| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
- Ladds, MJGW, et al.
(författare)
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Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2071-
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Tidskriftsartikel (refereegranskat)abstract
- The original PDF version of this Article listed the authors as “Marcus J.G.W. Ladds,” where it should have read “Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#”.Also in the PDF version, it was incorrectly stated that “Correspondence and requests for materials should be addressed to S. Lín.”, instead of the correct “Correspondence and requests for materials should be addressed to S. Laín.”This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.
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| 3. |
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| 6. |
- Domínguez-Gil, B., et al.
(författare)
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The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
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Ingår i: Transplantation. ; 106:11, s. 2111-2117
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 7. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 8. |
- Pollard, K. Michael, et al.
(författare)
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Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN
- 2017
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 199:11, s. 3739-3747
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Tidskriftsartikel (refereegranskat)abstract
- Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.
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| 9. |
- Wang, J., et al.
(författare)
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Final report of the CCQM-K145 : Toxic and essential elements in bovine liver
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 57:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids/semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 10. |
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| 11. |
- Carlborg, Carl Fredrik, et al.
(författare)
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Biosticker : patterned microfluidic stickers for rapid integration with microarrays
- 2011
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Ingår i: The 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences (microTAS 2011). - : Chemical and Biological Microsystems Society. - 9781618395955 ; , s. 311-313
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Konferensbidrag (refereegranskat)abstract
- We present a one-step, reversible, and biocompatible bonding method of a stiff patterned microfluidic "Biosticker", based on off-stoichiometry thiol-ene (OSTE) polymers [1], to state-of-the-art spotted microarray surfaces. The method aims at improving and simplifying the batch back-end processing of microarrays. We illustrate its ease of use in two applications: a high sensitivity flow-through protein assay; and a DNA-hybridization test. Read-out was performed in a standard highvolume array scanner, and showed excellent spot homogeneity and intensity. The Biosticker is aimed to be a plug-in for existing microarray platforms to enable faster protein assays and DNA hybridizations through mass transport optimization.
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| 12. |
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| 13. |
- Giovannucci, TA, et al.
(författare)
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Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound
- 2021
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.
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| 14. |
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| 15. |
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| 17. |
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| 18. |
- Bjarnadottir, G. D., et al.
(författare)
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Intravenous Use of Prescription Psychostimulants; A Comparison of the Pattern and Subjective Experience between Different Methylphenidate Preparations, Amphetamine and Cocaine
- 2016
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Ingår i: European Addiction Research. - : S. Karger AG. - 1022-6877 .- 1421-9891. ; 22:5, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Methylphenidate (MPH) has been the most commonly used intravenous (i.v.) substance in Iceland in recent years. In Iceland, MPH is available in 3 forms: immediate-release (IR) tablets (MPH IR, short-acting), sustainable-release (SR) capsules (MPH SR, long-acting) and osmotic-release (OROS) tablets (MPH OROS, long-acting). The aims of the study were to compare the pattern and subjective effects of i.v. MPH use to other i.v. psychostimulants and examine whether the pattern of use differs among MPH preparations. Methods: This is a nationwide descriptive study. Information was collected from 95 i.v. substance users undergoing inpatient detoxification and reporting i.v. MPH use in the last 30 days using a semi-structured interview. Results: MPH SR was both the most commonly used (96%) and preferred i.v. psychostimulant (57%). The intensity and duration of 'euphoria' did not differ between cocaine and MPH SR. No participant reported MPH OROS as their preferred substance even though a third had used it in the past month. Conclusions: The pattern of i.v. MPH use is similar to other psychostimulants among treatment seeking patients. MPH OROS was the least preferred i.v. psychostimulant, despite having the largest market share in Iceland. The results indicate that MPH OROS has less abuse potential than other MPH preparations. (C) 2016 S. Karger AG, Basel
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| 19. |
- Bjarnadottir, G. D., et al.
(författare)
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Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users
- 2017
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Ingår i: Drug and Alcohol Dependence. - : Elsevier BV. - 0376-8716. ; 178, s. 165-169
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. Methods: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. Results: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p < 0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. Conclusions: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations.
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| 20. |
- Bjarnadottir, G. D., et al.
