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Insulin resistance in adipocytes: Novel insights into the pathophysiology of metabolic syndrome.
No full textNo description supplied</p
Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing.
No full textBACKGROUND: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing. METHODS: Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format. RESULTS: We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing. CONCLUSION: Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.</p
Epidemiology and health economics in gastrointestinal diseases : real-world evidence from Swedish health registers
No full textIntroduction: Eosinophilic esophagitis (EoE) and microscopic colitis (MC) are chronic inflammatory diseases of the gastrointestinal tract. EoE is characterized by dysphagia, and predominantly affects children and young adults of male sex. On the contrary, MC is characterized by watery chronic diarrhea and predominantly affects elderly women. Similarly, the diagnosis of both EoE and MC rely on specific histopathological findings.EoE and MC have both associated with both been associated with a reduced wellbeing and impaired quality of life. Furthermore, previous epidemiological studies have confirmed association to other comorbidities that contribute to the disease burden of EoE and MC. However, despite rising incidence rates, health economic studies remain scarce. To date, only one prior study has investigated health economics in patients with EoE. Those data have, however, been limited to direct costs related to healthcare resource utilization among commercially insured patients, while no prior data on indirect costs related to productivity losses have been reported. For MC, neither direct nor indirect costs have previously been investigated.Aim: To investigate the economic burden of EoE and MC from a societal perspective.Methods: Two cost-of-illness studies with a matched case-control design were performed. To estimate the economic burden of EoE and MC from a societal perspective. The study populations consisted of patients with EoE and MC for Study I and II, respectively. Patients were identified from the ESPRESSO cohort which contains histopathology data on all Swedish individuals between 1963-2017. Each case was matched with up to five general- population comparators matched on year of birth, sex, and county of residence.Economic costs were derived from healthcare resource utilization, prescribed medications, and work loss due to sick leave or disability leave, based on real-world data from Swedish health registers. Stratified analyses were performed based on sociodemographic subgroups. In Study II, separate analyses were also performed by MC subtype, and by disease activity as defined by the number of required treatments during the first year of diagnosis. Linear regression models were used to calculate mean differences adjusted for age, sex, and education level, and cost ratios were used to construct relative cost measurements. All costs were adjusted for inflation according to the Swedish consumer price index (CPI) in 2023, and converted from Swedish currency, SEK, to USD according to the annual average exchange rate in 2023 (1 USD = 10.61 SEK).Results: In Study I, patients with EoE had a mean annual societal cost of 4,573 in the general population. The mean annual excess cost of patients with EoE was 1.947 [95%CI: 2,785]), corresponding to a cost ratio of 1.45 (+45%). The increased costs were mainly driven by an increased healthcare utilization, while no excess work loss was observed. The cost difference was highest among pediatric patients with EoE who had more than 6 times higher costs than their matched general-population comparators.The societal economic burden of all patients with EoE in Sweden was estimated to 1 million per million inhabitants. Out of the total, 0.3 million per million inhabitants.In Study II, patients with MC had a mean annual societal cost of 5,687 in the general population. The mean annual excess cost of patients with MC was 4,974 [5,298]), corresponding to a cost ratio of 1.84 (+84%). The increased costs were mainly driven by work loss. Furthermore, an additional analysis demonstrated that patients with a high disease activity, as defined by the requirement of budesonide treatment during the first year of diagnosis, was associated with higher societal costs in general, and work loss in particular, compared with patients with a more quiescent disease course during the first year of diagnosis.The societal economic burden of all patients with MC in Sweden was estimated to 12 million per million inhabitants. Out of the total, 5.6 million per million inhabitants.Conclusion: By exploring real-world data from Swedish health register, the research presented in this thesis demonstrate that EoE and MC are associated with an extensive economic burden with substantial impacts for both patients and society.In Study I, patients with EoE were found to have around 45% higher societal costs than the general-population