1.
Khoshnood, Ardavan
(author)
Prehospital Diagnosis and Oxygen Treatment in ST Elevation Myocardial Infarction
2017
Doctoral thesis (other academic/artistic) abstract
IntroductionPaper I: An Artificial Neural Network (ANN) was constructed to identify ST Elevation Myocardial Infarction (STEMI) and predict the need for Percutaneous Coronary Intervention (PCI). Paper II, III and IV: Studies suggest that O2 therapy may be harmful in STEMI patients. We therefore conducted the SOCCER study to evaluate the effects of O2 therapy in STEMI patients.MethodsPaper I: 560 ambulance ECGs sent to the Cardiac Care Unit (CCU), was together with the CCU physicians interpretation and decision of conducting an acute PCI or not collected, and compared with the interpretation and PCI decision of the ANN. Paper II, III, IV: Normoxic (≥94%) STEMI patients accepted for acute PCI were in the ambulance randomized to standard care with 10 L/min O2 or room air. A subset of the patients underwent echocardiography for determination of the Left Ventricular Ejection Fraction (LVEF) and the Wall Motion Score Index (WMSI). All patients had a Cardiac Magnetic Resonance Imaging (CMRI) to evaluate Myocardial area at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI).ResultsPaper I: The area under the ANN’s receiver operating characteristics curve for STEMI detection as well as predicting the need of acute PCI were very good.Paper II, III, IV: No significant differences could be shown in discussing MaR, MSI or IS between the O2 group (n=46) and the air group (n=49). Neither could any differences be shown for LVEF and WMSI at the index visit as well after six months between the O2 group (n=46) and the air group (n=41)ConclusionsPaper I: The results indicate that the number of ECGs sent to the CCU could be reduced with 2/3 as the ANN would safely identify ECGs not being STEMI.Paper II, III, IV: The results suggest that it is safe to withhold O2 therapy in normoxic, stable STEMI patients.
2.
Skånberg Dahlstedt, Ami, 1967
(author)
Älskade Vampyr - om livet med ett barn med diabetes typ 1
2010
Book (other academic/artistic) abstract
Älskade vampyr skildrar hur tillvaron ställs på ända för en svensk småbarnsfamilj när yngste sonen får en allvarlig diagnos: diabetes typ 1. Föräldrar och storebror tvingas anpassa sig till den nya situationen och framförallt vänja sig vid osäkerheten och rädslan för komplikationer som sjukdomen för med sig. Rutiner, kontroller och insulinsprutor blir sakta men säkert en naturlig del av tillvaron och de lyckas hålla ihop och hålla modet uppe. Och mer än så. De ger sig ut på äventyr tillsammans. Till Australien. Läsaren får en god inblick i hur det kan gå till när syskon, släkt, vänner, skol- och vårdpersonal, grannar med flera tvingas förhålla sig till den nya situationen - som väldigt många saknar kunskap om. Röster från läsare "Ami tröstar, förklarar, läker och bekräftar att man får lov att känna precis som man vill. Det är en bok som tar hand om känslorna när någon man älskar får en allvarlig sjukdom. Hennes bok handlar inte bara om diabetes, den handlar om alla som får kämpa för sin rätt att vara sig själva." Mia Skäringer, skådespelare och granne "Boken är skriven ur ett intressant och annorlunda perspektiv där författaren på ett gripande sätt tar med oss djupt in i vardagsdetaljerna hos en familj som lever med diabetes. Det är säkert många föräldrar som har barn med diabetes som kommer att känna igen sig i hur man från början kastas mellan hopp och förtvivlan, för att så småningom få ett nytt fäste i vardagen med diabetes. Diabeteslägret och sedan insulinpumpen blev en vändpunkt för Egil, och jag kan bara hålla med - pump är den bästa typen av behandling för ett barn med diabetes och på diabetesläger träffar man kompisar som förstår hur det är att ha diabetes." Ragnar Hanås, barnläkare och expert på diabetes typ 1
3.
4.
Theurich, Melissa Ann, et al.
(author)
Breastfeeding Rates and Programs in Europe : A Survey of 11 National Breastfeeding Committees and Representatives
2019
In: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 68:3, s. 400-407
Journal article (peer-reviewed) abstract
INTRODUCTION: Among the world's regions, the WHO European Region has the lowest rates of exclusive breastfeeding at age 6 months with around 25%. Low rates and early cessation of breastfeeding have important adverse health consequences for women, infants and young children. Protecting, promoting and supporting breastfeeding are a public health priority.OBJECTIVES: National breastfeeding data and monitoring systems among selected European countries and the WHO European Region are compared. Mechanisms for the support, protection and promotion of breastfeeding are reviewed and successes and challenges in implementation of national programs are presented.METHODS: National representatives of national breastfeeding committees and initiatives in eleven European countries, including Belgium, Croatia, Denmark, Germany, Ireland, Italy, The Netherlands, Norway, Spain, Sweden and Switzerland, participated in a standardized survey. Results are evaluated and compared in a narrative review.RESULTS: Variation exists in Europe on breastfeeding rates, methodology for data collection and mechanisms for support, protection and promotion of breastfeeding. Directly after birth, between 56 and 98 % of infants in all countries were reported to receive any human milk, and at 6 months 38-71% and 13-39 % of infants to be breastfed or exclusively breastfed, respectively. National plans addressing breastfeeding promotion, protection and support exist in 6 of the 11 countries.CONCLUSIONS: National governments should commit to evidence-based breastfeeding monitoring and promotion activities, including financial and political support, to improve breastfeeding rates in the Europe. Renewed efforts for collaboration between countries in Europe, including a sustainable platform for information exchange, are needed.
5.
Deyou, Tsegaye, et al.
(author)
Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp teitensis
2017
In: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:7, s. 2060-2066
Journal article (peer-reviewed) abstract
A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 mu M, respectively.
6.
Mabeyo, P. E., et al.