(författare)
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Prevalent intravenous abuse of methylphenidate among treatment-seeking patients with substance abuse disorders: A descriptive population-based study
- 2015
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Ingår i: Journal of Addiction Medicine. - : Lippincott Williams and Wilkins. - 1932-0620. ; 9:3, s. 188-194
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Prescription rates of methylphenidate (MPH) are sharply rising in most Western countries. Although it has been reported that MPH has abuse potential, little is known about the prevalence of intravenous (IV) abuse of MPH. The aim of the study was to investigate the prevalence of IV MPH abuse among treatment-seeking IV substance abusers in Iceland. Methods: This is a descriptive population-based study using a semistructured interview assessing sociodemographics, substance abuse history, and the method of administration of 108 IV substance abusers. During 1 year, consecutively admitted adult inpatients with substance use disorder at any detoxification center in Iceland that reported any IV substance abuse in the past 30 days were invited to participate. Abuse was defined as nontherapeutic use of a substance to gain psychological or physiological effect. Results: Prevalence of any IV MPH abuse among participants was 88% in the last 30 days (95% confidence interval [CI], 0.82-0.94) and MPH was the most commonly abused substance (65%) and the preferred substance (63%). Around one third (30%) reportedMPH as the first IV substance ever abused. However, among those reporting a shorter history than 10 years of IV abuse, 42% reported MPH as the first IV substance ever abused. Conclusions: This first nationwide study on IV abuse ofMPH shows that it is common among treatment-seeking IV abusers in Iceland and suggests that MPH has high abuse potential. Therefore, both the use and possible abuse of MPH in those with high abuse potential should be monitored, especially in countries where MPH prescriptions rates are on the rise. Copyright © 2015 American Society of Addiction Medicine.
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| 21. |
- Busker, S., et al.
(författare)
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Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.
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| 22. |
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| 23. |
- Fischbach, M., et al.
(författare)
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Measurement by magnetic resonance imaging of the peritoneal membrane in contact with dialysate in rats
- 2005
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Ingår i: Adv Perit Dial. - 1197-8554. ; 21, s. 17-20
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Tidskriftsartikel (refereegranskat)abstract
- To be optimal, a peritoneal dialysis prescription should consider the peritoneal surface area recruitment. In fact, as shown by computed tomography imaging, only a fraction of the available anatomic peritoneum is in contact with the dialysate (PDF). Various factors may dynamically affect the recruitment of the wetted membrane: posture, fill volume, PDF composition (biocompatibility), and pharmacologic agents (phospholipids). To precisely determine the peritoneal membrane recruitment capacity, we developed an animal model. In 5/6 bi-nephrectomized rats on peritoneal dialysis, between week 6 and week 8 post surgery, we used MRI to assess the contact area, with the dialysate acting as the contrast medium (fill volume: 10 mL per 100-g rat body weight). The MRI protocol consisted of axially oriented, turbo spin-echo, 3-mm slice, T2 weighted sequences. The contact area was measured using an adapted three-dimensional MRI reconstruction software based on DICOM (digital imaging and communications in medicine) images. The MRI studies (n=10) were successful. They showed that only a fraction of the presumed anatomic area (30% - 40%) was in contact with the PDF Peritoneal MRI in rats is a method that shows potential for assessing peritoneal contact area and its variation under experimental conditions.
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| 24. |
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| 25. |
- Hill, Daniel, et al.
(författare)
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Microfluidic and Transducer Technologies for Lab on a Chip Applications
- 2010
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Ingår i: 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC). - : IEEE conference proceedings. - 9781424441242 ; , s. 305-307
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Konferensbidrag (refereegranskat)abstract
- Point-of-care diagnostic devices typically require six distinct qualities: they must deliver at least the same sensitivity and selectivity, and for a cost per assay no greater than that of today's central lab technologies, deliver results in a short period of time (<15 min at GP; <2h in hospital), be portable or at least small in scale, and require no or extremely little sample preparation. State-of-the-art devices deliver information of several markers in the same measurement.
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| 26. |
- Hilmi, N., et al.
(författare)
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Exposure of Mediterranean Countries to Ocean Acidification
- 2014
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Ingår i: Water. - : MDPI AG. - 2073-4441. ; 6:6, s. 1719-1744
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Tidskriftsartikel (refereegranskat)abstract
- This study examines the potential effects of ocean acidification on countries and fisheries of the Mediterranean Sea. The implications for seafood security and supply are evaluated by examining the sensitivity of the Mediterranean to ocean acidification at chemical, biological, and macro-economic levels. The limited information available on impacts of ocean acidification on harvested (industrial, recreational, and artisanal fishing) and cultured species (aquaculture) prevents any biological impact assessment. However, it appears that non-developed nations around the Mediterranean, particularly those for which fisheries are increasing, yet rely heavily on artisanal fleets, are most greatly exposed to socioeconomic consequences from ocean acidification.
