| 223771. |
- Thude, Bettina Ravnborg, et al.
(författare)
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Staff acting resiliently at two hospital wards
- 2019
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Ingår i: Leadership in Health Services. - : Emerald Group Publishing Limited. - 1751-1879 .- 1751-1887. ; 32:3, s. 445-457
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of this paper is to understand how the hospital staff (nurses and physicians) at two hospital wards have coped with everyday work having leaders in conflict or longer periods without one or the other leader and whether the way the staff handled the challenges was resilient.DESIGN/METHODOLOGY/APPROACH: Through semi-structured interviews with the staff at the two wards, the authors analysed how the staff were working, if they had cooperation and interdisciplinary cooperation, how they would handle uncertainties and how they coped with the absence of their leaders.FINDINGS: The staff at both wards were handling the everyday work in a resilient way. The authors argue that to increase the resilience in an organisation, leaders should acknowledge the need to establish strong emotional ties among staff and at the same time ensure role structures that make sense in the everyday work.ORIGINALITY/VALUE: This study reports on original work and shows what decision makers could do to increase resilience in an organisation. This paper shows that the organisational context is important for the staff to act resiliently. As leaders come and go, it can be important for the stability of the organisation to promote the staff in acting resiliently independent of the leader situation.
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| 223772. |
- Thudium, Christian, et al.
(författare)
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A Comparison of Osteoclast-Rich and Osteoclast-Poor Osteopetrosis in Adult Mice Sheds Light on the Role of the Osteoclast in Coupling Bone Resorption and Bone Formation
- 2014
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 95:1, s. 83-93
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Tidskriftsartikel (refereegranskat)abstract
- Osteopetrosis due to lack of acid secretion by osteoclasts is characterized by abolished bone resorption, increased osteoclast numbers, but normal or even increased bone formation. In contrast, osteoclast-poor osteopetrosis appears to have less osteoblasts and reduced bone formation, indicating that osteoclasts are important for regulating osteoblast activity. To illuminate the role of the osteoclast in controlling bone remodeling, we transplanted irradiated skeletally mature 3-month old wild-type mice with hematopoietic stem cells (HSCs) to generate either an osteoclast-rich or osteoclast-poor adult osteopetrosis model. We used fetal liver HSCs from (1) oc/oc mice, (2) RANK KO mice, and (3) compared these to wt control cells. TRAP5b activity, a marker of osteoclast number and size, was increased in the oc/oc recipients, while a significant reduction was seen in the RANK KO recipients. In contrast, the bone resorption marker CTX-I was similarly decreased in both groups. Both oc/oc and Rank KO recipients developed a mild osteopetrotic phenotype. However, the osteoclast-rich oc/oc recipients showed higher trabecular bone volume (40 %), increased bone strength (66 %), and increased bone formation rate (54 %) in trabecular bone, while RANK KO recipients showed only minor trends compared to control recipients. We here show that maintaining non-resorbing osteoclasts, as opposed to reducing the osteoclasts, leads to increased bone formation, bone volume, and ultimately higher bone strength in vivo, which indicates that osteoclasts are sources of anabolic molecules for the osteoblasts.
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| 223773. |
- Thudium, Christian
(författare)
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Development of Novel Models for Studying Osteoclasts
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on developing and characterizing novel models for studying osteoclasts with an emphasis on how mutations abolishing osteoclastic acidification affect osteoclast signaling and bone remodeling, as well as how to treat patients bearing these rare mutations. Bone remodeling is under normal circumstances a tightly balanced process where resorption of bone by osteoclasts is followed by adequate amounts of bone formation by osteoblasts.Mutations in the TCIRG1 gene lead to severe autosomal recessive osteopetrosis (ARO) in both mice and man, characterized by lack of bone resorption as a result of abolished acid secretion, an increased number of non-resorbing osteoclasts, but normal or even increased bone formation. The first two papers are based on studies in adult mice transplanted with stem cells from either osteoclast-rich osteopetrotic mice (oc/oc) or osteoclast-poor osteopetrotic mice (RANK KO). The first paper focuses on characterizing the bone and cellular phenotype in the adult osteopetrotic mouse model and find that bones, are both bigger and, in contrast to the endogenous oc/oc mouse model, stronger in mice transplanted with osteopetrotic stem cells compared to wild type transplanted mice. In the second paper we compare the osteoclast-rich osteopetrotic oc/oc transplanted model to adult mice transplanted with stem cells from the osteoclast-poor RANK KO mouse, and find that maintaining non-resorbing osteoclasts in vivo increases bone formation. In the third paper we investigate the role of bone matrix, cell stage and resorptive function on osteoclast mediated anabolic signaling. In paper IV human stem cells from patients with ARO were investigated and we provide the first proof-of-principle for lentiviral mediated correction of resorptive function in CD34+ derived osteoclasts from ARO patients. The results can be devided into two exciting branges. Data obtained in the adult osteopetrotic mouse models encourage further development of molecules targeting the acidification process in osteoclasts when treating low bone mineral density diseases. Furthermore, the correctional results in the ARO patient cells are very promising, and will serve as basis for further development of clinical gene therapy of osteopetrosis.