(author)
Selenium Accumulating Leafy Vegetables Are a Potential Source of Functional Foods
2015
In: International Journal of Food Science. - : Hindawi Limited. - 2356-7015 .- 2314-5765. ; 2015
Journal article (peer-reviewed) abstract
Selenium deficiency in humans has been associated with various diseases, the risks of which can be reduced through dietary supplementation. Selenium accumulating plants may provide a beneficial nutrient for avoiding such illnesses. Thus, leafy vegetables such as Amaranthus hybridus, Amaranthus sp., Cucurbita maxima, Ipomoea batatas, Solanum villosum, Solanum scabrum, and Vigna unguiculata were explored for their capabilities to accumulate selenium when grown on selenium enriched soil and for use as a potential source of selenium enriched functional foods. Their selenium contents were determined by spectrophotometry using the complex of 3,3′-diaminobenzidine hydrochloride (DABH) as a chromogen. The mean concentrations in the leaves were found to range from to μg/g dry weight (DW), with C. maxima accumulating the most selenium. In stems, the accumulated selenium content ranged from μg/g in Amaranthus sp. to μg/g DW in C. maxima and was hence significantly different (). The cancer cell line MDA-MB-231 was used in cytotoxicity assays to determine the anticancer potential of these extracts. With exception of S. scabrum and S. villosum, no cytotoxicity was detected for the selenium enriched vegetable extracts up to 100μg/mL concentration. Hence, following careful evaluation the studied vegetables may be considered as selenium enriched functional foods.
7.
Makungu, Marco, et al.
(author)
Pterocarpans and isoflavones from the roots of Millettia micans and of Millettia dura
2016
In: Advances in Drug Discovery and Development. ; 1:1, s. 1-8
Journal article (peer-reviewed) abstract
From the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia micans, a new pterocarpan, (6aR,11aR)-7,8,9-trimethoxy-3-hydroxypterocarpan (1), named micanspterocarpan, was isolated. Similarinvestigation of the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia dura gave a further new pterocarpan,3-O-prenylmaackiain (2) along with six known isoflavones (3-8) and a chalcone (9). All purifiedcompounds were identified by NMR and MS, and the absolute configuration of 1 was established by quantumchemical CD calculation. The isolated constituents, calopogonium isoflavone B (3) and isoerythrin A-4'-(3-methylbut-2-enyl) ether (4) showed marginal activities against the 3D7 and the Dd2 strains of Plasmodiumfalciparum (70-90% inhibition at 40 M). Maximaisoflavone B (5) and 7,2'-dimethoxy-4',5'-methylenedioxyisoflavone (7) were weakly cytotoxic (IC50 153.5 and 174.1 uM, respectively) against theMDB-MB-231 human breast cancer cell line. None of the tested compounds showed toxicity against theHEK-293 human embryonic kidney cell line at 40 uM.
8.
Nyandoro, Stephen S., 1975, et al.
(author)
N-Cinnamoyltetraketide Derivatives from the Leaves of Toussaintia orientalis
2015
In: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 78:8, s. 2045-2050
Journal article (peer-reviewed) abstract
Seven N-cinnamoyltetraketides (1–7), including the new Z-toussaintine E (2), toussaintine F (6), and toussaintine G (7), were isolated from the methanol extract of the leaves of Toussaintia orientalis using column chromatography and HPLC. The configurations of E-toussaintine E (1) and toussaintines A (3) and D (5) are revised based on single-crystal X-ray diffraction data from racemic crystals. Both the crude methanol extract and the isolated constituents exhibit antimycobacterial activities (MIC 83.3–107.7 μM) against the H37Rv strain of Mycobacterium tuberculosis. Compounds 1, 3, 4, and 5 are cytotoxic (ED50 15.3–105.7 μM) against the MDA-MB-231 triple negative aggressive breast cancer cell line.
9.
Nyandoro, Stephen S., 1975, et al.
(author)
Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves
2017
In: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:1, s. 114-125
Journal article (peer-reviewed) abstract
Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A–F (6–11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15–21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2–40 μM, and against HEK293 mammalian cells (IC50 2.7–3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03–8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.
10.
Sukhovey, Yurij G., et al.
(author)
Functional Conjugation of the Different Regulatory Responses to the Stress Stimuli in Healthy Human Subjects
2016
In: Open Journal of Applied Sciences. - : Scientific Research Publishing, Inc.. - 2165-3917 .- 2165-3925. ; 6, s. 489-500
Journal article (peer-reviewed) abstract
Present article discusses the physiological mechanisms of the state employees adaptation duringactive training in temporary groups. It is suggested that adaptive mechanisms to adverse effectsmay be studied basing on the concept of functional isomorphism of the psychic and immune systems.Adaptive mechanisms were studied through the monitoring of the stress factors’ impact upon thelaw enforcement officers when training outside the places of permanent deployment. The specificpurpose of present study was to evaluate the physiological indicators of the psychic, immune andendocrine systems dynamics at different stages of adaptation of the live organism to a stressfulsituation, hoping to get better insight into possible relations between psychic and immune domains.Through monitoring of the dynamics of the endocrine and immune responses to the psychic stimuli,it was possible to correlate the stages of the stress onset to the phases of specific immune reactions.Strong correlations between the parameters characterizing activation of the psychic and immuneresponses support the hypothesis of the presence of “strong cooperation” between psychic andimmune domains. It supports earlier hypothesis that we are monitoring
11.
Dinér, Peter, 1976, et al.
(author)
Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo 3,4-d pyrimidin-4-amines as RET Kinase Inhibitors
2012
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:10, s. 4872-4876
Journal article (peer-reviewed) abstract
A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.
12.
Hadrévi, Jenny, 1977-, et al.
(author)
Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study
2013
In: European Journal of Applied Physiology. - : Springer Verlag (Germany). - 1439-6319 .- 1439-6327. ; 113:12, s. 2977-2989
Journal article (peer-reviewed) abstract
The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle. less thanbrgreater than less thanbrgreater thanMicrodialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography-mass spectrometry (GC-MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann-Whitney U test of group difference in individual metabolites was also performed. less thanbrgreater than less thanbrgreater thanA large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle. less thanbrgreater than less thanbrgreater thanThis study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.
13.
Xin, D. L., et al.
(author)
Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task
2017
In: BMC Neuroscience. - : BioMed Central. - 1471-2202. ; 18
Journal article (peer-reviewed) abstract
Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
14.
Mochalina, Natalia, et al.
(author)
ABC om Yrsel på akuten
2015
In: Läkartidningen. - 0023-7205. ; 112:9, s. 399-404
Journal article (peer-reviewed) abstract
The majority of patients who present to the Emergency Department with vertigo suffer from benign conditions. However, a few percent of these patients have life-threatening conditions, such as a cerebellar stroke. The HINTS clinical decision rule (Head-Impulse test, Nystagmus, Test-of-Skew) allows the physician to identify patients with an acute vestibular syndrome of central origin. HINTS is more sensitive than early magnetic resonance imaging. There is no role for computed tomography in the evaluation of patients with isolated acute vestibular syndrome in the Emergency Department. For patients with benign paroxysmal positional vertigo, simple reposition maneuvers are effective for symptom relief.