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| 27. |
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| 28. |
- Liu, Peidi, 1986, et al.
(författare)
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Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy
- 2017
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 28:10, s. 2961-2972
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Tidskriftsartikel (refereegranskat)abstract
- IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.
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| 29. |
- Matuleviciene Anängen, Viktorija, et al.
(författare)
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Glycaemic control and excess risk of major coronary events in persons with type 1 diabetes
- 2017
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 103:21, s. 1687-1695
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The excess risk of major coronary events (acute myocardial infarction (AMI) or death from coronary heart disease (CHD)) in individuals with type 1 diabetes (T1D) in relation to glycaemic control and renal complications is not known. METHODS: Individuals with T1D in the Swedish National Diabetes Registry after 1 January 1998, without a previous MI (n=33 170) and 1 64 698 controls matched on age, sex and county were followed with respect to non-fatal AMI or death from CHD. Data were censored at death due to any cause until 31 December 2011. RESULTS: During median follow-up of 8.3 and 8.9 years for individuals with T1D and controls, respectively, 1500 (4.5%) and 1925 (1.2%), experienced non-fatal AMI or died from CHD, adjusted HR 4.07 (95% CI 3.79 to 4.36). This excess risk increased with younger age, female sex, worse glycaemic control and severity of renal complications.The adjusted HR in men with T1D with updated mean haemoglobin A1c (HbA1c) <6.9% (52 mmol/mol) and normoalbuminuria was 1.30 (95% CI 0.90 to 1.88) and in women 3.16 (95% CI 2.14 to 4.65). HRs increased to 10.7 (95% CI 8.0 to 14.3) and 31.8 (95% CI 23.6 to 42.8) in men and women, respectively, with HbA1c >9.7% and renal complications. CONCLUSIONS: The excess risk of AMI in T1D is substantially lower with good glycaemic control, absence of renal complications and men compared with women. In women, the excess risk of AMI or CHD death persists even among patients with good glycaemic control and no renal complications.
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| 30. |
- Medvedevskikh, Maria, et al.
(författare)
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Report of the CCQM-K130 : Nitrogen mass fraction measurements in glycine
- 2017
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Ingår i: Metrologia. - 0026-1394 .- 1681-7575. ; 54:1A
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Tidskriftsartikel (refereegranskat)abstract
- Mass fraction of nitrogen is very important pointer because the results of these measurements are often used for determination of protein mass fraction that is an important indicator of the quality of the vast majority of food products and raw materials, in particular dry milk powder. Proteins-enzymes catalyze chemical reactions, protein along with fats and carbohydrates is one of the indicators characterizing the energy value of food, so its definition is mandatory for all food products. The aim of this key comparison CCQM-K130 and pilot study P166 is to support National Measurement Institutes (NMIs) and Designated Institutes (DIs) to demonstrate the validity of the procedures the employed for determination of nitrogen mass fraction in glycine. The study material for this key comparison and pilot study has been selected to be representative as one of the aminoacid-the simplest part of the protein. Glycine is an amino acid, single acid that does not have any isomers (melting point-290 °C; specific heat of evaporation-528,6 J/kg; specific melting heat-981,1 J/kg; pKa-2,34, molar mass-75,07 g/mol, density-1,607 g/cm3). Ural Scientific Research Institute for Metrology (UNIIM) acted as the coordinating laboratory of this comparison and pilot study. Eight NMIs participated in this key comparison and two NMIs participated in Pilot study. The results of Pilot study are excluded from the Report B.
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| 31. |
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| 32. |
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| 33. |
- Roziková, M., et al.
