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Cardiovascular magnetic resonance imaging of myocardium and pulmonary arterial pressure
No full textHeart failure (HF) is a clinical syndrome characterized by high morbidity and mortality. HF can be associated with alteration in myocardial tissue composition such as focal myocardial fibrosis, also referred to as scarring, as well as the development of pulmonary hypertension (PH). The prevalence of HF and PH is increasing worldwide, mainly due to the aging population. This emphasizes the need for early diagnosis, identification of underlying etiology and appropriate treatment.Cardiovascular magnetic resonance (CMR) is not only the reference standard for the assessment of cardiac morphology, function, and myocardial viability, but can also provide precise quantitative information on myocardial tissue composition and cardiovascular hemodynamics.In study I, we found that synthetic late gadolinium enhancement (SynLGE) generated from post-contrast T1 mapping was highly accurate in identifying both ischemic and non-ischemic focal myocardial fibrosis. This method proved to be a valuable complement to conventional late gadolinium enhancement (LGE) imaging. Study II, employed T1 mapping to quantify the dynamic distribution of an intravenous iron substitution agent, ferric carboxymaltose, into different tissues including the myocardium. This understanding is of value for determining the potential benefits of iron substitution therapy in patients with HF.In studies III and IV we investigated the application of the compressed sensing (CS) acceleration technique to multi-two-dimensional (CS-M2D) and true fourdimensional (4D) flow image acquisition by CMR. CS enabled a substantial reduction in image acquisition time while maintaining accuracy in determining mean pulmonary artery pressure (mPAP). Moreover, in study IV, we validated CSM2D and CS-4D flow and achieved excellent agreement in mPAP estimation when compared to invasively measured mPAP by right heart catheterization as the reference standard.In conclusion, this thesis highlights the importance of quantitative CMR in understanding etiological and pathophysiological aspects in HF. These findings are valuable for the early detection of HF and PH and show promise for guiding therapeutic decision to prevent disease progression and complications in patients with HF.List of scientific papersI. Abdula G, Nickander J, Sörensson P Lundin M, Klein M, Kellman P, Sigfridsson A, Ugander M. Synthetic late gadolinium enhancement cardiac magnetic resonance for diagnosing myocardial scar. Scand Cardiovasc J. 2018, 52:3, 127–132. https://doi.org/10.1080/14017431.2018.1449960 II. Abdula G, Lundin M, Nickander J, Sörensson P, Sigfridsson A, Themudo R, Ugander M. Ferric carboxymaltose has a higher distribution into myocardium than gadobutrol – a quantitative T1 mapping study in healthy volunteers. medRxiv. 2023. [Manuscript] https://doi.org/10.1101/2023.03.01.23285660III. Abdula G, Ramos J, Marlevi D, Fyrdahl A, Engblom H, Sörensson P, Giese D, Jin N, Sigfridsson A, Ugander M. Noninvasive estimation of mean pulmonary artery pressure by CMR in under 2 minutes scan time. Eur Heart J Imaging Methods and Practice. 2023. 1, 1–7. https://doi.org/10.1093/ehjimp/qyad014IV. Abdula G, Bergqvist P, Castaings J, Fyrdahl A, Jin N, Giese D, Testud F, Sörensson P, Sigfridsson A, Ugander M, Marlevi D. CS-4D and CSM2D flow sequences by CMR show excellent for non-invasive estimation of mean pulmonary artery pressure by CMR. medRxiv. 2024. [Manuscript] https://doi.org/10.1101/2024.02.07.24302465</p
Acute and chronic nephrotoxic effects from ambulatory medications
No full textOne in ten adults in Society suffer from chronic kidney disease (CKD), a disease characterized by progressive loss of kidney function. Altered kidney function can impact on the risk/benefit of many medications. In clinical practice, some medications are contraindicated to people with advanced CKD, others require dose adjustments or strict monitoring for safety. The extent by which potentially inappropriate medications or monitoring is given to people with CKD has not been sufficiently evaluated, particularly in Swedish healthcare.While the side effects and risks of certain drugs are well known, others remain less understood, in part because of the under-representation of people with CKD in clinical trials and the rarity of adverse kidney outcomes, which would require unrealistically large trial populations with years of intervention. Pharmacoepidemiological research in real-world settings can bridge this gap, offering a larger, more diverse cohort and longer follow-up to evaluate medication safety and efficacy in this population.The work presented in this thesis offers new findings into the potential nephrotoxicity of medications and the