| 1. |
- Aranda-Guillén, Maribel, et al.
(författare)
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A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.
- 2023
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Ingår i: Journal of internal medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 294:1, s. 96-109
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p<2e-16), and 1.2 SD higher in the young patients compared with the old (p=3e-4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.
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| 2. |
- Aybay, Erdem, et al.
(författare)
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Extended cleavage specificities of human granzymes A and K, two closely related enzymes with conserved but still poorly defined functions in T and NK cell-mediated immunity
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Granzymes A and K are two highly homologous serine proteases expressed by mammalian cytotoxic T cells (CTL) and natural killer cells (NK). Granzyme A is the most abundant of the different granzymes (gzms) expressed by these two cell types. Gzms A and K are found in all jawed vertebrates and are the most well conserved of all hematopoietic serine proteases. Their potential functions have been studied extensively for many years, however, without clear conclusions. Gzm A was for many years thought to serve as a key component in the defense against viral infection by the induction of apoptosis in virus-infected cells, similar to gzm B. However, later studies have questioned this role and instead indicated that gzm A may act as a potent inducer of inflammatory cytokines and chemokines. Gzms A and K form clearly separate branches in a phylogenetic tree indicating separate functions. Transcriptional analyses presented here demonstrate the presence of gzm A and K transcripts in both CD4+ and CD8+ T cells. To enable screening for their primary biological targets we have made a detailed analysis of their extended cleavage specificities. Phage display analysis of the cleavage specificity of the recombinant enzymes showed that both gzms A and K are strict tryptases with high selectivity for Arg over Lys in the P1 position. The major differences in the specificities of these two enzymes are located N-terminally of the cleavage site, where gzm A prefers small amino acids such as Gly in the P3 position and shows a relatively relaxed selectivity in the P2 position. In contrast, gzm K prefers large amino acids such as Phe, Tyr, and Trp in both the P2 and P3 positions and does not tolerate negatively charged residues in the P2 position. This major distinction in extended specificities is likely reflected also in preferred in vivo targets of these two enzymes. This information can now be utilized for high-precision screening of primary targets for gzms A and K in search of their highly conserved but still poorly defined functions in vertebrate immunity.
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| 3. |
- Bagher, Mariam, et al.
(författare)
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Crosstalk between mast cells and lung fibroblasts is modified by alveolar extracellular matrix and influences epithelial migration
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells play an important role in asthma, however, the interactions between mast cells, fibroblasts and epithelial cells in idiopathic pulmonary fibrosis (IPF) are less known. The objectives were to investigate the effect of mast cells on fibroblast activity and migration of epithelial cells. Lung fibroblasts from IPF patients and healthy individuals were co-cultured with LAD2 mast cells or stimulated with the proteases tryptase and chymase. Human lung fibroblasts and mast cells were cultured on cell culture plastic plates or decellularized human lung tissue (scaffolds) to create a more physiological milieu by providing an alveolar extracellular matrix. Released mediators were analyzed and evaluated for effects on epithelial cell migration. Tryptase increased vascular endothelial growth factor (VEGF) release from fibroblasts, whereas co-culture with mast cells increased IL-6 and hepatocyte growth factor (HGF). Culture in scaffolds increased the release of VEGF compared to culture on plastic. Migration of epithelial cells was reduced by IL-6, while HGF and conditioned media from scaffold cultures promoted migration. In conclusion, mast cells and tryptase increased fibroblast release of mediators that influenced epithelial migration. These data indicate a role of mast cells and tryptase in the interplay between fibroblasts, epithelial cells and the alveolar extracellular matrix in health and lung disease.
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| 4. |
- Bergman, Jonas, et al.