(författare)
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Electrolytic conductivity at pure water level final report
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 58:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Electrolytic conductivity in aqueous solutions is one of the most common electrochemical measurement techniques in industry. Since it is sensitive to the amount content of dissolved ions in a solution, a limiting value for conductivity is a clear and simple quality criterium for the ionic purity of water. The relevant measuring range for pure water applications is roughly between 0.055 μS cm-1 (ultrapure water) and 150 μS cm-1 at 25 °C. For instance, the European, Japanese and United States (USP) Pharmacopoeia have specified the requirements for purified water, highly purified water and water for injection for pharmaceutical use based on conductiv-ity. Sectors that also use conductivity limits for water purity are electrical power production, food industry, electronic industry and analytical laboratories. At low conductivity levels it is not feasible to circulate water samples for comparison measure-ments, since the conductivity value is instable due to inevitable ionic contamination. The main contamination results from carbon dioxide in ambient air that dissolves in water and builds H3O+ and hydrogen carbonate ions. The contribution of these ions to conductivity is around 1 μS cm-1. Hence, it is impossible to provide stable samples having usable uncertainties in the conductivity range of interest. EURAMET 1271, performed in 2013, was the first successful comparison measurement of pure water conductivity. In the meanwhile, more NMIs, the majority of which is situated in Europe, have built measurement capabilities in the pure water range. EURAMRET 1271 covered a measurement range up to 50 μS cm-1, whereas more and more customers request conductivity cell calibration in the range up to 150 μS cm-1. Consequently, this comparison intends to extend the measurement range and to enable more NMIs to get support for potential CMCs. Therefore, this comparison is additionally intended being a supplementary CCQM comparison. A commercial conductivity measurement meter, including a conductivity measurement cell, was used for the comparison in a Round-Robin scheme. The devices were provided by PTB and were sent from one institute to another. Each institute had to measure the conductivity of a reference solution using the conductivity meter. The reference solution could either be pure water or a measurement standard solution that was reasonably stable in the range of interest. In the first scheme, the cell had to be integrated in a closed pure water flow though system to minimize impurification by CO2. An adequate fixture for this setup was provided by PTB. In the second scheme, the cell was immersed into the measurement standard solution under tem-perature-controlled conditions. Essentially, the institutes had to report the conductivity values indicated by the conductivity meter and the conductivity reference value assigned to the water in the flow though system or that of the measurement standard solution, respectively. The co-ordinating institute calculated adjusted cell constants for the cell from the reported values, which were used to calculate linking conductivities, the actual quantities to be finally compared. The results showed good equivalence in all conductivity ranges, with only a few inconsistent values. Adequate comparison reference values are suggested that can serve to calculate robust degrees of equivalences for the participants usable to support respective CMC claims.
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| 34. |
- van Der Heijden, L. H., et al.
(författare)
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Quantitative food web modeling unravels the importance of the microphytobenthos-meiofauna pathway for a high trophic transfer by meiofauna in soft-bottom intertidal food webs
- 2020
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Ingår i: Ecological Modelling. - : Elsevier BV. - 0304-3800. ; 430
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Tidskriftsartikel (refereegranskat)abstract
- Meiofauna are known to have an important role on many ecological processes, although, their role in food web dynamics is often poorly understood, partially as they have been an overlooked and under sampled organism group. Here, we used quantitative food web modeling to evaluate the trophic relationship between meiofauna and their food sources and how meiofauna can mediate the carbon flow to higher trophic levels in five contrasting soft-bottom intertidal habitats (including seagrass beds, mudflats and sandflats). Carbon flow networks were constructed using the linear inverse model-Markov chain Monte Carlo technique, with increased resolution of the meiofauna compartments (i.e. biomass and feeding ecology of the different trophic groups of meiofauna) compared to most previous modeling studies. These models highlighted that the flows between the highly productive microphytobenthos and the meiofauna compartments play an important role in transferring carbon to the higher trophic levels, typically more efficiently so than macrofauna. The pathway from microphytobenthos to meiofauna represented the largest flow in all habitats and resulted in high production of meiofauna independent of habitat. All trophic groups of meiofauna, except for selective deposit feeders, had a very high dependency on microphytobenthos. Selective deposit feeders relied instead on a wider range of food sources, with varying contributions of bacteria, microphytobenthos and sediment organic matter. Ecological network analyses (e.g. cycling, throughput and ascendency) of the modeled systems highlighted the close positive relationship between the food web efficiency and the assimilation of high-quality food sources by primary consumers, e.g. meiofauna and macrofauna. Large proportions of these flows can be attributed to trophic groups of meiofauna. The sensitivity of the network properties to the representation of meiofauna in the models leads to recommending a greater attention in ecological data monitoring and integrating meiofauna into food web models.
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| 35. |
- Andelin, M., et al.
(författare)
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Assessing the Accuracy of Continuous Glucose Monitoring (CGM) Calibrated With Capillary Values Using Capillary or Venous Glucose Levels as a Reference.