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| 223774. |
- Thudium, Christian S., et al.
(författare)
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Protein biomarkers associated with pain mechanisms in osteoarthritis
- 2019
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919. ; 190, s. 55-66
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis (OA) is the most common arthritic disease in the world, leading to debilitating pain and destruction of joint tissues. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. OA pain is multifactorial and may arise from multiple distinct or concurrent mechanisms, and may thus present as different pain sub-types. Several biomarkers developed to reflect important pathological processes are available, and associations between such biomarkers and OA pain may give hints to important pathological features, which have not been possible to assess using clinical, radiographic or magnetic resonance imaging techniques. This review highlights a selection of important, protein-derived biomarkers measured in body fluids from OA patients, which have been associated with different types and aspects of OA pain, and discusses the potential mechanisms behind the associations. Significance: Osteoarthritis (OA) is a heterogenous disease affecting the entire joint, including cartilage, bone and synovium. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. Thus, there is clear need for biomarkers that can accurately describe the underlying processes and distinguish between different disease and pain pathologies. In this review we discuss a selected number of biomarkers which have been directly or indirectly associated with pain mechanisms and development of pain in OA either via structural correlates or as molecular sensitizing agents. We further evaluate the challenges that the OA field faces in the development and application of biomarkers for OA pain.
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| 223775. |
- Thudium, Christian Schneider, et al.
(författare)
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Regulation and Function of Lentiviral Vector-Mediated TCIRG1 Expression in Osteoclasts from Patients with Infantile Malignant Osteopetrosis : Implications for Gene Therapy
- 2016
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 99:6, s. 638-648
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Tidskriftsartikel (refereegranskat)abstract
- Infantile malignant osteopetrosis (IMO) is a rare, recessive disorder characterized by increased bone mass caused by dysfunctional osteoclasts. The disease is most often caused by mutations in the TCIRG1 gene encoding a subunit of the V-ATPase involved in the osteoclasts capacity to resorb bone. We previously showed that osteoclast function can be restored by lentiviral vector-mediated expression of TCIRG1, but the exact threshold for restoration of resorption as well as the cellular response to vector-mediated TCIRG1 expression is unknown. Here we show that expression of TCIRG1 protein from a bicistronic TCIRG1/GFP lentiviral vector was only observed in mature osteoclasts, and not in their precursors or macrophages, in contrast to GFP expression, which was observed under all conditions. Thus, vector-mediated TCIRG1 expression appears to be post-transcriptionally regulated, preventing overexpression and/or ectopic expression and ensuring protein expression similar to that of wild-type osteoclasts. Codon optimization of TCIRG1 led to increased expression of mRNA but lower levels of protein and functional rescue. When assessing the functional rescue threshold in vitro, addition of 30 % CB CD34+ cells to IMO CD34+ patient cells was sufficient to completely normalize resorptive function after osteoclast differentiation. From both an efficacy and a safety perspective, these findings will clearly be of benefit during further development of gene therapy for osteopetrosis.
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| 223776. |
- Thuesen, Anne Cathrine Baun, et al.
(författare)
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Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment
- 2023
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Ingår i: Molecular Genetics and Metabolism Reports. - : Elsevier BV. - 2214-4269. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.