risk-benefit profiles of treatments in people with CKD through the epidemiological analysis of healthcare data.Study I evaluates the use of nephrotoxic medications in patients with CKD at stages G3-5 within routine care settings. This analysis compared two distinct healthcare systems, one in Stockholm, Sweden, and the other in Pennsylvania, United States (US). Findings indicate that approximately one in five patients was prescribed potentially inappropriate nephrotoxic drugs, which could have been substituted with safer, non-nephrotoxic options. The association of a documented CKD diagnosis with reduced odds of inappropriate medication use suggests that increasing physicians' awareness of CKD in patients, along with enhancing knowledge about drug nephrotoxicity, may help reduce the prescription of nephrotoxic drugs and prevent medication-induced kidney damage.Study II examines adherence to guideline recommendations for laboratory test monitoring of lithium therapy among adults with bipolar disorder in Stockholm. We found that lithium therapy was frequently initiated without prior assessment of kidney function, and only a small proportion of individuals received consistent annual testing for the recommended laboratory markers, including serum lithium levels. This study highlights a significant inconsistency between routine care practices and guideline recommendations, underscoring the need for improvements in monitoring practices.Study III compares the risks of CKD progression and acute kidney injury (AKI) among patients initiating lithium versus valproate therapy. Within up to 10 years of therapy, we observed that patients receiving lithium experienced similar absolute risks of CKD progression or AKI than patients receiving valproate.However, elevated serum lithium levels were associated with future risks, emphasizing the need for close monitoring and lithium dose adjustment.Study IV investigates the potential of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) to lower hyperkalemia risk and improve renin-angiotensin system inhibitor (RASi) persistence in patients with type 2 diabetes. We observed that SGLT-2i users had a lower rate of hyperkalemia compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) users. However, the initiation of SGLT-2i did not significantly affect the rate of RASi discontinuation among RASi users, potentially explained by low treatment persistence.Study V aims to identify through agnostic approaches medications associated with AKI occurrence. We conducted a drug-wide association study (DWAS) analyzing the discordance of treatments received prior to AKI hospitalizations and other moments before in the life trajectory of the same patient. We used two large cohorts from Sweden and Denmark. The study identified some medications with already known AKI risks, medications that may have initiated in response to conditions that lead to AKI and other candidates that warrant further evaluation in subsequent studies.List of scientific papersI. Bosi A, Yunwen A, Gasparini A, Wettermark B, Barany P, Bellocco R, Inker LA, Chang AR, McAdams-DeMarco M, Grams ME, Shin JI, Carrero JJ. Use of nephrotoxic medications in adults with chronic kidney disease in Swedish and US routine care. Clin Kidney J. 2021 Oct 29;15(3):442-451. https://doi.org/10.1093/ckj/sfab210II. Bosi A, Ceriani L, Elinder CG, Bellocco R, Clase CM, Landen M, Carrero JJ, Runesson B. Quality of laboratory biomarker monitoring during treatment with lithium in patients with bipolar disorder. Bipolar Disord. 2023 Sep;25(6):499-506. https://doi.org/10.1111/bdi.13302III. Bosi A, Clase CM, Ceriani L, Sjölander A, Fu EL, Runesson B, Chang Z, Landén M, Bellocco R, Elinder CG, Carrero JJ. Absolute and Relative Risks of Kidney Outcomes Associated With Lithium vs Valproate Use in Sweden. JAMA Netw Open. 2023 Jul 3;6(7):e2322056. https://doi.org/10.1001/jamanetworkopen.2023.22056IV. Bosi A, Xu Y, Faucon AL, Huang T, Evans M, Shin JI, Fu EL, Carrero JJ, Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors. Nephrol Dial Transplant. 2024 Oct 9:gfae227. https://doi.org/10.1093/ndt/gfae227V. Bosi A, Lund LP, Mahalingasivam V, Mazhar F, Christiansen CF, Sjölander A, Pottegård A, Carrero JJ. Drug use and acute kidney injury: a Drug-Wide Association Study (DWAS) in Denmark and Sweden. https://doi.org/10.1093/ckj/sfae338Throughout this thesis, these articles are referred to by their Roman numerals.</p
Clinical aspects of perioperative fluid, sodium and glucose balance in children