and were mainly driven by an increased healthcare resource utilization while no excess work loss was observed. The societal economic burden of EoE was estimated to 12 million per million inhabitants. Improved treatment and disease control could potentially mitigate the societal cost of MC, primarily by reducing excess work loss.List of scientific papersThe Doctoral Degree is based on the following four papers, out of which the first two papers (i-ii) have already been defended as part of a Licentiate Degree at Örebro University. This doctoral thesis will thus be based on the latter two papers listed below (I-II), henceforth referred to by their Roman numerals.i. Bozorg SR, Song M, Emilsson L, Ludvigsson JF. Validation of serrated polyps (SPs) in Swedish pathology registers. BMC Gastroenterol. 2019 Dec 31;20(1):3. https://doi.org/10.1186/s12876-019-1134-6ii. Bozorg SR, Söderling J, Everhov ÅH, Lebwohl B, Green PHR, Neovius M, Ludvigsson JF, Mårild K. Work Loss in Patients With Celiac Disease: A Population-based Longitudinal Study. Clin Gastroenterol Hepatol. 2022 May;20(5):1068-1076.e6. https://doi.org/10.1016/j.cgh.2021.09.002I. Bozorg SR, Söderling J, Mårild K, Garber JJ, Uchida A, Neovius M, Ludvigsson JF, Everhov ÅH. Economic Burden of Eosinophilic Esophagitis: A Nationwide Cost-of-Illness Study. Am J Gastroenterol. 2024 Oct 1;119(10):2122-2125. https://doi.org/10.14309/ajg.0000000000002868II. Bozorg SR, Bergman D, Peery AF, Mårild K, Neovius M, Everhov ÅH, Khalili H, Ludvigsson JF. Economic Burden of Microscopic Colitis in Relation to Disease Activity: A Nationwide Cost-of-Illness Study. [Manuscript]</p
Strategies for expanding organ availability and improving transplant outcomes
No full textOrgan transplantation is a lifesaving treatment for patients suffering from end stage liver disease or heart failure. For patients with chronic kidney disease, transplantation reduces morbidity and decreases mortality. Successful organ transplantation programs are directly dependent on a sufficient supply of organs to meet the increasing demands. In addition, our smallest patients are at an increased risk of mortality while waiting for an organ transplantation due to the lack of size matched organs.This thesis focuses on avenues of expanding organ availability to enable more transplantations, as well as improving the outcomes after transplantation.Study I investigate risk factors for increased time of waiting and mortality while on the waiting list for a liver transplantation within Scandiatransplant. We could show that although Scandiatransplant utilizes an efficient and fair organ allocation system for liver, patient ABO blood group was strongly associated with both increased time of waiting and mortality.In study II we implemented and evaluated a controlled donation after circulatory death (cDCD) liver transplant program, utilizing normothermic regional perfusion. Here, we could show a successful implementation of a nationwide protocol and an increase in available livers for transplantation. In addition, we compared the outcomes to a retrospective cohort receiving liver transplants from brain dead donors. Our results show excellent patient and graft survival as well as a low level of biliary complications, further supported by magnetic resonance imaging.Study III and study IV focuses on the possibility of implementing neonatal organ donation in Sweden. In study III, using the Swedish Neonatal Quality Registry and digital medical records, we identified all potential donors. After applying organ specific criteria, we could show a potential of neonatal organ donation in central Sweden, which could significantly increase available organs. Thereafter in study IV, we successfully implemented a neonatal organ donation after circulatory death (DCD) program, showing that such a program is possible within the Swedish context. Here, we procured 12 livers, whereby we isolated and evaluated the hepatocytes after transplanting them into a humanized mouse model. We could show that neonatal hepatocytes were of excellent quality, resulting in a high yield, and resistance to cryopreservation injury. After hepatocyte transplantation into a humanized mouse model, we could show signs of continued maturation as well as function after transplantation.List of scientific papersI. Bluhme E, Renneus Guthrie V, Duus Weinreich I, Hagstršm H, Line PD, Isoniemi H, Bennet W, Rasmussen A, Ericzon BG, Melum E, and, Jorns C. Factors associated with waiting time and mortality on liver transplant waiting lists within Scandiatransplant Đ a multicenter cohort study. [Submitted]II. Bluhme E, GŠbel M, Martinez L, Nilsen V, Hildebrand K, JarsŠter J, BŚŚth C, Proos M, Romano A, Villard C, Oniscu G, Gustaffson N, Thomsen M, Hansson C, Lšfstedt M, Andersson Lindholm J, Falk L, Bennet W, and Jorns C. Normothermic regional perfusion in controlled DCD liver procurement: outcomes of the Swedish national implementation protocol. Liver Transplantation. 2024. https://doi.org/10.1097/LVT.0000000000000434 III. Bluhme E, Henckel E, Hallberg B, and Jorns C. The potential of neonatal organ donation in Central Sweden. [Submitted]IV. Bluhme E, Henckel E, Gramignoli R, Kjellin T, Hammarstedt C, Nowak G, Karadagi A, Johansson H, Jynge …, Sšderstršm M, Fischler B, Strom S, Ellis E, Hallberg B and Jorns C. Procurement and Evaluation of Hepatocytes for Transplantation From Neonatal Donors After Circulatory Death. Cell Transplant. 2022 Jan-Dec;31:9636897211069900. https://doi.org/10.1177/09636897211069900 </p