(författare)
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When the River Began—The Formation of River Motala Ström and Human Presence in the Early Holocene, Sweden
- 2020
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Ingår i: Quaternary. - : MDPI AG. - 2571-550X. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- In conjunction with the extensive archaeological projects conducted at the current outlet of Sweden’s second largest lake, Lake Vättern, macrofossil, pollen and diatom records have been studied from 14C-dated lake and river sediments from River Motala Ström in Motala and Lake Boren. These investigations have revealed sedimentary evidence of the Yoldia Sea regression, the Ancient Lake Vättern transgression, and the following stepwise river formation process. Around 9000 cal BC, two small kettlehole basins at Strandvägen and Kanaljorden became isolated from the Baltic basin. As the ice sheet retreated further north, the isostatic uplift isolated the Vättern basin from the Baltic basin. Due to the uneven isostatic uplift, the basin tilted toward the south, and the Ancient Lake Vättern transgression started in Motala. The threshold in Motala at 92.5 m a.s.l. was reached around 7200 cal BC, and River Motala Ström was formed. 14C-dated diatom records from Lake Boren, and shoreline deposits in Motala, confirm this event. The water level in Lake Vättern initially fell around 1.5 m, and around 5800 cal BC, a second erosional event cut down the threshold to modern day level. At this time, the Late Mesolithic settlements in Motala were established and expanded.
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| 5. |
- Bärnarp, Tora, et al.
(författare)
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Skönhet hållbarhet funktion
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna publikation redovisar studenternas enskilda arbeten. Materialet har tillkommit inom ramen för läsårets tema ”Skönhet, hållbarhet och funktion”, men varje studie utgår ifrån studenternas egna val av ämne.
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| 6. |
- Consiglio, Camila, et al.
(författare)
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Immune system adaptation during gender-affirming testosterone treatment
- 2023
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 159, s. 29-30
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Biological sex impacts human immune responses, modulating susceptibility and severity to immune-related diseases. Female generally mount more robust immune responses than males, resulting in lower infection severity and greater autoimmunity incidence. Here, we addressed the contribution of testosterone to human immune function by analyzing a cohort of subjects undergoing gender-affirming testosterone treatment. We performed systems-level immunomonitoring through mass cytometry, scRNA and scA-TAC-Sequencing, and proteome profiling of blood samples at baseline and following 3 and 12 months of treatment. Testosterone treatment was associated with a low-grade inflammatory profile, evidenced by upregulation of proinflammatory plasma proteome (e.g., EN-RAGE, OSM, TNF), and induction of an inflammatory transcriptional program associated with NFkB signaling, and TNF signaling. Following testosterone treatment, higher NFkB activity was revealed in CD4 T, CD8 T, and NK cells in scATACseq analyses. Further, testosterone increased monocytic inflammatory responses upon bacterial stimulation in vitro. Although testosterone was associated with this inflammatory profile, it also exerted negative effects on antiviral immunity. Firstly, the percentage of plasmacytoid dendritic cells (pDC) decreased over transition, with pDC also displaying phenotypic changes associated with lower IFN responses. Secondly, bulk transcriptomics analyses show an overall reduction of IFNa responses. Thirdly, testosterone treatment led to reduced IFNa production upon PBMCs stimulation with a viral agonist. Our results show that testosterone has broad effects on the human immune system, and significantly modulates important players in antiviral immunity and inflammatory response. Identifying pathways involved in immune sexual dimorphism will help define novel targets for effective prevention and treatment of immune-mediated diseases.
