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  • 5651.
    Zhang, Ling
    et al.
    Nanjing University, Peoples R China.
    Zhang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Nanjing University, Peoples R China.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Nanjing University, Peoples R China.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    Han, Xiaodong
    Nanjing University, Peoples R China.
    Li, Dongmei
    Nanjing University, Peoples R China.
    Roles of piRNAs in microcystin-leucine-arginine (MC-LR) induced reproductive toxicity in testis on male offspring2017Ingår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 105, s. 177-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study, we evaluated the toxic effects on the testis of the male offspring of MC-LR exposure during fetal and lactational periods. Pregnant females were distributed into two experimental groups: control group and MC-LR group which were exposed to 0 and 10 mu g/L of MC-LR, respectively, through drinking water separately during fetal and lactational periods. At the age of 30 days after birth, the male offspring were euthanized. The body weight, testis index, and histomorphology change were observed and the global changes of piwi-interacting RNA (piRNA) expression were evaluated. The results revealed that MC-LR was found in the testis of male offspring, body weight and testis index decreased significantly, and testicular tissue structure was damaged in the MC-LR group. In addition, the exposure to MCLR resulted in an altered piRNA expression profile and an increase of the cell apoptosis and a decrease of the cell proliferation in the testis of the male offspring. It was reasonable to speculate that the toxic effects on reproductive system of the male offspring in MC-LR group might be mediated by piRNAs through the regulation of the target genes. As far as we are aware, this is the first report showing that MC-LR could play a role in disorder of proliferative and cell apoptosis in the testis of the male offspring by the maternal transmission effect of toxicity. (C) 2017 Elsevier Ltd. All rights reserved.

  • 5652.
    Zhang, Ming-Ran
    et al.
    Sichuan University, Peoples R China; Sichuan University, Peoples R China; Sichuan University, Peoples R China.
    Xie, Tian-Hang
    Sichuan University, Peoples R China.
    Chi, Jun-Lin
    Sichuan University, Peoples R China.
    Li, Yuan
    Sichuan University, Peoples R China.
    Yang, Lie
    Sichuan University, Peoples R China.
    Yu, Yong-Yang
    Sichuan University, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Sichuan University, Peoples R China.
    Zhou, Zong-Guang
    Sichuan University, Peoples R China.
    Prognostic role of the lymph node ratio in node positive colorectal cancer: a meta-analysis2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 45, s. 72898-72907Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lymph node ratio (LNR) (i. e. the number of metastatic lymph nodes divided by the number of totally resected lymph nodes) has recently emerged as an important prognostic factor in colorectal cancer (CRC). However, the tumor node metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a meta-analysis to evaluate the prognostic role of the LNR in node positive CRC. A systematic search was performed in PubMed, Embase and the Cochrane Library for relevant studies up to November 2015. As a result, a total of 75,838 node positive patients in 33 studies were included in this meta-analysis. Higher LNR was significantly associated with shorter overall survival (OS) (HR = 1.91; 95% CI 1.71-2.14; P = 0.0000) and disease free survival (DFS) (HR = 2.75; 95% CI: 2.14-3.53; P = 0.0000). Subgroup analysis showed similar results. Based on these results, LNR was an independent predictor of survival in colorectal cancer patients and should be considered as a parameter in future oncologic staging systems.

  • 5653.
    Zhang, Xiaonan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    De Milito, Angelo
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
    Demiroglu-Zergeroglu, Asuman
    Department of Molecular Biology and Genetics, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey.
    Gullbo, Joachim
    Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, Uppsala, Sweden.
    D’Arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Eradicating Quiescent Tumor Cells by Targeting Mitochondrial Bioenergetics2016Ingår i: Trends in Cancer, ISSN 2405-8033, Vol. 2, nr 11, s. 7s. 657-663Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Solid tumors contain slowly proliferating cells that show limited sensitivity to conventional cell cycle-active chemotherapeutic drugs. Tumor cells that are not exposed to therapeutically relevant drug concentrations and/or are insensitive to drugs survive treatment and repopulate tumors between treatment cycles. Cancer cells residing in hypoxic and nutritionally compromised environments are expected to have limited metabolic plasticity and to be susceptible to the manipulation of energy supply pathways. Drug screening campaigns using glucose-depleted tumor cells and 3D tumor cell cultures have resulted in the identification of inhibitors of mitochondrial energy production.