Supportive resources for self-care and informal care : uncovering the role of patient-driven innovations
No full textBackground: Persons living with long-term conditions and informal caregivers are often dependent on support for their self-care and informal care. The experience of insufficient support may lead some to develop health innovations to address their unmet health needs (i.e., patient-driven innovations). Although research on patient-driven innovations is increasing, knowledge about the needs that such innovations address, how and by whom they are used, and their outcomes is still limited. Empirical studies are needed to understand the potential benefits and challenges of patient-driven innovations for self-care, informal care, as well as health service delivery. Further, the role of patient innovators in health services research merits investigation.Aim: The overall aim of this thesis was to explore which supportive resources matter to persons living with long-term conditions and informal caregivers and how patient-driven innovations can help facilitate self-care and informal care. The aim was addressed by exploring patient-driven innovations in different contexts. Study I explored the use of a caregiver-developed social network-mapping tool (CareMaps) to assess quality of social and healthcare relations. Study II explored how such relations could be used as supportive resources for self-care and informal care. Study III explored the objectives and outcomes of patient-driven innovations that have been published in peer-reviewed journals. Study IV explored patient innovators’ reasons for and experiences of authoring scientific publications about their innovations.Methods: Four qualitative studies were conducted. Studies I and II were conducted in the context of brain tumor self-care and informal care in Sweden. Study I was an interview study with persons living with brain tumors, informal caregivers, and bereaved caregivers, and collected data were analyzed using thematic analysis. Study II was an interview study with informal caregivers of persons living with brain tumors, and collected data were analyzed using a combination of conventional and directed content analysis. Study III was a content analysis of scientific publications that were included in a previously published scoping review of patient-driven innovations. Study IV was an interview study with international patient innovators from three continents who had published in scientific journals. Collected data were analyzed using the Framework Method.Findings: Study I found that persons living with brain tumors, informal caregivers, and bereaved caregivers expressed positive opinions about using the CareMaps tool but raised some questions regarding its design and how best to use it in their self-care and informal care. Self-care supportive relations and identity-preserving relations emerged as two distinct types of relations that participants valued. They were found in different contexts and emphasized contrasting qualities. Study II found that informal caregivers combined various resources both to manage emotional distress related to caregiving and to make space for valued activities and relationships disconnected from caregiving. In Study III, 83 publications covering 21 patient-driven innovations were analyzed. The patient-driven innovations illustrated a diversity of innovative approaches to facilitate daily lives of persons living with long-term conditions and informal caregivers, interactions with peers, and collaborations with healthcare. Few publications reported on outcomes. Most of the innovations have been developed for use on an individual or community level without healthcare involvement. Study IV found that patient innovators engaged in scientific publishing primarily to strengthen the patient voice in research and to gain recognition for their innovations. Although they had positive experiences of research and publication processes, they also faced cultural and structural barriers, such as conservative peer review practices and publications behind paywalls.Conclusions: This thesis indicates that persons living with long-term conditions and informal caregivers are central stakeholders in driving health service development and research forward to meet the needs that matter to persons living with long-term conditions and informal caregivers. The findings elucidate that continued efforts are needed to facilitate for patient innovators, as well as other patient and public contributors, to contribute with their experiences and expertise to the production of relevant and meaningful research and services supporting self-care and informal care.List of scientific papersI. Dahlberg M, Bylund A, Gustavsson P, Herlestam Calero T, Wannheden C. What matters to persons living with brain tumors and their informal caregivers? An interview study of qualities in interpersonal relations. Social Science and Medicine. 