15.
Palmnäs, Marie, 1988, et al.
(author)
Serum Metabolomics of Activity Energy Expenditure and its Relation to Metabolic Syndrome and Obesity
2018
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 8:1
Journal article (peer-reviewed) abstract
Modifiable lifestyle factors, including exercise and activity energy expenditure (AEE), may attenuate the unfavorable health effects of obesity, such as risk factors of metabolic syndrome (MetS). However, the underlying mechanisms are not clear. In this study we sought to investigate whether the metabolite profiles of MetS and adiposity assessed by body mass index (BMI) and central obesity are inversely correlated with AEE and physical activity. We studied 35 men and 47 women, aged 30–60 years, using doubly labeled water to derive AEE and the Sedentary Time and Activity Reporting Questionnaire (STAR-Q) to determine the time spent in moderate and vigorous physical activity. Proton nuclear magnetic resonance spectroscopy was used for serum metabolomics analysis. Serine and glycine were found in lower concentrations in participants with more MetS risk factors and greater adiposity. However, serine and glycine concentrations were higher with increasing activity measures. Metabolic pathway analysis and recent literature suggests that the lower serine and glycine concentrations in the overweight/obese state could be a consequence of serine entering de novo sphingolipid synthesis. Taken together, higher levels of AEE and physical activity may play a crucial part in improving metabolic health in men and women with and without MetS risk factors.
16.
Okroj, Marcin, et al.
(author)
Prevalence of antibodies against Kaposi's sarcoma associated herpes virus (KSHV) complement inhibitory protein (KCP) in KSHV-related diseases and their correlation with clinical parameters.
2011
In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 29, s. 1129-1134
Journal article (peer-reviewed) abstract
Kaposi's sarcoma-associated herpes virus (KSHV) encodes its own inhibitor of the complement system, designated KSHV complement control protein (KCP). Previously, we detected anti-KCP antibodies in a small group of 22 patients suffering from Kaposi's sarcoma (KS) and KSHV-related lymphoproliferative diseases (Vaccine, 25:8102-9). Anti-KCP antibodies were more prevalent in individuals suffering from KSHV-related lymphomas than KS and also in those with high titer of antibodies against lytic KSHV antigens. Herein we analyze anti-KCP antibodies in 175 individuals originating from three different groups from northern Sweden or Italy, which included patients suffering from classical or HIV-associated KS, Multicentric Castleman's Disease, KSHV-associated solid lymphoma, pleural effusion lymphoma and healthy individuals with detectable KSHV immune response. Our current study confirmed previous observations concerning antibody prevalence but we also analyzed correlations between anti-KCP antibodies and classical KS evolution, clinical stage and viral load in body fluids. Furthermore, we show that patient's anti-KCP antibodies are able to decrease the ability of KCP to inhibit complement. This fact combined with results of statistical analysis suggests that KCP inactivation by specific antibodies may influence progression of classical KS.
17.
Bally, Marta, 1981, et al.
(author)
Norovirus GII.4 Virus-like Particles Recognize Galactosylceramides in Domains of Planar Supported Lipid Bilayers.
2012
In: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 51:48, s. 12020-4
Journal article (peer-reviewed) abstract
A sticky situation: Domain-dependent recognition of the glycosphingolipid galactosylceramide by norovirus-like particles (see picture; red/yellow) is shown using supported lipid bilayers (purple) as model membranes. Optimal ligand presentation is found to promote strong binding to GalCer. This presentation can be found at the edges of the glycosphingolipid-enriched domains (green) and binding is repressed in the absence of these domains.
18.
Mukherjee, Sourav P., et al.
(author)
Graphene Oxide Elicits Membrane Lipid Changes and Neutrophil Extracellular Trap Formation
2018
In: Chem. - : Elsevier BV. - 2451-9294 .- 2451-9308. ; 4:2, s. 334-358
Journal article (peer-reviewed) abstract
Understanding the biological interactions of graphene-based materials is important for the safe use of these materials. Previous studies have explored the interaction between graphene oxide (GO) and macrophages but not the impact of GO on neutrophils, key cells of the immune system. Here, we synthesized GO sheets with differing lateral dimensions and showed by using an array of analytical and imaging techniques, including transmission and scanning electron microscopy, confocal microscopy, and time-of-flight secondary ion mass spectroscopy (ToF-SIMS), that GO elicited the formation of neutrophil extracellular traps (NETs). ToF-SIMS revealed pronounced perturbations of plasma membrane lipids, including a decrease in cholesterol and increased levels of oxidized cholesterol species. The induction of NETs was size dependent and associated with the production of mitochondrial reactive oxygen species and calcium influx. Importantly, antioxidant treatment reduced the production of NETs. These studies provide evidence that a previously undescribed biological effect of GO manifests through direct effects on membrane lipids. Graphene oxide (GO) is being investigated for various biomedical applications. Understanding the interactions between GO and living cells is of critical importance for the safe use of these materials in patients. In the present study, we identified effects of GO on neutrophils, the most common type of white blood cell. We first synthesized GO sheets of different sizes and carefully characterized the materials. Then, using various analytical and imaging techniques, we found that GO triggered so-called neutrophil extracellular traps or NETs. NETs are normally deployed by neutrophils to capture and destroy pathogens. We were able to show that GO caused significant changes in the lipid composition of the neutrophil cell membrane, whereby the oxidation of cholesterol set into motion a cascade of intracellular events leading to the formation of NETs. These studies show that GO acts directly on the neutrophil cell membrane and leads to the activation of a conserved anti-pathogen response. Graphene oxide (GO) is a promising material for a variety of biomedical and other applications. The increasing use of GO necessitates careful assessment of potential health hazards. Using primary neutrophils as a model, Mukherjee et al. show that GO elicits neutrophil extracellular traps. Furthermore, by using ToF-SIMS, the authors noted pronounced perturbations of plasma membrane lipids in cells exposed to GO.
19.
20.
von Otter, Malin, 1978, et al.
(author)
Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract
2010
In: Mechanisms of Ageing and Development. - : Elsevier BV. - 0047-6374 .- 1872-6216. ; 131:2, s. 105-110
Journal article (peer-reviewed) abstract
Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (pc 0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p(c) = 0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p(c) = 0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
21.
Uvnäs-Moberg, Kerstin, et al.
(author)
Maternal plasma levels of oxytocin during physiological childbirth : a systematic review with implications for uterine contractions and central actions of oxytocin
2019
In: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393. ; 19:1
Journal article (peer-reviewed) abstract
BACKGROUND: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies.METHODS: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects.RESULTS: Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin.CONCLUSIONS: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.