No full textBackgroundPerioperative fluid therapy aims at compensating for deficits related to preop- erative fasting or disease as well as covering basal needs and ongoing losses to keep the homeostasis of metabolism, electrolyte- and glucose balance. In gen- eral, the former widespread use of hypotonic solutions in paediatric anaesthesia has been replaced by isotonic solutions mainly due to the risk of dilutional hypo- natraemia caused by Arginine Vasopressin (AVP) induced water retention. In par- allel, low plasma sodium concentration (p-Na) has been found to be associated with disease severity. Therefore, p-Na may be used as a predictor to differenti- ate between different disease states such as perforated versus non-perforated acute appendicitis, which may bring substantial clinical benefits. Furthermore, in modern paediatric perioperative care, maintenance fluids with high glucose content have been abandoned in order to avoid intraoperative hyperglycaemia. New formulas with an isotonic profile, ensuring adequate sodium supply, and low glucose content are now predominant. However, the safe use in the smallest chil- dren, with their higher metabolic rate and smaller energy reserves, with regards to the risk of hypoglycaemia has not been proven.Aims1. To investigate possible differences in p-Na between children with non-perfo- rated and perforated acute appendicitis and if p-Na can be used as a predictor of perforation (Studies I and IV).2. To describe the physiological changes of p-Na and fluid balance in children with acute appendicitis (Study II).3. To investigate the safety of a balanced electrolyte solution with 1% glucose as intravenous maintenance fluid for infants undergoing surgery focusing on glu- cose, electrolyte and acid-base balance (Study III).MethodsStudy I, a prospective observational study, included 80 children with appendi- citis at Karolinska University Hospital. Blood sampling for p-Na and inflamma- tory markers was performed before any drug or fluid administration. The primary outcome was perforation status as decided by postoperative histopathological analysis. Study II investigated the same cohort as in study I. The children were followed prospectively from admission to hospital until end of surgery. Blood and urine sampling including blood-gas analysis, osmolality and regulatory hormones was done at admission, after induction of anaesthesia and postoperatively. Study III, a prospective observational multicentre study, included 365 infants (1-12 months of age) undergoing surgery. The participants were given a balanced elec- trolyte solution with 1% glucose as maintenance infusion during surgery. Blood- gas and ketone bodies were analysed after induction of anaesthesia and at the end of surgery. Study IV, a prospective observational multicentre study, included 451 children undergoing appendectomy. Blood sampling for blood-gas analysis and inflammatory markers as well as clinical examination was performed at ad- mission. Main outcome was perforation status decided by postoperative histo- pathological analysis or surgeon's assessment.ResultsIn study I, p-Na was lower in patients with perforated appendicitis as compared to those with non-perforated appendicitis, 134 (interquartile range (IQR) 132-136) mmol/L and 139 (IQR 137-140) mmol/L, respectively. A ROC-curve analysis re- sulted in an area under the curve (AUC) of 0.93 (95 % Confidence Interval (CI) 0.87-0.99) with a cut-off value of ConclusionsChildren with perforated acute appendicitis have lower p-Na at hospital admission as compared with children with non-perforated acute appendicitis.P-Na at hospital admission has a strong predictive value regarding perforation status in children with acute appendicitis.AVP secretion is increased in children with acute appendicitis as compared to normal levels, likely due to non-osmotic stimuli. The highest AVP secretion was seen if the appendix was perforated.Hypotonic maintenance infusion in the pre- and intraoperative phases may increase the risk of postoperative hyponatraemia in children with acute appendicitis.Intravenous near-isotonic maintenance solution with 1% Glucose, infused at rates corresponding to basal needs, is a safe alternative for infants (age 1-12 months) undergoing surgery.Keywords: Acid-base physiology, acute appendicitis, Arginine Vasopressin, diagnos- tic accuracy, electrolyte, glucose, infants, ketone bodies, paediatric, perioperative fluid management, plasma sodium concentration.List of scientific papersI. Low Plasma Sodium Concentration Predicts Perforated Acute Appendicitis in Children: A Prospective Diagnostic Accuracy Study Ulf Lindestam, Markus Almström, Johannes Jacks, Pia Malmquist, Per-Arne Lönnqvist, Boye L Jensen, Mattias Carlström, Rafael T Krmar, Jan F Svensson, Åke Norberg, Urban Fläring. European Journal of Pediatric Surgery, 30(4):350-356 (2020) https://doi.org/10.1055/s-0039-1687870II. Sodium and water homeostasis in children admitted with acute appendicitis: a prospective study Ulf Lindestam, Urban Fläring, Markus Almström, Andreas Andersson, Jan F Svensson, Pia Malmquist, Johannes Jacks, Per-Arne Lönnqvist, Boye L Jensen, Mattias