  • 5654.
    Zhang, Xiaonan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    de Milito, Angelo
    Karolinska Institute, Sweden.
    Hagg Olofsson, Maria
    Karolinska Institute, Sweden.
    Gullbo, Joachim
    Uppsala University, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors2015Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 11, s. 27313-27326Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an Achilles heel for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  • 5655.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Espinosa, Bela
    Karolinska Inst, Sweden.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment2019Ingår i: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, artikel-id 1659468Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (rho(0) cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.

  • 5656.
    Zhang, Xiaonan
    et al.
    Karolinska Institute, Sweden.
    Mofers, Arjan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hydbring, Per
    Karolinska Institute, Sweden.
    Hagg Olofsson, Maria
    Karolinska Institute, Sweden.
    Guo, Jing
    Karolinska Institute, Sweden; Duke NUS National University of Singapore Medical Sch, Singapore.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    MYC is downregulated by a mitochondrial checkpoint mechanism2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 52, s. 90225-90237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The MYC proto-oncogene serves as a rheostat coupling mitogenic signaling with the activation of genes regulating growth, metabolism and mitochondrial biogenesis. Here we describe a novel link between mitochondria and MYC levels. Perturbation of mitochondrial function using a number of conventional and novel inhibitors resulted in the decreased expression of MYC mRNA. This decrease in MYC mRNA occurred concomitantly with an increase in the levels of tumor-suppressive miRNAs such as members of the let-7 family and miR-34a-5p. Knockdown of let-7 family or miR-34a-5p could partially restore MYC levels following mitochondria damage. We also identified let-7-dependent downregulation of the MYC mRNA chaperone, CRD-BP (coding region determinant-binding protein) as an additional control following mitochondria damage. Our data demonstrates the existence of a homeostasis mechanism whereby mitochondrial function controls MYC expression.

  • 5657.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    Hillert, Ellin-Kristina
    Karolinska Inst, Sweden.
    Mazurkiewicz, Magdalena
    Karolinska Inst, Sweden.
    Olofsson, Maria Hagg
    Karolinska Inst, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and Check for mitochondrial damage2018Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 156, s. 291-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing alpha,beta-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5. Whereas similar overall mRNA and protein expression profiles were induced by b-AP15 and the clinically available proteasome inhibitor bortezomib, b-APIS induced stronger increases of chaperone expression. b-AP15 also induced a stronger accumulation of polyubiquitinated proteins in exposed cells. These proteins were found to partially colocalize with organelle structures, including mitochondria. Mitochondrial oxidative phosphorylation decreased in cells exposed to b-APIS, a phenomenon enhanced under conditions of severe proteotoxic stress caused by inhibition of the VCP/p97 ATPase and inhibition of protein translocation over the ER. We propose that mitochondrial damage caused by the association of misfolded proteins with mitochondrial membranes may contribute to the atypical cell death mode induced by b-AP15 and related compounds. The robust mode of cell death induction by this class of drugs holds promise for treatment of tumor cells characterized by apoptosis resistance.

  • 5658.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Selvaraj, Karthik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug2019Ingår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 162, s. 46-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Auranofin is a gold (1)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examined in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

    Publikationen är tillgänglig i fulltext från 2020-04-01 09:23
  • 5659.
    Zhang, Xueli
    et al.
    Orebro Univ, Sweden; Soochow Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Cao, Yang
    Orebro Univ, Sweden; Karolinska Inst, Sweden.
    Ye, Benchen
    Soochow Univ, Peoples R China.
    Peng, Qiliang
    Soochow Univ, Peoples R China.
    Liu, Xingyun
    Soochow Univ, Peoples R China.
    Shen, Bairong
    Soochow Univ, Peoples R China.
    Zhang, Hong
    Orebro Univ, Sweden.
    CBD: a biomarker database for colorectal cancer2018Ingår i: Database: The Journal of Biological Databases and Curation, ISSN 1758-0463, E-ISSN 1758-0463, Vol. 2018, nr 1 January 2018, artikel-id bay046Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Colorectal cancer (CRC) biomarker database (CBD) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data were collected, sorted, displayed and analysed. The CBD with the credible contents as a powerful and time-saving tool provide more comprehensive and accurate information for further CRC biomarker research. The CBD was constructed under MySQL server. HTML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD could provide to users the multiple individual biomarker information and categorized into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the average age of cohort, gender, race, the number of tumours, tumour location and stage. We only collect data from the articles with clear and credible results to prove the biomarkers are useful in the diagnosis, treatment or prognosis of CRC. The CBD can also provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high-quality research in CRC. They can submit their new findings to our database via the submission page and communicate with us in the CBD.