22.
Syberg, K., et al.
(author)
Toward a Conceptual Approach for Assessing Risks from Chemical Mixtures and Other Stressors to Coastal Ecosystem Services
2017
In: Integrated Environmental Assessment and Management. - : Wiley. - 1551-3777 .- 1551-3793. ; 13:2, s. 376-386
Journal article (peer-reviewed) abstract
Growth of human populations and increased human activity, particularly in coastal areas, increase pressure on coastal ecosystems and the ecosystem services (ES) they provide. As a means toward being able to assess the impact of multiple stressors on ES, in the present study we propose an 8-step conceptual approach for assessing effects of chemical mixtures and other stressors on ES in coastal areas: step A, identify the relevant problems and policy aims; step B, identify temporal and spatial boundaries; step C, identify relevant ES; step D, identify relevant stressors (e.g., chemicals); step E, translate impacts into ES units; step F, assess cumulative risk in ES units; step G, rank stressors based on their contribution to adverse effects on ES; and step H, implement regulation and management as appropriate and necessary. Two illustrative case studies (Swedish coastal waters and a coastal lagoon in Costa Rica) are provided; one focuses on chemicals that affect human food supply and the other addresses pesticide runoff and trade-offs among ES. The 2 cases are used to highlight challenges of such risk assessments, including use of standardized versus ES-relevant test species, data completeness, and trade-offs among ES. Lessons learned from the 2 case studies are discussed in relation to environmental risk assessment and management of chemical mixtures. Integr Environ Assess Manag 2017;13:376-386. (C) 2016 SETAC
23.
Tjernberg, L. O., et al.
(author)
Transmissible amyloid
2016
In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 280:2, s. 153-163
Research review (peer-reviewed) abstract
There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.
24.
Olsson, Lars E., et al.
(author)
In Vivo Measurements of T2 Relaxation Time of Mouse Lungs during Inspiration and Expiration
2016
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 11:12
Journal article (peer-reviewed) abstract
Purpose The interest in measurements of magnetic resonance imaging relaxation times, T1, T2, T2*, with intention to characterize healthy and diseased lungs has increased recently. Animal studies play an important role in this context providing models for understanding and linking the measured relaxation time changes to the underlying physiology or disease. The aim of this work was to study how the measured transversal relaxation time (T2) in healthy lungs is affected by normal respiration in mouse. Method T2 of lung was measured in anaesthetized freely breathing mice. Image acquisition was performed on a 4.7 T, Bruker BioSpec with a multi spin-echo sequence (Car-Purcell-MeiboomGill) in both end-expiration and end-inspiration. The echo trains consisted of ten echoes of inter echo time 3.5 ms or 4.0 ms. The proton density, T2 and noise floor were fitted to the measured signals of the lung parenchyma with a Levenberg-Marquardt least-squares three-parameter fit. Results T2 in the lungs was longer (p
25.
Sjörs, Anna, 1981-, et al.
(author)
Salivary cortisol response to acute stress and its relation to psychological factors in women with chronic trapezius myalgia-A pilot study
2010
In: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 35:5, s. 674-685
Journal article (peer-reviewed) abstract
This study investigated differences in HPA axis function, measured as salivary cortisol concentrations, between 18 women with chronic trapezius myalgia (MYA) and 30 healthy female controls (CON). In addition, the interactions between HPA axis reactions to psychosocial stress and aspects of pain, health and psychological symptoms were analyzed. Salivary cortisol was measured both in daily life, to assess the circadian profile, and in the laboratory during light repetitive work and standardized psychosocial stress (Trier Social Stress Test, TSST). MYA and CON exhibited similar circadian rhythms and comparable salivary cortisol response magnitudes after TSST. In subjects defined as responders to the TSST, the mean peak time point of the cortisol response after TSST differed significantly between MYA and CON. Furthermore, negative psychological states and higher pain intensity were related to a slower HPA axis response to TSST. Low circadian variations in cortisol and smaller cortisol responses to TSST were found among subjects scoring high on anxiety sensitivity. Thus, a relatively favorable sample of female chronic trapezius myalgia patients exhibited normal circadian rhythm and normal salivary cortisol response magnitudes after a psychosocial stress test. In the subgroup of responders, the MYA group showed indications of a slower salivary cortisol response to psychosocial stress. Further studies are needed to elucidate the possibility of altered HPA axis activity in terms of a slower salivary cortisol response. (c) 2009 Elsevier Ltd. All rights reserved.
26.
Sul, Young-Taeg, 1960, et al.
(author)
A novel in vivo method for quantifying the interfacial biochemical bond strength of bone implants
2010
In: Journal of the Royal Society Interface. - London, United Kingdom : Royal Society. - 1742-5689 .- 1742-5662. ; 7:42, s. 81-90
Journal article (peer-reviewed) abstract
Quantifying the in vivo interfacial biochemical bond strength of bone implants is a biological challenge. We have developed a new and novel in vivo method to identify an interfacial biochemical bond in bone implants and to measure its bonding strength. This method, named biochemical bond measurement (BBM), involves a combination of the implant devices to measure true interfacial bond strength and surface property controls, and thus enables the contributions of mechanical interlocking and biochemical bonding to be distinguished from the measured strength values. We applied the BBM method to a rabbit model, and observed great differences in bone integration between the oxygen (control group) and magnesium (test group) plasma immersion ion-implanted titanium implants (0.046 versus 0.086 MPa, n=10, p=0.005). The biochemical bond in the test implants resulted in superior interfacial behaviour of the implants to bone: (i) close contact to approximately 2 μm thin amorphous interfacial tissue, (ii) pronounced mineralization of the interfacial tissue, (iii) rapid bone healing in contact, and (iv) strong integration to bone. The BBM method can be applied to in vivo experimental models not only to validate the presence of a biochemical bond at the bone–implant interface but also to measure the relative quantity of biochemical bond strength. The present study may provide new avenues for better understanding the role of a biochemical bond involved in the integration of bone implants.
27.
Ihse, Elisabet, 1977-
(author)
Two Types of Fibrils in ATTR Amyloidosis : Implications for Clinical Phenotype and Treatment Outcome
2011
Doctoral thesis (other academic/artistic) abstract
Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B). In this thesis, the clinical importance of the two types of amyloid fibrils was investigated. We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients. The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development. By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations. In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.
28.
Noborn, Fredrik, et al.
(author)
Identification of chondroitin sulfate linkage region glycopeptides reveals prohormones as a novel class of proteoglycans.