2022;292:114575-114575. https://doi.org/10.1016/j.socscimed.2021.114575 II. Dahlberg M, Wannheden C, Andersson S, Bylund A. “Try to keep things going” – Use of various resources to balance between caregiving and other aspects of life: an interview study with informal caregivers of persons living with brain tumors. [Manuscript]III. Dahlberg M, Lek M, Malmqvist Castillo M, Bylund A, Hasson H, Riggare S, Reinius M, Wannheden C. Objectives and outcomes of patient-driven innovations published in peer-reviewed journals: a qualitative analysis of publications included in a scoping review. BMJ Open. 2023;13:e071363. https://doi.org/10.1136/bmjopen-2022-071363 IV. Dahlberg M, Luckhaus J.L, Hasson H, Jansson H, Lek M, Savage C, Riggare S, Wannheden C. Why publish? An interview study exploring patient innovators’ reasons for and experiences of scientific publishing. [Submitted]</p
Single-cell analysis on specification of mammalian germline and its role in health and diseases
No full textGerm cell specification is the first step for developing reproductive cells. The specification requires formative pluripotent stem cells as precursors. Previous attempts to capture formative pluripotency used opposite manipulation of Wnt signaling, activating or inhibiting, and achieved two distinctive states that indicated two ends of the formative pluripotency spectrum. Study I explored the role of Wnt signaling in the formative pluripotency spectrum. We produced a new form of formative pluripotency in epiblast-like stem cells (EpiLSCs) with activation of Wnt. We developed a computational single-cell method for transcriptionally aligning various cell lines within the formative pluripotency spectrum. Our analysis highlighted that EpiLSCs filled the gap in the pluripotency spectrum between previously published cell lines. Additionally, we revealed context-dependent roles of Wnt signaling in sustaining pluripotency and facilitating differentiation at the two ends of the formative pluripotency spectrum.Female germ cell specification in humans generally exhibits lower efficiencies than males in vitro. Human X chromosome inactivation has a large extent of incompleteness, resulting in escapees. Whether the female lower efficiencies are related to X-linked escapees is unknown. Study II investigated the influence of Xlinked escapees on germ cell specification in females and individuals with Klinefelter syndrome (KS), a condition typically characterized by an extra copy of the X chromosome and infertility. Through RNA sequencing and functional assays, we identified critical X-linked escapees, CHRDL1, IGSF1, and USP9X, inhibiting germ cell specification in females and KS. We found that USP9X elevated SOX2 to repress oxidative phosphorylation, promote mitochondria fusion and clustering, and perturb SOX17's regulation, exerting a profound reduction in germ cell specification.Germ cells carry both genetic and epigenetic information. Sperm's small RNA composition is shaped by the soma-to-germline communication pathway and, therefore, is responsive to environmental exposure. Polycystic ovary syndrome (PCOS) is an epigenetically heritable disorder affecting female offspring. The possibility of PCOS equivalent in males has prompted questions about the potential impact on male offspring and whether sperm small RNA plays a role in it. In study III, using a Swedish registered cohort, a Chile longitudinal cohort, and a mouse model, we found that women with PCOS transgenerationally transmitted reproductive and metabolic dysfunction into their male offspring. Using small RNA sequencing, we identified transgenerationally altered sperm small RNA in the mice, which overlapped with changes in the sons of women with PCOS, suggesting potential mechanistic parallels of inheritance between mice and humans.In this thesis, we uncover critical insights into the Wnt's context-dependent roles in the formative pluripotency spectrum, the repression of XCI escapees on germ cell development, and sperm small RNAs' transgenerational transmission. Additionally, this research paves the way for further exploration into germ cell development for individuals with KS and the inheritance of PCOS in male offspring, offering potential avenues for therapeutic interventions.List of scientific papersI. QING LUO, Han-Pin Pui, Jiayu Chen, Leqian Yu, Paulo R Jannig, Yu Pei, Linxuan Zhao, Xingqi Chen, Sophie Petropoulos, Jorge L Ruas, Jun Wu, Qiaolin Deng. Epiblast-like stem cells established by Wnt/β-catenin signaling manifest distinct features of formative pluripotency and germline competence. Cell Reports. 