Carlström, Rafael T Krmar. Pediatric Research, 86(1):5-8 (2019) https://doi.org/10.1038/s41390-019-0353-4III. Balanced electrolyte solution with 1% glucose as intraoperative maintenance fluid in infants. A prospective study of glucose, electrolyte, and acid-base homeostasis Ulf Lindestam, Åke Norberg, Peter Frykholm, Olav Rooyackers, Andreas Andersson, Urban Fläring. British Journal of Anaesthesia. [Accepted]IV. Plasma Sodium as a predictor of perforation in acute appendicitis, a prospective multi-centre study Ulf Lindestam, Åke Norberg, Jan F Svensson, Markus Almström, Andreas Andersson, Per-Arne Lönnqvist, Mark Bremholm Ellebæk, Inger Marie Drage, Kjetil Juul Stensrud, Marc Reismann, Heidi M Meyer, Urban Fläring. [Manuscript]</p
Brain heterogeneity within aging and cognitive impairment : implications for precision medicine and prevention
No full textThis doctoral thesis investigates the heterogeneity of grey matter (GM) atrophy patterns in aging, specifically focusing on cognitively unimpaired elderly individuals and those at risk of neurodegenerative diseases, including Alzheimer's disease (AD). Through the application of advanced clustering techniques, including unsupervised random forest and longitudinal Bayesian as well as regression models, we identified distinct GM trajectories and patterns across multiple cohorts.In cognitively unimpaired individuals aged 60-85, longitudinal Bayesian clustering revealed four GM atrophy trajectories, particularly in frontoparietal regions. These trajectories were associated with varying degrees of cerebrovascular burden and cognitive decline, highlighting the heterogeneity of age-related brain changes and the potential for identifying at-risk populations before the onset of cognitive symptoms. Similarly, clustering analysis in dementia-free 70-year-olds revealed five distinct GM clusters, differentiated by cortical thickness and associated with cardiometabolic and cognitive factors, underscoring the role of vascular health in brain aging.Further, this thesis explores the response to lifestyle interventions and pharmacological treatments based on patterns of atrophy. In the FINGER trial, six GM patterns were identified, each showing differential responses to a multidomain lifestyle intervention aimed at preventing cognitive decline in at-risk older adults. Additionally, in a randomized clinical trial of Donepezil in individuals with mild cognitive impairment (MCI), those with hippocampal-sparing or minimal atrophy subtypes exhibited slower atrophy rates compared to other subtypes, suggesting that brain heterogeneity may influence treatment efficacy.Overall, this work emphasizes the importance of understanding GM heterogeneity in aging and its implications for the early detection and prevention of cognitive decline. By identifying distinct GM patterns, this thesis contributes to more personalized approaches for interventions, enhancing the potential for precision medicine in neurodegenerative disease prevention and treatment.List of scientific papersI. Lorenzon G, Poulakis K, Mohanty R, Kivipelto M, Eriksdotter M, Ferreira D, Westman E; Alzheimer's Disease Neuroimaging Initiative. Frontoparietal atrophy trajectories in cognitively unimpaired elderly individuals using longitudinal Bayesian clustering. Comput Biol Med. 2024 Oct 1;182:109190. https://doi.org/10.1016/j.compbiomed.2024.109190II. Lorenzon G, Marseglia A, Poulakis K, Rydén L, Lindberg O, Shams S, Mohanty R, Ferreira D, Kivipelto M, Eriksdotter M, Kern S, Skoog I, Westman E; Risk and protective factors associated with grey matter patterns in older adults. [Manuscript]III. Lorenzon G, Marseglia A, Mohanty R, Lehtisalo J, Poulakis K, Ngandu T, Solomon A, Kivipelto M, Westman E; Brain patterns and risk factors influencing the effect of the FINGER multimodal intervention trial. [Manuscript]IV. Diaz-Galvan P, Lorenzon G, Mohanty R, Mårtensson G, Cavedo E, Lista S, Vergallo A, Kantarci K, Hampel H, Dubois B, Grothe MJ, Ferreira D, Westman E. Differential response to donepezil in MRI subtypes of mild cognitive impairment. Alzheimers Res Ther. 2023 Jun 23;15(1):117. https://doi.org/10.1186/s13195-023-01253-2</p
Order-disorder transitions in cancer-related proteins