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| 7. |
- Dondalska, Aleksandra, 1985-
(författare)
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Harnessing the immunoregulatory capacity of single-stranded oligonucleotides to modulate innate immunity
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As the first line of defense, the innate immune system is exceptionally efficacious against invading pathogens but must be tightly regulated to avoid immune-related pathogenesis. Accordingly, the innate immune system recognizes highly conserved components associated with infections and damaged cells using a limited number of pattern-recognition receptors (PRRs), which are differentially expressed across cell types. Importantly, tissue damage and viral infections can induce the release and production of nucleic acids, which can be sensed by nucleic-acid sensing Toll-like-receptors (TLRs), a subset of PRRs located in cellular endosomes that encompass the receptors TLR3,7,8 or 9. It is imperative that these receptors can differentiate “self” nucleic acids from “non-self” in order to avoid autoimmune reactions. However, increasing data has shown that over-active signaling from these receptors can contribute to TLR-mediated inflammatory and auto-immune consequences. Previously, a 35 bases long single-stranded oligonucleotide (ssON) was revealed to inhibit TLR3 activation in dendritic cells (DCs). Hence, the research presented in this thesis aims to harness the capacity of certain immunosuppressive oligonucleotides to modulate the innate immune response to inflammation and viral infection. In Paper I we demonstrated that ssON inhibits certain receptor-mediated endocytosis, thereby preventing activation from TLR3/4/7 signaling endosomes Additionally, ssON modulated TLR3-mediated activation in vivo in the skin. Therefore, in Paper II, we further assessed ssON’s effect on prominent symptoms of inflammatory skin disorders. We demonstrated that ssON inhibits non-IgE-mediated degranulation of mast cells induced by certain ligands of the pseudo-allergic receptor MRGPRX2, thereby alleviating the respective downstream itch and inflammation. There is currently an urgent need to develop new broad-spectrum antivirals against acute respiratory tract infections, which at present remain the deadliest communicable diseases. Since ssON inhibits clathrin-mediated and caveolin-dependent endocytosis, which are cellular entry pathways utilized by many viruses, we investigated ssON’s potential as an anti-viral agent against two major respiratory viruses. In Paper III we aimed to assess the effect of ssON on influenza A virus (IAV) infection. We demonstrated that ssON inhibits the infection of IAV, and more specifically the pandemic H1N1, in vitro in DCs and reduces viral load and disease in murine models of IAV infection. In Paper IV we aimed to assess the anti-viral capacity of ssON on respiratory syncytial virus (RSV) infection. We discovered that ssON acts as an efficient antiviral agent against RSV in vitro, seemingly by competing with the virus for binding to the entry receptor nucleolin. Additionally, ssON inhibits viral infection in vivo in a murine model of RSV infection, and the combination of ssON treatment and RSV infection leads to an upregulation of immune-related genes in the lungs, which most likely aid in viral clearance.In summary, the research presented in this thesis uncovers novel immunomodulatory functions of synthetic, noncoding ssONs to modulate the innate immune responses in the context pseudo- allergic itch and inflammation as well as in IAV and RSV infection. Furthermore, these studies unveil prospective therapeutic possibilities for ssON as an antiviral agent or as a treatment for certain inflammatory dermatoses.
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| 8. |
- Emmesjö, Lina, et al.
(författare)
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Patients’ and next of kin’s expectations and experiences of a mobile integrated care model with a home health care physician : a qualitative thematic study
- 2023
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Ingår i: BMC Health Services Research. - : BioMed Central (BMC). - 1472-6963. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The organizational principle of remaining at home has offset care from the hospital to the home of the older person where care from formal and informal caregivers is needed. Globally, formal care is often organized to handle singular and sporadic health problems, leading to the need for several health care providers. The need for an integrated care model was therefore recognized by health care authorities in one county in Sweden, who created a cross-organisational integrated care model to meet these challenges. The Mobile integrated care model with a home health care physician (MICM) is a collaboration between regional and municipal health care. Descriptions of patients’ and next of kin’s experiences of integrated care is however lacking, motivating exploration.Method: A qualitative thematic study. Data collection was done before the patients met the MICM physician, and again six months later.Results: The participants expected a sense of relief when admitted to MICM, and hoped for shared responsibility, building a personal contact and continuity but experienced lack of information about what MICM was. At the follow-up interview, participants described having an easier daily life. The increased access to the health care personnel (HCP) allowed participants to let go of responsibility, and created a sense of safety through the personalised contact and continuity. However, some felt ignored and that the personnel teamed up against the patient. The MICM structure was experienced as hierarchical, which influenced the possibility to participate. However, the home visits opened up the possibility for shared decision making.Conclusion: Participants had an expectation of receiving safe and coherent health care, to share responsibility, personal contact and continuity. After six months, the participants expressed that MICM had provided an easier daily life. The direct access to HCP reduced their responsibility and they had created a personalised contact with the HCP and that the individual HCP mattered to them, which could be perceived as in line with the goals in the shift to local health care. The MICM was experienced as a hierarchic structure with impact on participation, indicating that all dimensions of person-centred care were not fulfilled.