2015
In: Molecular & cellular proteomics : MCP. - 1535-9484 .- 1535-9476. ; 14:1, s. 41-9
Journal article (peer-reviewed) abstract
Vertebrates produce various chondroitin sulfate proteoglycans (CSPGs) that are important structural components of cartilage and other connective tissues. CSPGs also contribute to the regulation of more specialized processes such as neurogenesis and angiogenesis. Although many aspects of CSPGs have been studied extensively, little is known of where the CS chains are attached on the core proteins and so far, only a limited number of CSPGs have been identified. Obtaining global information on glycan structures and attachment sites would contribute to our understanding of the complex proteoglycan structures and may also assist in assigning CSPG specific functions. In the present work, we have developed a glycoproteomics approach that characterizes CS linkage regions, attachment sites, and identities of core proteins. CSPGs were enriched from human urine and cerebrospinal fluid samples by strong-anion-exchange chromatography, digested with chondroitinase ABC, a specific CS-lyase used to reduce the CS chain lengths and subsequently analyzed by nLC-MS/MS with a novel glycopeptide search algorithm. The protocol enabled the identification of 13 novel CSPGs, in addition to 13 previously established CSPGs, demonstrating that this approach can be routinely used to characterize CSPGs in complex human samples. Surprisingly, five of the identified CSPGs are traditionally defined as prohormones (cholecystokinin, chromogranin A, neuropeptide W, secretogranin-1, and secretogranin-3), typically stored and secreted from granules of endocrine cells. We hypothesized that the CS side chain may influence the assembly and structural organization of secretory granules and applied surface plasmon resonance spectroscopy to show that CS actually promotes the assembly of chromogranin A core proteins in vitro. This activity required mild acidic pH and suggests that the CS-side chains may also influence the self-assembly of chromogranin A in vivo giving a possible explanation to previous observations that chromogranin A has an inherent property to assemble in the acidic milieu of secretory granules.
29.
Elgqvist, Jörgen, 1963, et al.
(author)
Targeting prostate cancer stem cells with alpha-particle therapy
2017
In: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 6
Journal article (peer-reviewed) abstract
Modern molecular and radiopharmaceutical development has brought the promise of tumor-selective delivery of antibody-drug conjugates to tumor cells for the diagnosis and treatment of primary and disseminated tumor disease. The classical mode of discourse regarding targeted therapy has been that the antigen targeted must be highly and homogenously expressed in the tumor cell population, and at the same time exhibit low expression in healthy tissue. However, there is increasing evidence that the reason cancer patients are not cured by current protocols is that there exist subpopulations of cancer cells that are resistant to conventional therapy including radioresistance and that these cells express other target antigens than the bulk of the tumor cells. These types of cells are often referred to as cancer stem cells (CSCs). The CSCs are tumorigenic and have the ability to give rise to all types of cells found in a cancerous disease through the processes of self-renewal and differentiation. If the CSCs are not eradicated, the cancer is likely to recur after therapy. Due to some of the characteristics of alpha particles, such as short path length and high density of energy depositions per distance traveled in tissue, they are especially well suited for use in targeted therapies against microscopic cancerous disease. The characteristics of alpha particles further make it possible to minimize the irradiation of non-targeted surrounding healthy tissue, but most importantly, make it possible to deliver high-absorbed doses locally and therefore eradicating small tumor cell clusters on the submillimeter level, or even single tumor cells. When alpha particles pass through a cell, they cause severe damage to the cell membrane, cytoplasm, and nucleus, including double-strand breaks of DNA that are very difficult to repair for the cell. This means that very few hits to a cell by alpha particles are needed in order to cause cell death, enabling killing of cells, such as CSCs, exhibiting cellular resistance mechanisms to conventional therapy. This paper presents and evaluates the possibility of using alpha-particle emitting radionuclides in the treatment of prostate cancer (PCa) and discusses the parameters that have to be considered as well as pros and cons of targeted alpha-particle therapy in the treatment of PCa. By targeting and eradicating the CSCs responsible of tumor recurrence in patients who no longer respond to conventional therapies, including androgen deprivation and castration, it may be possible to cure the disease, or prolong survival significantly. © 2017 Ceder and Elgqvist.
30.
Fagman, Johan Bourghardt, 1980, et al.
(author)
The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
2015
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
Journal article (peer-reviewed) abstract
Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
31.
Hörnblad, Andreas, 1982-
(author)
Imaging the pancreas : new aspects on lobular development and adult constitution
2011
Doctoral thesis (other academic/artistic) abstract
The mouse pancreas is a mixed exocrine and endocrine glandconsisting of three lobular compartments: the splenic, duodenal and gastric lobes. During embryogenesis, the pancreas forms from two progenitor populations located on the dorsal and ventral side of the primitive gut tube. These anlagen are brought in close proximity as the gut elongates and rotates, and fuse to form a single organ. The splenic and duodenal lobes develop from the dorsal and ventral anlagen, respectively. In the adult pancreas, exocrine tissue secretes digestive enzymes intothe gut lumen to support nutrient uptake. The endocrine Islets of Langerhans are scattered throughout the exocrine tissue and aid in regulation of energy homeostasis through the secretion of hormones. One of the key players in energy homeostasis is the pancreatic ß-cell, which is the most abundant cell type of the islets. The β-cells regulates blood glucose levels through the action of insulin. Conditions where this regulation does not function properly are gathered under the common name of Diabetes mellitus. Type 1 diabetes (T1D) is characterized by insulin deficiency due to autoimmune destruction of the ß-cells. Using recently developed protocols for optical projection tomography (OPT) whole-organ imaging, we have revealed new spatial and quantitative aspects on ß-cell mass dynamics and immune infiltration during the course of T1D development in the non-obese diabetic (NOD) mouse model. We show that although immune infiltration appears to occur asynchronously throughout the organ, smaller islets, mainly located in the periphery of the organ, preferentially loose their ß-cells during early stages of disease progression. Larger islets appear more resistant to the autoimmune attack and our data indicate the existence of a compensatory proliferative capacity within these islets. We also report the appearance of structures resembling tertiary lymphoid organs (TLOs) in association with the remaining islets during later phases of T1D progression. OPT has already proven to be a useful tool for assessments of ß-cellmass in the adult mouse pancreas. However, as with other techniques, previous protocols have relied on a tedious degree of manual postivacquisition editing. To further refine OPT-based assessment of pancreatic ß-cell mass distribution in the murine pancreas, we implemented a computational statistical approach, Contrast-Limited Adaptive Histogram Normalisation (CLAHE), to the OPT projection data of pancreata from C57Bl/6 mice. This methodology provided increased islet detection sensitivity, improved islet morphology and diminished subjectivity in thresholding for reconstruction and quantification. Using this approach, we could report a substantially higher number of islets than previously described for this strain and provide evidence of significant differences in islet mass distribution between the pancreatic lobes. The gastric lobe stood out in particular and contained a 75% higher islet density as compared to the splenic lobe. Although the development of the early pancreatic buds has been relatively well studied, later morphogenetic events are less clear and information regarding the formation of the gastric lobe has largely been missing. Using OPT we have generated a quantitative three-dimensional road map of pancreatic morphogenesis in the mouse. We show that the gastric lobe forms as a perpendicular outgrowth fromthe stem of the dorsal pancreas at around embryonic day (e) 13.5, which grows into a mesenchymal domain overlaying the pyloric sphincter and proximal part of the glandular stomach. By analyzing mutant mice with aberrant spleen development, we further demonstrate that proper formation of the gastric lobe is dependent on the initial formation of the closely positioned spleen, indicating a close interplay between pancreatic and splenic mesenchyme during development. Additionally, we show that the expression profile of markers for pancreatic multipotent progenitors within the pancreas is heterogenous with regards to lobular origin. Altogether, our studies regarding the morphogenesis and adult constitution of the mouse pancreas recognize lobular heterogeneities that add important information for future interpretations of this organ.