2023 Jan 31;42(1):112021. (QL and HP contributed equally to this work.) https://doi.org/10.1016/j.celrep.2023.112021 II. Wenteng He, QING LUO, Jian Zhao, Allan Zhao, Luohua Feng, Ahmed Reda, Eva Lindgren, Jan-Bernd Strukenborg, Qiaolin Deng. SOX2 upregulation as downstream of X-linked gene dosage affects the specification of human primordial germ cell-like cells. (WH and QL contributed equally to this work.) [Manuscript]III. Sanjiv Risal , Congru Li, QING LUO, Romina Fornes, Haojiang Lu, Gustaw Eriksson, Maria Manti, Claes Ohlsson, Eva Lindgren, Nicolas Crisosto, Manuel Maliqueo, Barbara Echiburú, Sergio Recabarren, Teresa Sir Petermann, Anna Benrick, Nele Brusselaers, Jie Qiao, Qiaolin Deng, Elisabet Stener-Victorin. Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome. Cell Reports Medicine. 2023 May 16;4(5):101035. (SR, CL, QL and RF contributed equally to this work.) https://doi.org/10.1016/j.xcrm.2023.101035 </p
Circulating factors affecting skeletal muscle metabolism
No full textThe overall aim of this doctoral thesis was to study the role of circulating factors in modulating skeletal muscle metabolism. To this end, we investigated two different scenarios: Type 2 diabetes, which is characterised by impaired skeletal muscle metabolism and reduced insulin sensitivity, and exercise training, which induces various adaptations in skeletal muscle that ultimately improve insulin sensitivity and substrate handling.Specifically, the aims of the studies presented in the thesis were to determine whether an increase in the circulating levels of the amino acid glutamine improves whole-body and skeletal muscle metabolism and insulin sensitivity (Study I), and whether three weeks of endurance exercise training alters the microRNA cargo of circulating extracellular vesicles (Study II).Study I revealed that increasing circulating levels of the amino acid glutamine improves whole-body glucose homeostasis and skeletal muscle insulin action. This effect was attributed to the modulation of inflammatory gene expression and the downregulation of Growth factor receptor-bound protein (GRB10), an inhibitor of insulin signalling. Study II found that three weeks of supervised endurance exercise training changes the microRNA content of serumderived extracellular vesicles, specifically increasing the content of microRNA miR-136-3p. microRNA miR-136-3p increases glucose uptake, oxygen consumption rate and extracellular acidification rate in human skeletal muscle cells. In skeletal muscle, miR-136-3p directly targets NRDC, an exercise- and inactivity-responsive gene, although the metabolic effects induced by mir-136-3p are not solely mediated through the silencing of NRDC.List of scientific papersI. Dollet L, Kuefner M, Caria E, Rizo-Roca D, Pendergrast L, Abdelmoez AM, Karlsson HKR, Björnholm M, Dalbram E, Treebak JT, Harada J, Naslund E, Rydén M, Zierath JR, Pillon NJ, Krook A. Glutamine regulates skeletal muscle immunometabolism in Type 2 Diabetes. Diabetes. 2022;71:624-636. https://doi.org/10.2337/db20-0814 II. Katayama M, Caria E, Yagüe Sanz A, Barrès R, Caidahl K, Wiklander OPB, El-Andaloussi S, Zierath JR, Krook A. Exercise-training-induced exosomal miR-136-3p modulates mitochondrial function by targeting NRDC in human skeletal muscle. [Manuscript]</p
Cellular and molecular mechanisms of inflammatory arthritis and fibromyalgia
No full textIn Study I, we examined the impact of the hR100E-NGF mutation on inflammatory pain and bone erosion in both female and male mice. Our findings indicate that the hR100E-NGF mutation did not affect the development of the peripheral sensory nervous system at the lumbar DRG, sciatic nerve, ankle joint, or glabrous skin. Moreover, hR100E-NGF mice displayed sensory thresholds similar to those of the hWT-NGF mice in response to mechanical, heat, or cold stimulation under normal conditions. The hR100E-NGF and hWT-NGF mice developed comparable mechanical and heat sensitivity impairments after the intra-articular injection of complete Freund’s adjuvant. Notably, the hR100E-NGF mice were insensitive to nociceptive stimulation in the deeper tissues assessed by weight bearing and gait analysis. Furthermore, mRNA analysis from the inflamed joint showed a differential sex-dependent gene expression profile between hR100E-NGF female and male mice. Finally, the hR100E-NGF female but not the male mice were protected against the CFA-bone erosion. These data collectively demonstrate that the R100E NGF mutation effectively protects against joint pain-like behaviors in both male and female mice while providing bone protection exclusively to female mice in a monoarthritis model. We propose that manipulating the signaling of NGF and its receptors in a manner similar to the R100E mutation could be a promising approach to treating chronic pain and maintaining bone health, particularly in women.Study II investigated the effects of injecting purified IgG from fibromyalgia (FM) patients and healthy controls (HC) in mice. We found that the injection of FM IgG but not IgG from healthy controls (HC) induces pressure, mechanical, and cold hypersensitivity in mice that were