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| 9. |
- Emmesjö, Lina
(författare)
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Within an integrated home health care model : Registered nurses’, physicians’, patients’ and their next of kin’s perspectives
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many older patients receive health care from several different healthcare organizations, which may lead uncertainty about the responsibility for their healthcare needs. Integrated care has been argued to aid the healthcare system by addressing the challenge of the complex care needs of older patients with multiple health problems. Previous research has stated that integrated care models often have been developed with a focus on a single diagnosis, which risks overlooking the extensive and complex care needs of older patients. Prior research has also expressed the need to deepen knowledge about how integrated care models influence health care professionals, patients and their next of kin. Moreover, it is important to understand how the COVID-19 pandemic affected integrated care models which may expand knowledge about integrated home health care in crisis situations.The overall aim is to study expectations, perceptions and experiences of integrated home health care through the perspective of registered nurses, physicians, patients and their next of kin.Inductive qualitative designs where data was collected through interviews and field notes in the setting of the mobile integrated care model with a home health care physician (MICM) with registered nurses, physicians and patients and next of kin. Analysis was conducted using qualitative content analysis, phenomenography, and thematic analysis.The emphasis on person-centered care in the MICM was evident in the perceptions of the healthcare professionals about the patients and their next of kin, whom they viewed as persons, not simply recipients of health care. Differences were found in the health care provided in the MICM and in comparison, to other healthcare organizations which did not align with the person-centered care ethics. However, providing health care to patients in their own home benefited the provision of person-centered care – the value base of the MICM. The MICM was created with the goal of implementing individually tailored and coherent health care with increased continuity. The healthcare professionals viewed individual medical healthcare plans as co-created with each patient, and yet no patient could recall participating in this co-creation. The coherency of the MICM was regarded as having been improved by teamwork between the registered nurse and the home healthcare physician. Collaborations with other healthcare professionals rarely occurred and should be improved in the future. Participants reported varying experiences of continuity in the MICM, which influenced the possibility of building relationships. Providing continuity with a home healthcare physician for patients is therefore preferable. The work described in this thesis was conducted during the COVID-19 pandemic. The thesis provides unique insights into an integrated care model during a crisis situation, which the healthcare system may face in similar or different ways in the future. The MICM was upheld as the best way to work in home health care, especially as patients and their next of kin regarded the model as making their daily lives easier.
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| 10. |
- Eriksson, Daniel, et al.
(författare)
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GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).
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| 11. |
- Ghaidan, Haider, et al.
(författare)
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Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.
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| 12. |
- Hallgren, Filip, et al.
(författare)
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Particle flow rate from the airways as fingerprint diagnostics in mechanical ventilation in the intensive care unit : A randomised controlled study
- 2021
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Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Mechanical ventilation can be monitored by analysing particles in exhaled air as measured by particle flow rate (PFR). This could be a potential method of detecting ventilator-induced lung injury (VILI) before changes in conventional parameters can be detected. The aim of this study was to investigate PFR during different ventilation modes in patients without lung pathology. Method A prospective study was conducted on patients on mechanical ventilation in the cardiothoracic intensive care unit (ICU). A PExA 2.0 device was connected to the expiratory limb on the ventilator for continuous measurement of PFR in 30 patients randomised to either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) for 30 min including a recruitment manoeuvre. PFR measurements were continued as the patients were transitioned to pressure-regulated volume control (PRVC) and then pressure support ventilation (PSV) until extubation. Results PRVC resulted in significantly lower PFR, while those on PSV had the highest PFR. The distribution of particles differed significantly between the different ventilation modes. Conclusions Measuring PFR is safe after cardiac surgery in the ICU and may constitute a novel method of continuously monitoring the small airways in real time. A low PFR during mechanical ventilation may correlate to a gentle ventilation strategy. PFR increases as the patient transitions from controlled mechanical ventilation to autonomous breathing, which most likely occurs as recruitment by the diaphragm opens up more distal airways. Different ventilation modes resulted in unique particle patterns and could be used as a fingerprint for the different ventilation modes.