32.
Jansson Löfmark, Rasmus, 1979, et al.
(author)
Determination of eflornithine enantiomers in plasma by precolumn derivatization with o-phthalaldehyde-N-acetyl-l-cysteine and liquid chromatography with UV detection
2010
In: BMC Biomedical chromotography. - : Wiley. - 0269-3879 .- 1099-0801. ; 24:7, s. 768-773
Journal article (peer-reviewed) abstract
A bioanalytical method for indirect determination of eflornithine enantiomers in 75 mu L human plasma has been developed and validated. L- and D-eflornithine were derivatized with o-phthalaldehyde and N-acetyl-L-cysteine to generate diastereomers which were separated on two serially connected Chromolith Performance columns (RP-18e 100 x 4.6 mm i.d.) by a isocratic flow followed by a gradient flow for elution of endogenous compounds. The diastereomers were detected with UV (340 nm). The between-day precisions for L- and D-eflornithine in plasma were 8.4 and 2.3% at 3 mu m, 4.0 and 5.1% at 400 mu m, and 2.0 and 3.7% at 1000 mu m. The lower limit of quantification was determined to be 1.5 mu m, at which precision was 14.9 and 9.9% for 1- and D-eflornithine, respectively.
33.
Chapman, Henry N, et al.
(author)
Femtosecond X-ray protein nanocrystallography.
2011
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 470:7332, s. 73-7
Journal article (peer-reviewed) abstract
X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200nm to 2μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.
34.
Nordén, Rickard, 1977, et al.
(author)
O-linked glycosylation of the mucin domain of the herpes simplex virus type 1 specific glycoprotein gC-1 is temporally regulated in a seed-and-spread manner.
2015
In: The Journal of biological chemistry. - 1083-351X. ; 290:8, s. 5078-5091
Journal article (peer-reviewed) abstract
The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1, participating in viral receptor interactions and immunity interference, harbors a mucin-like domain with multiple clustered O-linked glycans. Using HSV-1 infected diploid human fibroblasts, an authentic target for HSV-1 infection, and a protein immunoaffinity procedure, we enriched fully glycosylated gC-1 and a series of its biosynthetic intermediates. This fraction was subjected to trypsin digestion and a LC-MS/MS glycoproteomics approach. In parallel, we characterized the expression patterns of the 20 isoforms of human GalNAc transferases responsible for initiation of O-linked glycosylation. The gC-1 O-glycosylation was regulated in an orderly manner initiated by synchronous addition of one GalNAc unit each to T87 and T91, and one GalNAc unit to either T99 or T101, forming a core glycopeptide for subsequent additions of in all 11 GalNAc residues to selected Ser and Thr residues of the T76-L107 stretch of the mucin domain. The expression patterns of GalNAc transferases in the infected cells suggested that initial additions of GalNAc were carried out by initiating GalNAc transferases, in particular GalNAc-T2, whereas subsequent GalNAc additions were carried out by follow up transferases, in particular GalNAc-T10. Essentially all of the susceptible Ser or Thr residues had to acquire their GalNAc units before any elongation to longer O-linked glycans of the gC-1-associated GalNAc units was permitted. Since the GalNAc occupancy pattern is of relevance for receptor binding of gC-1, the data provides a model to delineate biosynthetic steps of O-linked glycosylation of the gC-1 mucin domain in HSV-1 infected target cells.
35.
Vallöf, Daniel, 1988, et al.
(author)
The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.
2016
In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 21:2, s. 422-437
Journal article (peer-reviewed) abstract
The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans.
36.
Tapani, Sofia, 1982, et al.
(author)
Joint feedback analysis modeling of nonesterified fatty acids in obese zucker rats and normal sprague-dawley rats after different routes of administration of nicotinic acid
2014
In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 103:8, s. 2571-2584
Journal article (peer-reviewed) abstract
Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation.
37.
38.
Karlsson, Oskar, et al.
(author)
Detection of long non-coding RNAs in human breastmilk extracellular vesicles : Implications for early child development.
2016
In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 11:10, s. 721-729
Journal article (peer-reviewed) abstract
Breastmilk has many documented beneficial effects on the developing human infant, but the components of breastmilk that influence these developmental pathways have not been fully elucidated. Increasing evidence suggests that non-coding RNAs encapsulated in extracellular vesicles (EVs) represent an important mechanism of communication between the mother and child. Long non-coding RNAs (lncRNAs) are of particular interest given their key role in gene expression and development. However, it is not known whether breastmilk EVs contain lncRNAs. We used qRT-PCR to determine whether EVs isolated from human breastmilk contain lncRNAs previously reported to be important for developmental processes. We detected 55 of the 87 screened lncRNAs in EVs from the 30 analyzed breastmilk samples, and CRNDE, DANCR GAS5, SRA1 and ZFAS1 were detected in >90% of the samples. GAS5, SNHG8 and ZFAS1 levels were highly correlated (Spearman's rho>0.9; P<0.0001), which may indicate that the loading of these lncRNAs into breastmilk EVs is regulated by the same pathways. The detected lncRNAs are important epigenetic regulators involved in processes such as immune cell regulation and metabolism. They may target a repertoire of recipient cells in offspring and could be essential for child development and health. Further experimental and epidemiological studies are warranted to determine the impact of breastmilk EV-encapsulated lnRNAs in mother to child signaling.