No full textIntrinsically disordered proteins (IDPs) lack a stable secondary and tertiary structure, making them highly flexible and dynamic. The flexibility provides a challenge for finding drugs that target intrinsically disordered proteins through a structure-based approach. IDPs play a crucial role in the rise of many cancers, over 65% of all cancer- related proteins are intrinsically disordered.In paper I, we studied the transactivation domains TAD1 and TAD2 of tumor suppressor p53, which is known for extremely low expression levels and poor conformational stability. As a result of these limitations, p53 is a difficult target for therapeutics development. We investigated whether these characteristics can be altered through fusion of p53 to a highly soluble spider silk domain termed NT *. The chimeric protein shows efficient translation and exhibits increased activity in cells. Biophysical characterization of NT*p53 revealed a more compact conformation of the transactivation domains, which are wrapped around the spider silk protein domain. The interactions between NT* and the disordered p53 N-terminus increase translation efficiency and unblocks translation in vitro.In paper II, we changed our focus from p53 to c-MYC. We used a reductionist approach to characterize the local dynamics and structural heterogeneity of c-MYC. Using molecular dynamics simulations and machine learning, we identified a conformational switch in the transactivation domain of c-MYC, which we later defined as coreMYC, that alternates between a compact, inactive and an extended, active conformational state. Use of epigallocatechin gallate (EGCG) allows compaction of coreMYC and promotion of the inactive state. We show the effect of EGCG on both coreMYC and full-length c-MYC through a selection of biophysical and cellular assays. We find that the induction of a compact conformation of coreMYC inhibits its interactions with binding partners that are essential for transcriptional and oncogenic activity of c-MYC. Our study provides insight in the structure-activity relationship of c- MYC and identifies a potential target for therapeutic intervention.In paper III, we investigate the structural features of MYC-box II and its role in ligand binding. To do so, we used a selection of techniques, including NMR, molecular dynamics simulations and native mass spectrometry. We found that specific functional groups such as a positive charge and an aromatic ring will drive ligand binding to a highly conserved DCMW motif at the center of MBII, while hydrophilic groups will interact with the transient helices that surround the DCMW motif. The results indicate how we can select specific small molecules with predetermined functional group that can target MBII in a more specific way.List of scientific papersI. Kaldmäe Margit, Vosselman Thibault, Zhong Xueying, Lama Dilraj, Chen Gefei, Saluri Mihkel, Kronqvist Nina, Siau Jia Wei, Ng Aik Seng, Ghadessy Farid J, Sabatier Pierre, Vojtesek Borivoj, Sarr Medoune, Sahin Cagla, Osterlund Nicklas, Leopold L Llag, Väänänen Venla A, Sedimbi Saikiran, Arsenian-Henriksson Marie, Zubarev Roman A, Nilsson Lennart, Koeck Philip J B, Rising Anna, Abelein Axel, Fritz Nicolas, Johansson Jan, Lane David P, Landreh Michael. A "spindle and thread" mechanism unblocks p53 translation by modulating N-terminal disorder. Structure, 2022 May 5;30(5):733-742.e7. https://doi.org/10.1016/j.str.2022.02.013II. Lama Dilraj*, Vosselman Thibault, Sahin Cagla, Liaño-Pons Judit, Cerrato Carmine P, Nilsson Lennart, Teilum Kaare, Lane David P, Landreh Michael, Arsenian Henriksson Marie. A druggable conformational switch in the c-MYC transactivation domain. Nat Commun., 2024 Feb 29;15(1):1865. https://doi.org/10.1038/s41467-024-45826-7* Equal ContributionIII. Vosselman Thibault, Sahin Cagla, Lane David P, Teilum Kaare, Arsenian Henriksson Marie, Landreh Michael and Lama Dilraj. Specific targeting of MYC-box II using small molecules. [Manuscript]</p
Mechanisms of action of thioredoxin reductase inhibitors in the context of cancer
No full textThe increased understanding of the role of redox homeostasis in cancer survival and progression has placed a spotlight on studying the perturbations in redox signaling as cancer vulnerabilities. These vulnerabilities are in part under the control of antioxidant systems such as the thioredoxin system, with its main effector, the selenoprotein thioredoxin reductase (TXNRD). The selenocysteine- containing (Sec) active site of TXNRD is highly susceptible to alkylation by electrophiles and this has in fact been shown to be a part of the mechanism of action of a range of anticancer compounds in the clinic and in trials, including cisplatin and auranofin. Discovering and developing compounds with a focused target profile on TXNRD has been a major aim of the Arner group, so as to limit the side effects seen with drugs with broader target profiles and to study the precise downstream effects of TXNRD inhibition on redox signaling in cancer. These efforts led to the discovery of thioredoxin reductase inhibitor 1 (TRi-1), a highly selective TXNRD inhibitor with good antitumoral activity in mouse models. This thesis has focused on further characterizing the effects of TRi-1 in cancer cells and better understanding the role of TXNRD as a cancer vulnerability.Paper I further confirmed the narrow target profile of TRi-1 in comparison to auranofin on a proteomics scale by