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| 13. |
- Hovlin, Lina, et al.
(författare)
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Mutual trust is a prerequisite for nurses’ sense of safety and work satisfaction – Mobile Integrated Care Model : A qualitative interview study
- 2023
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Ingår i: Nordic journal of nursing research. - : Sage Publications. - 2057-1585 .- 2057-1593. ; 43:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of older persons have complex health care needs. This, along with the organizational principle of remaining at home, emphasizes the need to develop collaborations among organizations caring for older persons. A health care model developed in Sweden, the Mobile Integrated Care Model aims to promote work in teams across organizations. The aim of the study was to describe nurses’ experiences in working and providing health care in the Mobile Integrated Care Model in the home with home health care physicians. Semi-structured interviews were conducted with 18 nurses and analyzed through qualitative content analysis. The method was compliant with the COREQ checklist. A mutually trusting collaboration with physicians, which formed person-centered care, created work satisfaction for the nurses. Working within the Mobile Integrated Care Model was negatively impacted by being employed by different organizations, lack of time to provide health care, and physicians’ person-centered work abilities.
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| 14. |
- Hovlin, Lina, et al.
(författare)
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The role of the home health care physician in mobile integrated care : a qualitative phenomenograpic study
- 2022
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Ingår i: BMC Geriatrics. - : BioMed Central (BMC). - 1471-2318. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: An increasing older population, along with the organizational principle of remaining at home, has moved health care from institutions into the older person’s home, where several health care providers facilitate care. The Mobile Integrated Care Model strives to provide cost-efficient, coherent, person-centered health care in the home. In the integrated care team, where the home health care physician is the medical authority, several health care professions work across organizational borders. Therefore, the aim of this study was to describe Home Health Care Physicians perceptions of working and providing health care in the Mobile Integrated Care Model, as well as perceptions of participating in and forming health care.Methods: A phenomenographic qualitative study design, with semi-structured interviews using an interview guide.Results: Working within Mobile Integrated Care Model was a different way of working as a physician. The physicians’ role was to support the patient by making safe medical decisions. Physicians described themselves as a piece in the team puzzle, where the professional knowledge of others was crucial to give quality health care. Being in the patients’ homes was expressed as adding a unique dimension in the provision of health care, and the physicians learned more about the patients by meeting them in their homes than at an institution. This aided the physicians in respecting patient autonomy in medical decision making, even though the physicians sometimes disregarded patient autonomy in favor of their own medical experience. There was a divided view on next of kin participation among the home health care physicians, ranging from always including to total absence of involving next of kin in decision making.Conclusions: The home health care physicians described the Mobile Integrated Care Model as the best way to work, but there was still a need for additional resources and structure when working in different organizations. The need for full-time employment, additional time or hours, more equipment, access to each other’s medical records, and additional collaboration with other health care providers were expressed, which could contribute to increased work satisfaction and facilitate further development of person-centered care in the Mobile Integrated Care Model.
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| 15. |
- Johansson, Linda, 1978-, et al.