39.
40.
Tullberg, Cecilia, 1987, et al.
(author)
Oxidation of marine oils during in vitro gastrointestinal digestion with human digestive fluids – Role of oil origin, added tocopherols and lipolytic activity
2019
In: Food Chemistry. - : Elsevier BV. - 0308-8146 .- 1873-7072. ; 270, s. 527-537
Journal article (peer-reviewed) abstract
The formation of malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE), and 4-oxo-2-nonenal (ONE) in cod liver-, anchovy-, krill-, and algae oil during in vitro digestion with human gastrointestinal fluids was investigated. Adding rabbit gastric lipase, lipase inhibitor (orlistat) and tocopherols to cod liver oil, lipolysis and oxidation was also studied. Among the marine oils, the highest aldehyde levels (18 µM MDA, 3 µM HHE and 0.2 µM HNE) were detected after digestion of cod liver oil, while the lowest levels were detected in krill and algae oils. Addition of rabbit gastric lipase significantly increased the release of HNE during the digestion. Orlistat significantly reduced lipolysis and MDA formation. Formation of MDA and HHE was delayed by tocopherols, the tocopherol mix Covi-ox® T 70 EU being more effective than pure α-tocopherol.
41.
42.
Kerje, Susanne, et al.
(author)
Is low molecular hyaluronan an early indicator of disease in avian systemic sclerosis?
2016
In: Connective Tissue Research. - : Taylor & Francis. - 0300-8207 .- 1607-8438. ; 57:5, s. 337-346
Journal article (peer-reviewed) abstract
AIM OF THE STUDY: To further elucidate the pathogenesis of systemic sclerosis (SSc) an experimental avian model was used. University of California at Davies line 200-chicken (UCD-200) spontaneously develops a SSc like disease that has most features of human SSc with vascular effects, inflammation, autoimmunity and fibrosis. The first signs of disease in UCD-200 are swelling and ischemic lesions of the comb, a tissue containing high amounts of the glycosaminoglycan hyaluronan. The aim was to evaluate inflammatory and fibrotic processes of the disease with regard to the molecular weight of hyaluronan.MATERIAL AND METHODS: Comb biopsies from UCD-200 and healthy White Leghorn (WL) chickens as controls at different ages were studied with histochemical localization of hyaluronan, hyaluronidase 1, CD3, IgY and collagen I and III. Hyaluronan molecular weight distribution was estimated with gas phase electrophoretic analysis.RESULTS: At 2 days of age hyaluronan was visualized in UCD-200 at the dermal part of the comb with no simultaneous staining of Hyal-1. In adult UCD-200 the comb skin was almost totally devoid of hyaluronan compared to WL of the same age. An increase of low molecular weight (LMW) hyaluronan was detected in comb tissue from UCD-200 at 1 day, 1, 2, 4 weeks in contrast to adult animals.CONCLUSIONS: An early inflammatory process involving LMW hyaluronan was confirmed as a possible profibrotic process. This indicates that hyaluronan might be an important participant in early inflammatory events of SSc in UCD-200 chicken and that disappearance of hyaluronan in skin predisposes to fibrosis.
43.
Essling, Elise, et al.
(author)
Pharmacy employees’ self-rated knowledge, use and attitudes toward homeopathy: A comparative survey in Sweden and Germany
2019
In: European Pharmaceutical Journal. - : de Gruyter. - 2453-6725. ; 66:1, s. 19-27
Journal article (peer-reviewed) abstract
Background: Homeopathy is being increasingly practiced within different medical areas of use. Homeopathic medicines are sold in German pharmacies, whereas the assortment of Swedish pharmacies does not include homeopathic medicines. Despite differences between Sweden and Germany, homeopathic medicines are classified as drugs in both countries. Objective: The aim of this study was to compare the pharmacy employees’ self-rated knowledge, use, and attitudes toward homeopathy in Sweden and Germany. Methods: A quantitative web survey was sent to 30 pharmacies in Sweden and 30 pharmacies in Germany, which were selected by using a multi-stage clustering sampling. The questionnaire contained closed-ended rating scales. To compare the self-rated knowledge, use, and attitudes toward homeopathy of Swedish and German pharmacy employees, chi-square tests and Mann-Whitney tests were performed in SPSS. Results: A total of 209 pharmacy employees answered the survey (108 in Sweden and 101 in Germany). German participants estimated their knowledge higher than the Swedish participants (p < 0.01). In both countries, most participants thought that pharmacy employees should have knowledge about homeopathy. Although most Swedish participants stated that they receive questions about homeopathy, the German pharmacy employees receive questions about homeopathy more frequently (p <0.01). Swedish participants reported less experience of own use of homeopathic medicines and less belief in their effectiveness as compared to the German participants (p < 0.01). However, in both countries, most participants stated that homeopathic medicines should be sold in pharmacies. Conclusion: As pharmacy employees should act professionally to advise customers on all drugs, increased homeopathic knowledge in pharmacy employees could potentially improve pharmaceutical practice.
44.
Svenson, Ulrika, et al.
(author)
Telomere length in relation to immunological parameters in patients with renal cell carcinoma
2013
In: PLOS ONE. - : Public Library Science. - 1932-6203. ; 8:2
Journal article (peer-reviewed) abstract
Over the last decade, telomere length (TL) has gained attention as a potential biomarker in cancer disease. We previously reported that long blood TL was associated with a poorer outcome in patients with breast cancer and renal cell carcinoma. Based on these findings, we hypothesized that certain immunological components may have an impact on TL dynamics in cancer patients. One aim of the present study was to investigate a possible association between serum cytokines and TL of peripheral blood cells, tumors and corresponding kidney cortex, in patients with clear cell renal cell carcinoma. For this purpose, a multiplex cytokine assay was used. Correlation analysis revealed significant positive correlations between tumor TL and peripheral levels of three cytokines (IL-7, IL-8 and IL-10). In a parallel patient group with various kidney tumors, TL was investigated in whole blood and in immune cell subsets in relation to peripheral levels of regulatory T cells (Tregs). A significant positive association was found between whole blood TL and Treg levels. However, the strongest correlation was found between Tregs and TL of the T lymphocyte fraction. Thus, patients with higher Treg levels displayed longer T cell telomeres, which might reflect a suppressed immune system with fewer cell divisions and hence less telomere shortening. These results are in line with our earlier observation that long blood TL is an unfavorable prognostic factor for cancer-specific survival. In summary, we here show that immunological components are associated with TL in patients with renal cell carcinoma, providing further insight into the field of telomere biology in cancer.