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| 223777. |
- Thuijs, Daniel J F M, et al.
(författare)
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Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
- 2019
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Ingår i: Lancet (London, England). - 1474-547X. ; 394:10206, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results.The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary endpoint of the SYNTAXES study was 10-year all-cause death, which was assessed according to the intention-to-treat principle. Prespecified subgroup analyses were performed according to the presence or absence of left main coronary artery disease and diabetes, and according to coronary complexity defined by core laboratory SYNTAX score tertiles. This study is registered with ClinicalTrials.gov, NCT03417050.From March, 2005, to April, 2007, 1800 patients were randomly assigned to the PCI (n=903) or CABG (n=897) group. Vital status information at 10 years was complete for 841 (93%) patients in the PCI group and 848 (95%) patients in the CABG group. At 10 years, 244 (27%) patients had died after PCI and 211 (24%) after CABG (hazard ratio 1·17 [95% CI 0·97-1·41], p=0·092). Among patients with three-vessel disease, 151 (28%) of 546 had died after PCI versus 113 (21%) of 549 after CABG (hazard ratio 1·41 [95% CI 1·10-1·80]), and among patients with left main coronary artery disease, 93 (26%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (0·90 [0·68-1·20], pinteraction=0·019). There was no treatment-by-subgroup interaction with diabetes (pinteraction=0·66) and no linear trend across SYNTAX score tertiles (ptrend=0·30).At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease.German Foundation of Heart Research (SYNTAXES study, 5-10-year follow-up) and Boston Scientific Corporation (SYNTAX study, 0-5-year follow-up).
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| 223778. |
- Thuille, Nikolaus, et al.
(författare)
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PKC theta/beta and CYLD Are Antagonistic Partners in the NF kappa B and NFAT Transactivation Pathways in Primary Mouse CD3(+) T Lymphocytes
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- In T cells PKC theta mediates the activation of critical signals downstream of TCR/CD28 stimulation. We investigated the molecular mechanisms by which PKC theta regulates NF kappa B transactivation by examining PKC theta/beta single and double knockout mice and observed a redundant involvement of PKCh and PKC beta in this signaling pathway. Mechanistically, we define a PKC theta-CYLD protein complex and an interaction between the positive PKC theta/beta and the negative CYLD signaling pathways that both converge at the level of TAK1/IKK/I-kB alpha/NF kappa B and NFAT transactivation. In Jurkat leukemic T cells, CYLD is endoproteolytically processed in the initial minutes of stimulation by the paracaspase MALT1 in a PKC-dependent fashion, which is required for robust IL-2 transcription. However, in primary T cells, CYLD processing occurs with different kinetics and an altered dependence on PKC. The formation of a direct PKC theta/CYLD complex appears to regulate the short-term spatial distribution of CYLD, subsequently affecting NF kappa B and NFAT repressional activity of CYLD prior to its MALT1dependent inactivation. Taken together, our study establishes CYLD as a new and critical PKC theta interactor in T cells and reveals that antagonistic PKC theta/beta-CYLD crosstalk is crucial for the adjustment of immune thresholds in primary mouse CD3(+) T cells.
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| 223779. |
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| 223780. |
- Thulesius, Hans, et al.
(författare)
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Balancing : a basic process in end-of-life cancer care.
- 2003
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Ingår i: Qualitative Health Research. - : Sage Publications. - 1049-7323 .- 1552-7557. ; 13:10, s. 1353-1377
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Tidskriftsartikel (refereegranskat)abstract
- In this grounded theory study, the authors interviewed caregivers and patients in end-of-life cancer care and found Balancing to be a fundamental process explaining the problem-solving strategies of most participants and offering a comprehensive perspective on both health care in general and end-of-life cancer care in particular. Balancing stages were Weighing--sensing needs and wishes signaled by patients, gauging them against caregiver resources in diagnosing and care planning; Shifting--breaking bad news, changing care places, and treatments; and Compensating--controlling symptoms, educating and team-working, prioritizing and "stretching" time, innovating care methods, improvising, and maintaining the homeostasis of hope. The Balancing outcome is characterized by Compromising, or "Walking a fine line," at best an optimized situation, at worst a deceit.
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