combining thermal proteome profiling, protein expression and redox proteomics approaches. It also established that TRi-1 does not result in a stable downregulation of cellular TXNRD activity, but instead causes rapid inhibition followed by a compensatory increase.In Paper II, we explored the activities of TRi-1 analogs with functionalizations allowing for increased mitochondrial uptake or differential electrophilicity of the selenocysteine-interacting moiety, both against cytosolic and mitochondrial TXNRD isoforms. We arrived at a diverse collection of novel compounds with a range of efficacies in recombinant systems and cancer cell lines, including scaffolds with improved activity compared to TRi-1.Paper III identified surprising connections between TXNRD and ferroptosis by confirming ferroptosis inducers as inhibitors of TXNRD and by establishing that TRi-1-induced cell death cannot be classified as ferroptosis and indeed cannot be rescued by any of the most common death inhibitors. We also reported differential glutathione peroxidase 4 migration patterns in response to ferroptosis inducing TXNRD1 inhibitors and TRi-1, hinting their effects on antioxidant systems in recombinant and cellular contexts are more complex than previously anticipated.Paper IV characterized in detail the kinetics of cellular events taking place after TRi-1 and thereby comprehensively portrayed the mechanisms of action of this compound in cancer cells. We established that short term exposure of the cells, in the order of one hour, to the compound is in every way equivalent to a continuous exposure and showed the kinetics of TRi-1 derivatization of the TXNRD selenopeptide in cells. The anticancer effects were predominantly caused by an arrest in cell cycle progression characterized by a downregulation of CDK1/2. Cells experienced peroxiredoxin dimerization and overoxidation, suggestive of increased oxidative stress, but without major perturbations in protein or nucleotide homeostasis.Paper V established the efficacy of TRi-1 in parasite TXNRD isoforms with unusual structural domains, suggesting that a broader application of this compound to pathologies beyond cancer may be possible, much like the broader indications for using the more promiscuous auranofin.Overall, the papers comprising this thesis have focused on exploring different aspects of the mechanism of action of TRi-1 as a TXNRD inhibitor and have painted a multifaceted picture of the compound's activities extending far beyond its target engagement.List of scientific papersI. Pierre Sabatier, Christian M. Beusch, Radosveta Gencheva, Qing Cheng, Roman Zubarev, Elias S.J. Arnér. Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin. Redox Biol. 2021 Nov 11;48:102184. https://doi.org/10.1016/j.redox.2021.102184II. Miloš Jović#, Radosveta Gencheva #, Qing Cheng, Karoline C. Scholzen, Života Selaković, Elias S.J. Arnér, Igor M. Opsenica. Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles. [Submitted]III. Dorian M. Cheff, Chuying Huang, Karoline C. Scholzen, Radosveta Gencheva, Michael H. Ronzetti, Qing Cheng, Matthew D. Hall, Elias S. J. Arnér. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD. Redox Biol. 2023 Jun;62:102703. https://doi.org/10.1016/j.redox.2023.102703IV. Radosveta Gencheva, Giovanni Chiappetta, Karoline C. Scholzen, Praveen Pandey, Zhao Wenchao, Lucia Coppo, Qing Cheng, Joelle Vinh, Andrei Chabes, Elias S.J. Arnér. Insights into the kinetics of thioredoxin reductase derivatization and associated cancer cell death by the small molecule inhibitor TRi-1. [Manuscript]V. Francesca Fata#, Radosveta Gencheva #, Qing Cheng, Rachel Lullo, Matteo Ardini, Ilaria Silvestri, Federica Gabriele, Rodolfo Ippoliti, Christina A. Bulman, Judy A. Sakanari, David L. Williams, Elias S.J. Arnér, Francesco Angelucci. Biochemical and structural characterizations of thioredoxin reductase selenoproteins of the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus. Redox Biol. 2022 May;51:102278. https://doi.org/10.1016/j.redox.2022.102278</p
Hip fractures in an aging population : clinical and epidemiological aspects
No full textHip fracture, a fracture of the proximal femur is a common and serious injury that mostly affects older people. Almost all hip fractures are treated surgically and optimizing perioperative and operative care is important to allow the patients the best possible chance of continued life and, ideally, good health and independence.The purpose of this thesis is to fill some of the knowledge gaps regarding patients with hip fracture: to explore the association between time to hip fracture surgery and death, as well as other adverse outcomes, to compare two surgical methods for trochanteric hip fracture in a context where a newer method is continually winning ground from an older, to describe regional differences in hip