coupled to enhanced nociceptor responsiveness to mechanical and cold stimulation. The FM IgG-injected mice also developed impaired muscular strength and decreased locomotor activity. Moreover, FM IgG bound and stimulated satellite glial cells (SGCs) in vivo and in vitro. No FM or HC IgG accumulation was found in the brain or spinal cord of the injected mice. Our study also demonstrated that FM IgG can bind to satellite glial cells and neurons in the human DRG. In addition, we observed a significant reduction in the intraepidermal nerve fiber density in the mice 14 days after the FM IgG injection. Our results suggest that transferring FM IgG into mice can replicate some peripheral FM symptoms. This study can provide a valuable animal model for studying the peripheral physiology of FM. Our discovery could significantly advance the understanding and treatment of fibromyalgia and other related conditions. However, more research is needed to understand the cellular and molecular mechanisms involved in FM-IgG-mediated changes in mice.Study III aimed to investigate the frequency of anti-satellite glial cell (SGC) antibodies and the antibody association with the disease severity in FM patients. We used serum (Karolinska Institutet, Sweden; n=30/group) and plasma (McGill University, Canada; n=35/group) samples collected from FM patients and HCs. Our results showed a higher binding intensity of the FM IgG to SGC in vitro. Furthermore, the frequency of SGC bound to FM IgG was significantly higher than HC IgG-treated cells. These findings correlated with pain intensity and fibromyalgia impact questionnaire scores (FIQ, questionnaire was only assessed in the Karolinska cohort). Further cluster analysis separated the FM group into severe and mild groups. Additionally, we found that serum from FM patients contains IgG that binds in greater proportion to SGC in the human DRG, measured by higher signal intensity. There were no differences in the binding intensity to neuronal cell bodies or axons between FM and HC serum samples. Finally, the previous results were confirmed using an FM serum sample with high levels of anti-SGC antibodies in 5 more human DRGs. To summarize, our report indicates that levels of anti-human SGC and anti-mouse SGC antibodies are elevated in patients with FM, which are linked to a more severe form of the disease. Patient stratification based on their profile of anti-SGC antibodies might benefit from therapies aiming to decrease circulating IgG or prevent IgG binding. Our results point to the possible involvement of anti-SGC antibodies and SGCs in the severity of FM; however, more in-depth studies are necessary to elucidate the antigen or antigens expressed in the SGC that bind to the circulating anti-SGC antibodies.In Study IV, we aimed to explore the neuroimmune signature of the FM skin. We processed 16 FM and 16 HC sex-matched skin biopsies by immunohistochemistry. Using a pan-neuronal marker, we found lower intraepidermal nerve fiber density (IENFD) in the FM compared with HC skin. Moreover, the length and volume of dermal NF200+ nerve profiles were significantly elevated, but we found no changes in the length of dermal or epidermal Gap43+ nerve profiles in the FM group. Similarly, we found no changes in the total volume of CD31+ blood vessels between FM and HC skin. Our results showed that the density of non-nerve associated S100b+, CD68+, and CD163+ cells was significantly lower in the FM skin. Furthermore, the dermal CD117+FcERI+ mast cells in the dermis of FM patients were significantly increased compared with the HCs. Additionally, we found similar densities of CD207+, CD3+, or Neutrophil elastase+ cells between FM and HC skin biopsies. mRNA analysis of FM skin showed no changes in Cd68, Cd163, Cx3cr1, or FceR1 mRNA levels between FM and HC skin. In summary, this study reveals crucial dermal and epidermal changes in FM skin, particularly regarding nerve fibers and certain immune cell populations. These findings are highly relevant as they provide deeper insights into the complex interactions between the nervous and immune systems in FM. Understanding these changes could be key to developing more effective treatments for FM, focusing on both the neuropathic and immune components of the disease.List of scientific papersI. Sex-dependent effects of the NGF R100E mutation on pain behavior, joint inflammation, and bone erosion in mice. Carlos E. Morado-Urbina*, Jungo Kato*, Katalin Sandor, Kristina Ängeby Möller, Jaira Villarreal Salcido, Arisai Martinez, Enriqueta Munoz-Islas, Juan Miguel Jimenez-Andrade, Camilla I Svensson. *Contributed equally. [Manuscript]II. Passive transfer of fibromyalgia symptoms from patients to mice. Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Morado Urbina C, Sandor K, Vastani N, Maurer M, Cuhadar U, Sensi S, Nomura Y, Menezes J, Baharpoor A, Brieskorn L, Sandström A, Tour J, Kadetoff D, Haglund L, Kosek E, Bevan S, Svensson CI, Andersson DA. J Clin Invest. 2021 Jul 1;131(13):e144201. https://doi.org/10.1172/JCI144201 III. Fibromyalgia patients with elevated levels of anti-satellite glia cell IgG antibodies present with more severe symptoms. Emerson Krock, Carlos E. Morado-Urbina, Joana Menezes, Matthew A. Hunt, Angelica Sandström, Diana Kadetoff, Jeanette Tour, Vivek Verma, Kim Kultima, Lisbet Haglund, Carolina B. Meloto, Luda Diatchenko, Eva Kosek, Camilla I. Svensson. Pain. [Accepted] https://doi.org/10.1097/j.pain.0000000000002881 IV. Exploring Fibromyalgia: Unveiling the Neuroimmune Signature of Skin. Carlos E. Morado-Urbina, Matthew Hunt, Alexandra Jurzack, Katalin Sandor, Sigita Venckute-Larsson, Karolina af Ekenstam, Diana Kadetoff, Jeanette Tour, Eva Kosek, Camilla I. Svensson. [Manuscript]</p