45.
Russell, Floyd A., et al.
(author)
Stemodin-derived analogues with lipid peroxidation, cyclooxygenase enzymes and human tumour cell proliferation inhibitory activities
2011
In: Phytochemistry. - : Elsevier BV. - 0031-9422. ; 72:18, s. 2361-2368
Journal article (peer-reviewed) abstract
A series of analogues, derived from the antiviral and cytotoxic diterpene stemodin, were prepared and evaluated for their lipid peroxidation (LPO), cyclooxygenase enzyme-1 (COX-1) and -2 (COX-2), and tumour cell proliferation inhibitory activities. Oxidation of stemodin produced stemodinone, which was then converted to stemod-12-en-2-one. Reaction of the latter under Petrow conditions (bromine; silver acetate/pyridine) yielded mainly dibrominated abeo-stachanes. Solvolysis of the dibromo compounds gave products of hydrolysis, some with rearranged skeleta. In the lipid peroxidation inhibitory assay three of the compounds exhibited prominent activity. Interestingly, all the analogues showed higher COX-1 enzyme inhibition than COX-2. Although a few of the diterpenes limited the growth of some human tumour cell lines, most compounds induced proliferation of such cells.
46.
Noborn, Fredrik, et al.
(author)
Expanding the chondroitin glycoproteome of Caenorhabditis elegans. : Chondroitin proteoglycans in C. elegans
2018
In: The Journal of biological chemistry. - 1083-351X. ; 293:1, s. 379-389
Journal article (peer-reviewed) abstract
Chondroitin sulfate proteoglycans (CSPGs) are important structural components of connective tissues in essentially all metazoan organisms. In vertebrates, CSPGs are involved also in more specialized processes such as neurogenesis and growth factor signaling. In invertebrates, however, knowledge of CSPGs core proteins and proteoglycan-related functions is relatively limited, even for Caenorhabditis elegans. This nematode produces large amounts of non-sulfated chondroitin in addition to low-sulfated chondroitin sulfate chains. So far, only nine core proteins (CPGs) have been identified, some of which have been shown to be involved in extracellular matrix formation. We recently introduced a protocol to characterize proteoglycan core proteins by identifying CS-glycopeptides with a combination of biochemical enrichment, enzymatic digestion, and nano-scale liquid chromatography MS/MS analysis. Here, we have used this protocol to map the chondroitin glycoproteome in C. elegans, resulting in the identification of 15 novel CPG proteins in addition to the nine previously established. Three of the newly identified CPGs displayed homology to vertebrate proteins. Bioinformatics analysis of the primary protein sequences revealed that the CPG proteins altogether contained 19 unique functional domains, including Kunitz and endostatin domains, suggesting direct involvement in protease inhibition and axonal migration, respectively. The analysis of the core protein domain organization revealed that all chondroitin attachment sites are located in unstructured regions. Our results suggest that CPGs display a much greater functional and structural heterogeneity than previously appreciated and indicate that specialized proteoglycan-mediated functions evolved early in metazoan evolution.
47.
Sukonina, Valentina, et al.
(author)
FOXK1 and FOXK2 regulate aerobic glycolysis.
2019
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
Journal article (peer-reviewed) abstract
Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
48.
Vieira, Taian Martins, et al.
(author)
Specificity of surface EMG recordings for gastrocnemius during upright standing
2017
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 7:1, s. 1-11
Journal article (peer-reviewed) abstract
The relatively large pick-up volume of surface electrodes has for long motivated the concern that muscles other than that of interest may contribute to surface electromyograms (EMGs). Recent findings suggest however the pick-up volume of surface electrodes may be smaller than previously appreciated, possibly leading to the detection of surface EMGs insensitive to muscle activity. Here we combined surface and intramuscular recordings to investigate how comparably action potentials from gastrocnemius and soleus are represented in surface EMGs detected with different inter-electrode distances. We computed the firing instants of motor units identified from intramuscular EMGs detected from gastrocnemius and soleus while five participants stood upright. We used these instants to trigger and average surface EMGs detected from multiple skin regions along gastrocnemius. Results from 66 motor units (whereof 31 from gastrocnemius) revealed the surface-recorded amplitude of soleus action potentials was 6% of that of gastrocnemius and did not decrease for inter-electrode distances smaller than 4 cm. Gastrocnemius action potentials were more likely detected for greater inter-electrode distances and their amplitude increased steeply up to 5 cm inter-electrode distance. These results suggest that reducing inter-electrode distance excessively may result in the detection of surface EMGs insensitive to gastrocnemius activity without substantial attenuation of soleus crosstalk.
49.
Xia, Yihan, 1990, et al.
(author)
Large number of putative chemoreception and pheromone biosynthesis genes revealed by analyzing transcriptome from ovipositor-pheromone glands of Chilo suppressalis
2015
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 5
Journal article (peer-reviewed) abstract
The chemoreception role of moth ovipositor has long been suggested, but its molecular mechanism is mostly unknown. By transcriptomic analysis of the female ovipositor-pheromone glands (OV-PG) of Chilo suppressalis, we obtained 31 putative chemoreception genes (9 OBPs, 10 CSPs, 2 ORs, 1 SNMP, 8 CXEs and 1 AOX), in addition to 32 genes related to sex pheromone biosynthesis (1 FAS, 6 Dess, 10 FARs, 2 ACOs, 1 ACC, 4 FATPs, 3 ACBPs and 5 ELOs). Tissue expression profiles further revealed that CsupCSP2 and CsupCSP10 were OV-PG biased, while most chemoreception genes were highly and preferably expressed in antennae. This suggests that OV-PG employs mostly the same chemoreception proteins as in antennae, although the physiological roles of these proteins might be different in OV-PG. Of the 32 pheromone biosynthesis related genes, CsupDes4, CsupDes5 and CsupFAR2 are strongly OV-PG biased, and clustered with functionally validated genes from other moths, strongly indicating their involvement in specific step of the pheromone biosynthesis. Our study for the first time identified a large number of putative chemoreception genes, and provided an important basis for exploring the chemoreception mechanisms of OV-PG in C. suppressalis, as well as other moth species.
50.
Alaei-Mahabadi, Babak, et al.
(author)
Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers.
2016
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 113:48, s. 13768-13773
Journal article (peer-reviewed) abstract
Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevated TERT mRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)-nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.