(författare)
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Using aggregated data from Swedish national quality registries as tools to describe health conditions of older adults with complex needs
- 2021
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Ingår i: Aging Clinical and Experimental Research. - : Springer. - 1594-0667 .- 1720-8319. ; 33:5, s. 1297-1306
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Tidskriftsartikel (refereegranskat)abstract
- Background: Combining National Quality Registries (NQRs) with existing National Health Registries (NHRs) might make it possible to get a wider picture of older adults health situation. The aim was to examine the feasibility of aggregating data across different NQRs and existing NHRs to explore the possibility to investigate trajectories and patterns of disease and care, specifically for the most ill older adults. Method: A Swedish twin population (N = 44,816) was linked to nine NQRs and four NHRs. A descriptive mixed-method study was performed. A manifest content analysis identified which health parameters were collected from each NQR. Factor analysis identified patterns in representation across NQRs. Two case studies illustrated individual trajectories of care by using NQRs and NHRs. Results: About 36% of the population was registered in one or more NQRs. NQRs included 1849 variables that were sorted into 13 categories with extensive overlap across the NQRs. Health and function variables were identified, but few social or cognitive variables. Even though most individuals demonstrated unique patterns of multi-morbidities, factor analysis identified three clusters of representation in the NQRs with sufficient sample sizes for future investigations. The two cases illustrated the possibility of following patterns of disease and trajectories of care. Conclusions: NQRs seem to be a significant source for collecting data about a population that may be underrepresented in most research on aging because of their age and poor health. However, NQRs are primarily disease related, and further development of the registries to maximize coverage and utility is needed.
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| 16. |
- Larsson-Callerfelt, Anna-Karin, et al.
(författare)
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VEGF synthesis and VEGF receptor 2 expression in patients with bronchiolitis obliterans syndrome after lung transplantation
- 2020
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 166
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Chronic lung allograft dysfunction including Bronchiolitis obliterans syndrome (BOS) is common after lung transplantation. Histologically, BOS is recognized as fibrotic lesions with accumulated extracellular matrix (ECM) in small airways. Lung fibroblasts are major producers of ECM and vascular endothelial growth factor (VEGF). In this study we hypothesize that VEGF is involved in BOS development after lung transplantation.METHODS: We investigated the effect of profibrotic transforming growth factor (TGF-β) on VEGF synthesis in lung fibroblasts isolated from distal lung tissue biopsies taken from patients at 3, 6 and 12 months after lung transplantation (n = 14). Co-expression of VEGF receptor (VEGFR) 2 and collagen marker prolyl4-hydroxylase (p4OH) were analyzed in lung tissue from patients with BOS (n = 11).RESULTS: VEGF synthesis from distal derived lung fibroblasts were significantly lower 3 months after lung transplantation (168.6 ± 133.7; n = 7) compared to non-transplanted subjects (451.8 ± 185.9; n = 9; p = 0.0033) and increased over time at 6 months (584.1 ± 264.9; n = 9; p = 0.0033) and 12 months (451.1 ± 207.5; n = 8; p = 0.0065) post transplantation. TGF-β significantly induced VEGF synthesis at all time points. At 12 months post transplantation there was significantly less VEGF synthesis after TGF-β stimulation in fibroblasts obtained from BOS patients (1170 ± 450.2; n = 4) compared to patients without any chronic rejection process (1980 ± 417.9; n = 4; p < 0.039). The numbers of cells expressing VEGFR2/p4OH were increased in patients with BOS (33.2 ± 10.9; n = 11) compared to control subjects (10.1 ± 9.9; n = 11; p < 0.001).CONCLUSIONS: Our results support that changes in VEGF/VEGFR2 axis could be involved in BOS development and marker of poor outcome.
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| 17. |
- Montelin, Hanna, 1984-, et al.
(författare)
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Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales : a prospective multicentre study
- 2024
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091.