fracture incidence in Sweden and to explore some explanatory factors as to why there are regional differences.Study I was a retrospective, nationwide cohort study using prospectively collected data from the Swedish Hip Fracture Register RIKSHÖFT (SHR). The study explored the association between time from hospital arrival to start of hip fracture surgery (24 hours) and death within 4 months of surgery. We included 59,675 patients and found that longer time to surgery was associated with increased mortality, primarily for women. When stratifying the analyses by American Society of Anesthesiologists (ASA) classification, a statistically significant association between longer time to surgery and death remained among the sickest patient (ASA classification 3 and 4) only.Study II was a retrospective, nationwide cohort study using data from SHR, the Swedish National Patient Register (NPR), the Swedish Cause of Death Register (CDR) and the Swedish National Prescribed Drug Register PDR. The study explored the association between time to hip fracture surgery (divided into 24 hours, with 24 hours for hip fracture surgery and having AF, CHF and "acute ischemia". Stratification by ASA classification revealed that these associations were present only in patients with ASA 3-4.Study III was a retrospective, nationwide cohort study using data from SHR, NPR and the Swedish Dwelling Register. The study explored the association between surgical method for trochanteric hip fracture (Sliding Hip Screw (SHS) vs Intramedullary Nail (IMN)) and death within 120 days after surgery; as well as between surgical method and return to independent living among a sub-set of patients living independently at baseline. 27,530 patients were included in the study, and 12,041 of them were investigated for the outcome return to independent living. There were no overall differences in death within 120 days or return to independent living between SHS and IMN. IMN was associated with lower return to independent living among men and younger (70-84 years) patients with two-fragmented fractures, but these results need to be interpreted with caution due to substantial loss to follow-up.Study IV was a retrospective, nationwide cohort study using data from the Swedish Total Population Register (TPR), NPR, PDR, The Longitudinal Integration Database for Health Insurances and Labour Market Studies (LISA) and The National Register of Care and Social Services for the Elderly and Persons with Impairments (SSR). The study explored regional differences in first hip fracture incidence in Sweden, differences between the yearly quarters and whether potential explanatory factors eliminated the differences in incidence between counties. 2,879,444 individuals were included in the study. Sex-and county specific crude and age standardized incidence rates were calculated, revealing regional differences with higher incidence rates in the north of the country. The summer half of the year had lower incidence rates overall. Differences between counties persisted despite adjustments for several potential explanatory factors.Conclusions: Waiting >24 hours for hip fracture surgery was associated with increased 4 month-mortality and increased postoperative morbidity within 120 days after index hospital discharge. There were no differences in death at 120 days after surgery when comparing SHS and IMN for trochanteric fracture. Subgroups of patients with two-fragmented fracture had lower return to independent living when operated with IMN, but the results must be interpreted with caution. There were regional differences in first hip fracture incidence that cannot be explained by differences in the factors investigated in our study.List of scientific papersI. Greve K, Modig K, Talback M, Bartha E, Hedstrom M. No association between waiting time to surgery and mortality for healthier patients with hip fracture: a nationwide Swedish cohort of 59,675 patients. Acta Orthop. 2020;91(4):396-400. https://doi.org/10.1080/17453674.2020.1754645II. Greve K, Ek S, Bartha E, Modig K, Hedstrom M. Waiting more than 24 hours for hip fracture surgery is associated with increased risk of adverse outcomes for sicker patients: a nationwide cohort study of 63,998 patients using the Swedish Hip Fracture Register. Acta Orthop. 2023;94:87- 96. https://doi.org/10.2340/17453674.2023.9595III. Greve K, Ek S, Bartha E, Modig K, Hedström M. Sliding hip screw versus intramedullary nail for trochanteric hip fracture regarding death within 120 days and ability to return to independent living. Bone & Joint Open. 2024;5(10):843-50. https://doi.org/10.1302/2633-1462.510.BJO-2024-0028.R1IV. Greve, K, Ek, S, Bartha E, Sääf M, Hedström M, Modig, K. Regional differences in hip fracture incidence in Sweden. [Manuscript]</p
Albuminuria predicts kidney events in IgA nephropathy.