- 2016
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Ingår i: Journal of Diabetes Science and Technology. - : Diabetes Technology Society. - 1932-2968. ; 10:4, s. 876-884
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Tidskriftsartikel (refereegranskat)abstract
- Background: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM.less thanbr /greater thanMethods: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples.less thanbr /greater thanResults: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P less than .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P less than .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P less than .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82.less thanbr /greater thanConclusion: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.less thanbr /greater than (© 2016 Diabetes Technology Society.)
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| 36. |
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| 37. |
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| 38. |
- Bergsson, G, et al.
(författare)
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Antimicrobial components of vernix caseosa
- 2004
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Ingår i: PEDIATRIC RESEARCH. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 56:3, s. 469-469
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 39. |
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| 40. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 41. |
- Carlsson, Lena M S, 1957, et al.
(författare)
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The incidence of albuminuria after bariatric surgery and usual care in swedish obese subjects (SOS): a prospective controlled intervention trial.
- 2015
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 39:1, s. 169-175
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Tidskriftsartikel (refereegranskat)abstract
- Background:Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.Subjects:The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI⩾34 in men and BMI⩾38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30mg per 24h) over up to 15 years.Results:During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P<0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Conclusions:Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.International Journal of Obesity advance online publication, 10 June 2014; doi:10.1038/ijo.2014.72.
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| 42. |
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| 43. |
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| 44. |
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| 45. |
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| 46. |
- Dinasquet, Julie, et al.
(författare)
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Cascading effects of the ctenophore Mnemiopsis leidyi on the planktonic food web in a nutrient-limited estuarine system
- 2012
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Ingår i: Marine Ecology Progress Serie. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 460, s. 49-61
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Tidskriftsartikel (refereegranskat)abstract
- Increasing biomasses of gelatinous zooplankton presumably have major implications for the structure and function of marine food webs at large; however, current data on lower trophic levels are scarce, as most studies have focused on the immediate effects on zooplankton and fish larvae only. We examined the short-term impact of larvae and adults of the invasive ctenophore Mnemiopsis leidyi on a summer planktonic food web in the estuarine southern Baltic Sea, with special emphasis on the microbial loop. Grazing by M. leidyi reduced the mesozooplankton biomass, followed by increased dinoflagellate biomass in treatments with M. leidyi. While chlorophyll a increased most in the treatments with M. leidyi, small phytoplankton and ciliates decreased in all treatments. M. leidyi had a slight effect on bacterial abundance, but not on bacterial production, ectoenzymatic activities, or community composition. Undetectable levels of phosphate and a gradual accumulation of dissolved organic carbon during the experiment suggested a malfunctioning microbial loop scenario. The experiment shows that direct and indirect short-term effects of M. leidyi on the estuarine food web are limited to higher trophic levels and indicates that top-down and bottom-up consequences of M. leidyi expansions on the microbial loop will likely depend on local nutrient conditions.
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| 47. |
- Ebefors, Kerstin, 1977, et al.
(författare)
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Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
- 2019
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 96:4, s. 957-970
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-beta receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondria! reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.
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| 48. |
- Fischbach, M., et al.
(författare)
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Effect of peritoneal dialysis fluid composition on peritoneal area available for exchange in children
- 2004
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Ingår i: Nephrol Dial Transplant. - : Oxford University Press (OUP). - 0931-0509. ; 19:4, s. 925-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although conventional peritoneal dialysis fluids (PDFs), such as Dianeal, are non-physiological in composition, new PDFs including Physioneal have a more neutral pH, are at least partially buffered with bicarbonate and, most importantly, contain low concentrations of glucose degradation products (GDPs). METHODS: To evaluate the impact of new PDFs in childcare, we performed a comparative crossover study with Dianeal and Physioneal. We examined both intraperitoneal pressure (IPP), which partly reflects pain induction, and the total pore area available for exchange, which indicates the number of capillaries perfused in the peritoneal membrane at any given moment and therefore partly reflects peritoneal dialysis capacity. The IPP was determined after inflow of 1000 ml/m(2) body surface area (BSA) of dialysate (intraperitoneal volume; IPV). The steady-state unrestricted area over diffusion distance (A(0)/ triangle up x, in cm(2)/cm per 1.73 m(2) BSA) was calculated from the three-pore theory. Six children were enrolled in the study. On the first day, two consecutive peritoneal equilibration tests of 90 min each were performed using first Dianeal and then Physioneal. On the second study day, the procedure was repeated with the fluids given in the opposite order. RESULTS: The mean IPP normalized to IPV (ml/m(2)) was significantly higher for Dianeal (9.5 +/- 0.9 cm/1000 ml/m(2)) than for Physioneal (7.9 +/- 1.2 cm/1000 ml/m(2), P < 0.01). The mean A(0)/ triangle up x was 17 +/- 4% larger with Dianeal (36 095 +/- 2009 cm(2)/cm per 1.73 m(2)) than with Physioneal (31 780 +/- 2185 cm(2)/cm per 1.73 m(2), P < 0.001; based on 24 data pairs). CONCLUSIONS: These pilot study results suggest a higher biocompatibility for Physioneal than for Dianeal. Less inflow pain associated with Physioneal induced a lower IPP reflecting enhanced fill volume tolerance, and the lower A(0)/ triangle up x reflected less capillary recruitment. Taken together, these results suggest that the new more biocompatible PDFs will improve peritoneal dialysis therapy, although this conclusion will require verification in extended clinical trials.
