4% of the database. The overall hit rate (7.6%) was also higher than, when using docking alone (5.2%). When limiting the search to the top scored compounds from docking, 39.6% of the active compounds could be identified, compared to 13.5% when screening the same number of compounds solely based on docking. The use of conformal predictors also gives a clear indication of the number of compounds to screen in the next iteration. These results indicate that iterative screening based on molecular docking and conformal prediction can be an efficient way to find active compounds while screening only a small part of the compound collection.

  • 27.
    Udekwu, Klas I.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Weiss, Howard
    Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen2018In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 12, p. 2249-2257Article in journal (Refereed)
    Abstract [en]

    Introduction: Antibiotics have greatly reduced the morbidity and mortality due to infectious diseases. Although antibiotic resistance is not a new problem, its breadth now constitutes a significant threat to human health. One strategy to help combat resistance is to find novel ways to use existing drugs, even those that display high rates of resistance. For the pathogens Escherichia coif and Pseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug 1.3 and vice versa. These research groups have proposed cycling such pairs to treat infections, and similar treatment strategies are being investigated for various cancer forms as well. While an exciting treatment prospect, no cycling experiments have yet been performed with consideration of pharmacokinetics and pharmacodynamics. To test the plausibility of such schemes and optimize them, we create a mathematical model with explicit pharmacokinetic/pharmacodynamic considerations.

    Materials and methods: We evaluate antibiotic cycling protocols using pairs of such antibiotics and investigate the speed of ascent of multiply resistant mutants.

    Results: Our analyses show that when using low concentrations of antibiotics, treatment failure will always occur due to the rapid ascent and fixation o f resistant mutants. However, moderate to high concentrations of some combinations of bacteriostatic and bactericidal antibiotics with multiday cycling prevent resistance from developing and increase the likelihood of treatment success.

    Conclusion: Our results call for guarded optimism in application and development of such treatment protocols.

  • 28. Wallerstedt, Susanna M.
    et al.
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Linke, Johannes
    Vitols, Sigurd
    Long-term use of proton pump inhibitors and prevalence of disease-and drug-related reasons for gastroprotection-a cross-sectional population-based study2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, no 1, p. 9-16Article in journal (Refereed)
    Abstract [en]

    Purpose To analyse the prevalence of long-term use of proton pump inhibitors (PPI) with respect to underlying diseases and drugs, and to find predictors for such treatment when an evident rationale for the PPI treatment is lacking. Methods The study cohort consisted of individuals, >= 65 years in 2010, residing in the Region Vastra Gotaland during 2005-2010. For individuals with and without long-term use of PPI in 2010, we investigated the prevalence of an underlying diagnosis, that is, an acid-related disease during the five preceding years, as well as concomitant long-term use of antiplatelet agents or cyclooxygenase inhibitors. Results In all, 278 205 individuals (median age: 74 years; 55% female; median 3 drugs per person; 5% nursing home residents, 11% with multi-dose drug dispensing) were included in the analyses, 32 421 (12%) of whom were on long-term treatment with PPI in 2010. For 12 253 individuals (38%) with such treatment, no underlying rationale was found. In individuals without a disease-or a drug-related reason for PPI use, nursing home residence, number of drugs, female sex, but not multi-dose drug dispensing, were associated with long-term use of PPI; adjusted odds ratios (95% confidence interval): 1.63 (1.49; 1.78), 1.27 (1.26; 1.28), 1.24 (1.19; 1.29), and 0.94 (0.88; 1.01), respectively. Conclusions Long-term use of PPI occurs in one out of nine individuals in the older population. For four out of ten of these, no reason for PPI use can be identified. Nursing home residence, female sex, and greater number of drugs predict non-rational long-term use of PPI.

  • 29.
    Westerstrom, Alexander
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Petrov, Boyan
    Tzankov, Nikolay
    Envenoming following bites by the Balkan adder Vipera berus bosniensis - First documented case series from Bulgaria2010In: Toxicon, ISSN 0041-0101, E-ISSN 1879-3150, Vol. 56, no 8, p. 1510-1515Article in journal (Refereed)
    Abstract [en]

    We report the first detailed accounts of bites by the Balkan adder, Vipera bents bosniensis from Bulgaria. Documentation of bites by this subspecies is very rare in the literature and most available accounts are from the northern limit of its distribution. V berus bosniensis is considered to possess neurotoxic venom but little evidence has hitherto been available to support this supposition. In this case series symptoms typical of adder bites developed including oedema, nausea, dizziness, lymphangitis, vomiting, and diarrhoea together with aberrant symptoms such as diplopia and ptosis that confirm the presence of neurotoxic venom in Balkan adders. In addition, unusual and atypical symptoms of adder bites such as painless bites and muscle cramps appeared. The inadequate treatment in hospital and the remote habitats in which this species is encountered are potential sources of complication.

1 - 29 of 29
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