No full textBACKGROUND & HYPOTHESIS: KDIGO recommends proteinuria 30% decline in eGFR). We also explored the risk of kidney events associated with change in uACR within a year. RESULTS: We included 1269 IgAN patients (74% men, median 53 years, mean eGFR 33 mL/min/1.73m², median uACR 0.7 g/g). Over median follow-up of 5.5 [2.8;9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced > 30% eGFR decline. Compared with uACR 30% (HR ranging from 1.76 to 3.47). In 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. CONCLUSIONS: There is substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.</p
Enhancers regulate genes linked to severe and mild childhood asthma
No full textBACKGROUND: Children with severe asthma suffer from recurrent symptoms and impaired quality of life despite advanced treatment. Underlying causes of severe asthma are not completely understood, although genetic mechanisms are known to be important. OBJECTIVE: The aim of this study was to identify gene regulatory enhancers in leukocytes, to describe the role of these enhancers in regulating genes related to severe and mild asthma in children, and to identify known asthma-related SNPs situated in proximity to enhancers.METHODS: Gene enhancers were identified and expression of enhancers and genes were measured by Cap Analysis Gene Expression (CAGE) data from peripheral blood leukocytes from children with severe asthma (n = 13), mild asthma (n = 15), and age-matched controls (n = 9).RESULTS: From a comprehensive set of 8,289 identified enhancers, we further defined a robust sub-set of the high-confidence and most highly expressed 4,738 enhancers. Known single nucleotide polymorphisms, SNPs, related to asthma coincided with enhancers in general as well as with specific enhancer-gene interactions. Blocks of enhancer clusters were associated with genes including TGF-beta, PPAR and IL-11 signaling as well as genes related to vitamin A and D metabolism. A signature of 91 enhancers distinguished between children with severe and mild asthma as well as controls.CONCLUSIONS: Gene regulatory enhancers were identified in leukocytes with potential roles related to severe and mild asthma in children. Enhancers hosting known SNPs give the opportunity to formulate mechanistic hypotheses about the functions of these SNPs.</p
Interdisciplinary pain rehabilitation for culturally and linguistically diverse patients
No full textBackground and aim: Chronic pain constitutes a major health problem. Associated symptoms such as depression, anxiety and fear of movement, and reduction in activity and function, make it a complex condition, often affecting the individual's entire life situation. Interdisciplinary pain rehabilitation (IPR) is an evidence-based and recommended intervention for patients with complex chronic pain. Patients from culturally and linguistically diverse (CALD) backgrounds constitute 20% of those referred to IPR in Sweden, but they are seldom selected for this intervention due to various challenges caused by, among other things, language barriers. This has led to a lack of knowledge regarding IPR regarding the specific patient group. The overall aim of this thesis was to explore if IPR has positive effects for CALD patients with chronic pain with limited profiency in the Swedish language.Methods and results: Three studies (I, II and III) were performed at two specialised pain clinics, and one study (IV) at just one of the clinics. In these clinics, IPR with language interpreter (IPR-LI) was offered, which was the intervention studied. Study I and study II are prospective multi-center cohort studies where descriptive and comparative statistics are used. Sociodemografic data and data from instruments in the Swedish Registry of Pain Rehabilitation (SQRP) were analysed before and after (study I) for 95 patients; and before, after and one-year after (study II) for 74 patients (from the same group as in study I). The baseline data (sociodemographic and SQRP) showed a poor state for the studied patients in both study I and II. Significant improvements were seen after the programme in pain intensity, fear of movement and depression (study I), and at one-year follow-up in pain intensity, fear of movement, depression and visits to the doctor (study II). When subgrouping for gender, it was shown that the women followed the result for the whole group, while the men did not improve in any of the instruments measured. Study III and study IV are qualitative studies based on data from semi-structured interviews with healthcare professionals (study III) and patients (study IV). In study III the interviews with 12 informants were analysed according to Grounded theory, and the theory developed about the experience of working in the programme is described in the core category "The Demanding and Meaningful Work", consisting of the categories "Challenges", "Frustration" and "Solutions". In study IV the interviews with ten informants were analysed using content analysis. The core theme "Pain rehabilitation makes a difference", which describes the informants' experiences of managing chronic pain, their life situations after the IPR-LI, and their experiences of participating in the IPR-LI, consisted of the themes "A shrunken life", "Respectful learning together", and "A more active life".Conclusions: The IPR-LI showed positive results, even in the long term, for patients with chronic pain and low profiency in the Swedish language. The result could be of value for the further development of rehabilitation programmes with language interpreters. The men participating should be offered extra attention during rehabilitation.List of scientific papersI. Uhlin K, Persson E, Bäärnhielm S, Borg K, Löfgren M, Stålnacke BM. Interdisciplinary pain rehabilitation for immigrants with chronic pain who need language interpretation. J Rehabil Med. 2024 Feb 26;56:jrm13466. PMID: 38407432; PMCID: PMC10910276. doi: https://doi.org/10.2340/jrm.v56.13466II. Uhlin K, Löfgren M, Bäärnhielm S, Borg K, Stålnacke BM. Interdisciplinary pain rehabilitation for immigrants with chronic pain who need language interpretation - a one-year follow-up. [Manuscript]III. Uhlin K, Persson E, Stålnacke BM, Löfgren M. Healthcare professionals' experiences and perspectives of team-based interdisciplinary pain rehabilitation with immigrants requiring an interpreter. A qualitative study. Disabil Rehabil. 2023 Jul;45(15):2434-2445. Epub 2022 Aug 23. PMID: 35996890. doi: https://doi.org/10.1080/09638288.2022.2111608. IV. Uhlin K, Bani-Shoraka H, Bäärnhielm S, Stålnacke BM, Löfgren M. Interdisciplinary pain rehabilitation makes a difference - A qualitative interview study with culturally and linguistically diverse patients. [Manuscript]</p