Neurocomputational modelling of human decision making and volition : from neural mechanisms to behavioral outcomes
No full textIn today's world, amidst the bombardment of information, the mental health and well-being of a society with higher level of responsibility hinge on a central issue related to decision making and human agency. The essence of studying these issues lies in unraveling the role of individual and social life experiences in evolving human choices and intentional actions. Researchers aim to unravel the foundational principles shaping individual behavior by comprehending how the brain, as a complex system, can be conceptualized, understood psychologically, and addressed socially.In this thesis, neurocomputational models are developed to bridge the gaps between micro (neuronal), meso (brain areas), and macro (cognition/behavior) levels. These models primarily focus on the mesoscale neurodynamics of cortical structures, with the goal of linking neural structures, functions, and the influences of internal and environmental factors on decision-making processes and volitional action control. These are neurally-inspired models, providing insight into the dynamics of neural oscillations through attractor networks, recognized as distinctive markers of various cognitive functions. My research is divided into two parts based on studying decision making without and with considering human agency, respectively.In the first part, the focus is on studying the neural mechanisms underlying decision making without explicitly considering human agency. Two slightly different neurocomputational models are developed based on the sources of input information, i.e. either internal or external. In both these models, an integration of rational and emotional processes is the essence of decision-making process. This interplay results in different model behaviors due to the sources of information: 1) the subjective values and attitudes and 2) the observational-based perceived behavior of others. The former model type addresses how an individual's behavior dynamically changes in response to the interplay between rational and emotional factors regarding internal signals while the latter one deals with the social adaptive characteristic of an individual, where dynamic changes in her behaviors are connected with the impact of trust on rational-emotional interactions. This part was part of the EU-funded project COMPLEX - Knowledge Based Climate Mitigation Systems for a Low Carbon Economy.In the second part, the central premise is understanding volitional decision-making process while individual’s actions are goal-directed guided by either internal or predicted external triggers. In this context, fundamental questions concerning the causal efficacious of intentions in decision making, as well as distinctions between 1) self-initiated and 2) externally-triggered actions, were explored. In this regard, a neurocomputational model has been developed to study the neurodynamics of structures involved in the intentional preparatory process of these two volitional processes, while shedding light on the dynamics of attractor networks and neurodynamical changes. Furthermore, the obtained results in both volitional contexts have been compared qualitatively with real EEG data to validate the models as well as explain the observed real neural behavior regarding this descriptive comparison. This research was conducted as a part of the Neurophilosophy of Free Will project funded by a joint Templeton/Fetzer grant.Regarding the fact that the simulation results mimic EEG and MEG readouts, further qualitative comparisons with experimental and clinical data should be conducted in the future. However, due to limitations in the available data, the next step can involve providing data with higher resolution using source-localized electrodes. Additionally, I intend to disentangle a meta-model to investigate how two models of self-initiated and externally-triggered actions can be transformed to each other. This exploration can provide insights into the behavioral adaptations of human beings in everyday life.List of scientific papersI. Azadeh Hassannejad Nazir, Hans Liljenström. (2015). A cortical network model of cognitive and emotional influences in human decision making. BioSystems. 