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Treatment options for urinary tract infections (UTIs) caused by ESBL-producing Enterobacterales are limited. Moreover, evidence to support therapeutic decisions is lacking. This study assessed current treatment strategies and patient and pathogen characteristics in relation to clinical and microbiological outcomes.Methods: Patients with UTI caused by ESBL-producing Enterobacterales were prospectively recruited by investigators at 15 infectious disease hospital departments. Data were collected on patient characteristics, treatments, clinical and microbiological cure 10–14 days after the end of treatment, and relapse within 3 months. Bacterial isolates were subjected to MIC determination and WGS.Results: In total, 235 patients (107 febrile UTI, 128 lower UTI) caused by Escherichia coli (n = 223) and Klebsiella spp. (n = 12) were included. Clinical and microbiological cure rates were 83% and 64% in febrile UTI, and 79% and 65% in lower UTI. Great variability in treatments was observed, especially in oral therapy for febrile UTI. No difference was seen in clinical outcomes with piperacillin/tazobactam (n = 28) compared with carbapenems (n = 41). Pivmecillinam was frequently used in lower UTI (n = 62), and was also associated with high clinical cure rates when used as initial therapy (10/10) or follow-up (7/8) for febrile UTI. Recurrent infection, diabetes mellitus and urogenital disease were associated (P < 0.05) with clinical failure and relapse. In E. coli, ST131 was significantly associated with relapse, and haemolysin with microbiological failure or relapse.Conclusions: Antibiotic treatments were highly variable. Patient and pathogen factors were identified as potential determinants of disease presentation and outcomes and may prove useful to guide individualized treatment and follow-up.
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| 18. |
- Niroomand, Anna, et al.
(författare)
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Corticotropin releasing hormone as an identifier of bronchiolitis obliterans syndrome
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Lung transplantion (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS), an inflammation of the small airways in chronic rejection of a lung allograft. There is great clinical need for a minimally invasive biomarker of BOS. Here, 644 different proteins were analyzed to detect biomarkers that distinguish BOS grade 0 from grades 1-3. The plasma of 46 double lung transplant patients was analyzed for proteins using a high-component, multiplex immunoassay that enables analysis of protein biomarkers. Proximity Extension Assay (PEA) consists of antibody probe pairs which bind to targets. The resulting polymerase chain reaction (PCR) reporter sequence can be quantified by real-time PCR. Samples were collected at baseline and 1-year post transplantation. Enzyme-linked immunosorbent assay (ELISA) was used to validate the findings of the PEA analysis across both time points and microarray datasets from other lung transplantation centers demonstrated the same findings. Significant decreases in the plasma protein levels of CRH, FERC2, IL-20RA, TNFB, and IGSF3 and an increase in MMP-9 and CTSL1 were seen in patients who developed BOS compared to those who did not. In this study, CRH is presented as a novel potential biomarker in the progression of disease because of its decreased levels in patients across all BOS grades. Additionally, biomarkers involving the remodeling of the extracellular matrix (ECM), such as MMP-9 and CTSL1, were increased in BOS patients.
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| 19. |
- Rosmark, Oskar, et al.
(författare)
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A tunable physiomimetic stretch system evaluated with precision cut lung slices and recellularized human lung scaffolds
- 2022
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Ingår i: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Breathing exposes lung cells to continual mechanical stimuli, which is part of the microenvironmental signals directing cellular functions together with the extracellular matrix (ECM). Therefore, developing systems that incorporate both stimuli is urgent to fully understand cell behavior. This study aims to introduce a novel in vitro culture methodology combining a cyclic stretch that simulates in vivo breathing with 3D cell culture platforms in the form of decellularized lung slices (DLS) and precision cut lung slices (PCLS). To this end, we have constructed a device that mimics the amplitudes and frequencies of distensions seen in the breathing human lung. For its validation, we cultured H441 lung epithelial cells in human DLS exposed to 16 stretch cycles per minute with a 10% stretch amplitude. Cell viability (resazurin reduction), proliferation (Ki-67) and YAP1 activation were evaluated at 24 and 96 h by immunohistochemistry, while the expression of SFTPB, COL3A1, COL4A3 and LAMA5 was evaluated by qPCR. Cyclic stretch induced an increase in SFTPB expression after 24 h without a concomitant increase in the stretch responsive gene YAP1. Moreover, the ECM milieu lowered the expression of the basement membrane protein genes COL4A3 and LAMA5 compared to tissue culture plastic control cultures, but no effect was observed by the mechanical stimuli. The device also confirmed good compatibility with PCLS culture, showing preserved morphology and metabolism in rat PCLS after 72 h of mechanical stretch. Thus, we present a novel device and methodology for the easy assembling and study of lung tissue slice cultures subjected to physiomimetic mechanical stimuli, which shows promise for future studies of cell and tissue function in a lung ECM milieu with physiological or pathological mechanical stimuli.