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| 49. |
- Fischbach, M., et al.
(författare)
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The influence of peritoneal surface area on dialysis adequacy
- 2005
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Ingår i: Perit Dial Int. - 0896-8608. ; 25 Suppl 3
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Tidskriftsartikel (refereegranskat)abstract
- In children, the prescription of peritoneal dialysis is based mainly on the choice of the peritoneal dialysis fluid, the intraperitoneal fill volume (mL/m2 body surface area (BSA)], and the contact time. The working mode of the peritoneal membrane as a dialysis membrane is more related to a dynamic complex structure than to a static hemodialyzer. Thus, the peritoneal surface area impacts on dialysis adequacy. In fact, the peritoneal surface area may be viewed as composed of three exchange entities: the anatomic area, the contact area, and the vascular area. First, in infants, the anatomic area appears to be two-fold larger than in adults when expressed per kilogram body weight. On the other hand, the anatomic area becomes independent of age when expressed per square meter BSA. Therefore, scaling of the intraperitoneal fill volume by BSA (m2) is necessary to prevent a too low ratio of fill volume to exchange area, which would result in a functional "hyperpermeable" peritoneal exchange. Second, the contact area, also called the wetted membrane, is only a portion of the anatomic area, representing 30% to 60% of this area in humans, as measured by computed tomography. Both posture and fill volume may affect the extent of recruitment of contact area. Finally, the vascular area is influenced by the availability of both the anatomic area and the recruited contact area. This surface is governed essentially by both peritonealvascular perfusion, represented by the mesenteric vascular flow and, hence, by the number of perfused capillaries available for exchange. This vascular area is dynamically affected by different factors, such as composition of the peritoneal fluid, the fill volume, and the production of inflammatory agents. Peritoneal dialysis fluids that will be developed in the future for children should allow an optimization of the fill volume owing to a better tolerance in terms of lower achieved intraperitoneal pressure for a given fill volume. Moreover, future peritoneal dialysis fluids should protect the peritoneal membrane from hyperperfusion (lower glucose degradation products).
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| 50. |
- Fischbach, M., et al.
(författare)
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The peritoneal membrane: a dynamic dialysis membrane in children
- 2003
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Ingår i: Adv Perit Dial. ; 19, s. 265-8
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Tidskriftsartikel (refereegranskat)abstract
- Peritoneal dialysis prescription in children should be individualized--based not only on numerical targets (Kt/Vurea, Kcreat), but also on consideration of the peritoneal membrane, a dynamic dialysis membrane. In fact, the effective peritoneal surface area is at least a triple entity: an anatomic area, a contact area, and an exchange area. The anatomic area appears to be twice as large in infants as in adults if expressed per kilogram of body weight (BW), although the area is independent of age if expressed per square meter of body surface area (BSA). Therefore, scaling of the intraperitoneal fill volume (IPV) by BSA in square meters is necessary to avoid a low IPV/area ratio, which results in a functionally "hyperpermeable" peritoneal exchange. The contact area (the wetted membrane) is only a fraction of the anatomic area--that is, 30%-60% in humans (by computed tomography). Contact area depends on a variety of factors, such as posture and fill volume, that affect the degree of recruitment of membrane contact area. The exchange area is influenced by both the anatomic are and the contact area. However, it is mainly governed by the specific vascular area as determined by the peritoneal vascular perfusion and the capillaries available for exchange. Vascular area is dynamically affected by a variety of factors, such as the composition of the peritoneal dialysis fluid, the fill volume, and possible inflammatory agents.
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