13, pp.128–141. -Paper was also included in the licentiate thesis. https://doi.org/10.1016/j.biosystems.2015.07.004 II. Azadeh Hassannejad Nazir, Hellgren Kotaleski, J., Hans Liljenström. (2024). A Neurocognitive model of observation-based decision making with a focus on trust. Paper was also included in the licentiate thesis. [Manuscript]III. Hassannejad Nazir, A., Hellgren Kotaleski, J. & Liljenström, H. (2023). Computational modeling of attractor-based neural processes involved in the preparation of voluntary actions. Cogn Neurodyn. https://doi.org/10.1007/s11571-023-10019-3 IV. Hassannejad Nazir, A., Watanabe, T., Lundqvist, M. Khalighinejad, N. Hellgren Kotaleski, J. Liljenström, H. (2024). Neurodynamics of prefrontal areas in volitional contexts- a comparative study based on computational modelling and EEG data. [Manuscript]</p
Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms
No full textThe flow from transcription of genes through translation and processing of proteins is a common basis for all life. Redox homeostasis is crucial for the defence against oxidative stress. We adapt through hormesis; non-lethal stress regulates redox-sensitive systems to maintain homeostasis. If the stress is chronic or acutely overwhelming, the cells can either go into apoptosis or into senescence to maintain homeostasis. Similar effects have been seen with HBOT as with intermittent oxygen deprivation. Hyperbaric oxygen therapy (HBOT) is delivered in a pressure chamber by breathing 100% oxygen intermittently, several times a week, in an ambient pressure equivalent to 10-20 meters of seawater. The aim of this thesis was to evaluate potential harms of HBOT for novel indications and to explore biomarkers in experimental and clinical trials in order to enable future precision medicine. We used methods evaluated on healthy volunteers in randomised clinical trials (RCTs) conducted in compliance with good clinical practice (ICH-GCP).In Paper I, we evaluated Electron paramagnetic resonance (EPR) spectroscopy for measuring reactive oxygen species (ROS) in blood and RNA sequencing (RNAseq) of monocytes in peripheral blood (PBMC), and compared HBOT and HIIT in ten healthy volunteers. We could measure ROS in blood in the same physiological range in both interventions. We also discovered pathways involved in adaption to hypoxia and inflammation that were similar in both interventions. In Papers II and III, we evaluated harms and explored RNAseq in PBMC in an open label RCT where 31 patients with severe COVID- 19 were randomised to HBOT or best practice. We observed similar frequencies of adverse events (AEs) in the two groups and could not see any negative effect on vital signs or oxygenation. We discovered a unique transcriptomic signature in the subjects that had received HBOT. The differentially expressed genes were associated with the unfolded protein response, apoptosis, and immune response. In Paper IV, we evaluated harms and described health related quality of life (HRQoL)in an interim analysis of the first 20 subjects froma placebo controlled RCT where 80 patients with Long COIVD were randomised to HBOT or sham treatment. We reported more AEs than expected and severe physical and mental disabilities with a very poor HRQoL. Most AEs were mild, and all were transient.We have shown that HBOT shares similarities in immune response with HIIT in healthy volunteers. HBOT has a favourable profile of harms and has a potent immunomodulatory effect that is associated with fast recovery for critical COVID-19 patients. HBOT has a favourable profile of harms for patients with post COVID-19 condition. The results provide a base for future clinical trials with HBOT.List of scientific papersI. Comparing the blood response to hyperbaric oxygen with high intensity interval training - a cross-over study in healthy volunteers. Kjellberg A, Lindholm ME, Zheng X, Liwenborg L, Rodriguez-Wallberg KA, Catrina S-B, Lindholm P. Antioxidants. 2023;12:2043. https://doi.org/10.3390/antiox12122043 II. COVID-19-Induced Acute Respiratory Distress Syndrome Treated with Hyperbaric Oxygen: Interim Safety Report from a Randomized Clinical Trial (COVID-19-HBO). Kjellberg A, Douglas J, Hassler A, Al-Ezerjawi S, Bostrom E, Abdel-Halim L, Liwenborg L, Hetting E, Jonasdottir Njastad AD, Kowalski J, Catrina SB, Rodriguez-Wallberg KA, Lindholm P. J Clin Med. 2023;12. https://doi.org/10.3390/jcm12144850 III. Fast recovery of COVID-19-induced acute respiratory distress syndrome after hyperbaric oxygen treatment and changes in endoplasmic reticulum (ER) stress response in peripheral monocytes – A randomized-controlled trial. Kjellberg A, Zhao A, Lussier A, Hassler A, Al- Ezerjawi S, Boström E, Catrina S-B, Bergman P, Rodriguez-Wallberg KA, Lindholm P. Pre-print: doi.org/10.21203/rs.3.rs-3699049/v1 [Manuscript]IV. Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial. Kjellberg A, Hassler A, Bostrom E, El Gharbi S, Al-Ezerjawi S, Kowalski J, Rodriguez Wallberg KA, Bruchfeld J, Stahlberg M, Nygren-Bonnier M, Runold M, Lindholm P. BMC Infect Dis. 2023;23:33. https://doi.org/10.1186/s12879-023-08002-8 </p