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| 20. |
- Rosmark, Oskar, et al.
(författare)
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Alveolar epithelial cells are competent producers of interstitial extracellular matrix with disease relevant plasticity in a human in vitro 3D model
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Alveolar epithelial cells (AEC) have been implicated in pathological remodelling. We examined the capacity of AEC to produce extracellular matrix (ECM) and thereby directly contribute towards remodelling in chronic lung diseases. Cryopreserved type 2 AEC (AEC2) from healthy lungs and chronic obstructive pulmonary disease (COPD) afflicted lungs were cultured in decellularized healthy human lung slices for 13 days. Healthy-derived AEC2 were treated with transforming growth factor ß1 (TGF-β1) to evaluate the plasticity of their ECM production. Evaluation of phenotypic markers and expression of matrisome genes and proteins were evaluated by RNA-sequencing, mass spectrometry and immunohistochemistry. The AEC2 displayed an AEC marker profile similar to freshly isolated AEC2 throughout the 13-day culture period. COPD-derived AECs proliferated as healthy AECs with few differences in gene and protein expression while retaining increased expression of disease marker HLA-A. The AEC2 expressed basement membrane components and a complex set of interstitial ECM proteins. TGF-β1 stimuli induced a significant change in interstitial ECM production from AEC2 without loss of specific AEC marker expression. This study reveals a previously unexplored potential of AEC to directly contribute to ECM turnover by producing interstitial ECM proteins, motivating a re-evaluation of the role of AEC2 in pathological lung remodelling.
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| 21. |
- Stenlo, Martin, et al.
(författare)
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Monitoring lung injury with particle flow rate in LPS- and COVID-19-induced ARDS
- 2021
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 9:13
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Tidskriftsartikel (refereegranskat)abstract
- In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.
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| 22. |
- von Beek, Christopher, et al.
(författare)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 23. |
- von Beek, Christopher, et al.
(författare)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 24. |
- Zhang, Shuping, et al.
(författare)
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Mapping coastal upwelling in the Baltic Sea from 2002 to 2020 using remote sensing data
- 2022
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Ingår i: International Journal of Applied Earth Observation and Geoinformation. - : Elsevier. - 1569-8432 .- 1872-826X. ; 114
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Tidskriftsartikel (refereegranskat)abstract
- Coastal upwelling (CU) is an elementary phenomenon in coastal waters. CU brings up deep, often cold, saline water rich of nutrients and carbon, and plays a vital role in local air-sea exchange of gases and heat, marine ecosystem maintenance, and ocean physical dynamics. In this study, regional CU in the Baltic Sea was mapped on the daily MODIS SST from 2002 to 2020, using a method modified developed by Lehmann et al. (2012). Based on the individual CU event detected, the spatiotemporal distribution of CU in the Baltic Sea was depicted, the CU-wind relationship and potential CU drivers in the Baltic Sea on different temporal scale were analyzed. The results found that: 1) The modified approach can effectively delineate the CUs formed by upwelled cold water; 2) The 19 zones delineated with frequent CU occurrences aligned well with previous study and the overall CU occurrence spatial heterogeneity was casted by the different directional relationship between the local coastline and wind; 3) The occurrences of the CU detected in this study showed strong seasonality and primarily driven by SST seasonality and then intensified by local wind in fall; 4) The interannual difference of CU occurrences were affected by heatwaves and its monthly timing. The CUs detected in this study have a high potential for facilitating investigations with respect to oceanic modeling, air-sea exchange of heat and greenhouse gases, and physical dynamics in the Baltic Sea.
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