  • 5660.
    Zhang, Xueli
    et al.
    Orebro Univ, Sweden; Soochow Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Shen, Bairong
    Soochow Univ, Peoples R China.
    Zhang, Hong
    Orebro Univ, Sweden.
    Potential Applications of DNA, RNA and Protein Biomarkers in Diagnosis, Therapy and Prognosis for Colorectal Cancer: A Study from Databases to AI-Assisted Verification2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 2, artikel-id 172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In order to find out the most valuable biomarkers and pathways for diagnosis, therapy and prognosis in colorectal cancer (CRC) we have collected the published CRC biomarkers and established a CRC biomarker database (CBD: http://sysbio.suda.edu.cn/CBD/index.html). In this study, we analysed the single and multiple DNA, RNA and protein biomarkers as well as their positions in cancer related pathways and protein-protein interaction (PPI) networks to describe their potential applications in diagnosis, therapy and prognosis. CRC biomarkers were collected from the CBD. The RNA and protein biomarkers were matched to their corresponding DNAs by the miRDB database and the PubMed Gene database, respectively. The PPI networks were used to investigate the relationships between protein biomarkers and further detect the multiple biomarkers. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) annotation were used to analyse biological functions of the biomarkers. AI classification techniques were utilized to further verify the significances of the multiple biomarkers in diagnosis and prognosis for CRC. We showed that a large number of the DNA, RNA and protein biomarkers were associated with the diagnosis, therapy and prognosis in various degrees in the CRC biomarker networks. The CRC biomarkers were closely related to the CRC initiation and progression. Moreover, the biomarkers played critical roles in cellular proliferation, apoptosis and angiogenesis and they were involved in Ras, p53 and PI3K pathways. There were overlaps among the DNA, RNA and protein biomarkers. AI classification verifications showed that the combined multiple protein biomarkers played important roles to accurate early diagnosis and predict outcome for CRC. There were several single and multiple CRC protein biomarkers which were associated with diagnosis, therapy and prognosis in CRC. Further, AI-assisted analysis revealed that multiple biomarkers had potential applications for diagnosis and prognosis in CRC.

  • 5661.
    Zhang, Xueli
    et al.
    Orebro Univ, Sweden; Soochow Univ, Peoples R China.
    Zhang, Hong
    Orebro Univ, Sweden.
    Shen, Bairong
    Soochow Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Chromogranin-A Expression as a Novel Biomarker for Early Diagnosis of Colon Cancer Patients2019Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, nr 12, artikel-id 2919Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Colon cancer is one of the major causes of cancer death worldwide. The five-year survival rate for the early-stage patients is more than 90%, and only around 10% for the later stages. Moreover, half of the colon cancer patients have been clinically diagnosed at the later stages. It is; therefore, of importance to enhance the ability for the early diagnosis of colon cancer. Taking advantages from our previous studies, there are several potential biomarkers which have been associated with the early diagnosis of the colon cancer. In order to investigate these early diagnostic biomarkers for colon cancer, human chromogranin-A (CHGA) was further analyzed among the most powerful diagnostic biomarkers. In this study, we used a logistic regression-based meta-analysis to clarify associations of CHGA expression with colon cancer diagnosis. Both healthy populations and the normal mucosa from the colon cancer patients were selected as the double normal controls. The results showed decreased expression of CHGA in the early stages of colon cancer as compared to the normal controls. The decline of CHGA expression in the early stages of colon cancer is probably a new diagnostic biomarker for colon cancer diagnosis with high predicting possibility and verification performance. We have also compared the diagnostic powers of CHGA expression with the typical oncogene KRAS, classic tumor suppressor TP53, and well-known cellular proliferation index MKI67, and the CHGA showed stronger ability to predict early diagnosis for colon cancer than these other cancer biomarkers. In the protein-protein interaction (PPI) network, CHGA was revealed to share some common pathways with KRAS and TP53. CHGA might be considered as a novel, promising, and powerful biomarker for early diagnosis of colon cancer.

  • 5662.
    Zhang, Yin
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China; Shandong University, Peoples R China.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Huang, Guichun
    Karolinska Institute, Sweden.
    Zang, Jingwu
    BioSciKin Biopharma, Peoples R China.
    Chen, Fang
    Zhejiang Chinese Medical University, Peoples R China.
    Zhang, Yun
    Karolinska Institute, Sweden; Shandong University, Peoples R China; Shandong University, Peoples R China.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Gen Hospital, England.
    Cao, Yihai
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Gen Hospital, England; Second Hospital Wuxi, Peoples R China.
    Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 15, s. 4158-4163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects.

  • 5663.
    Zhao, Jin J.
    et al.
    Uppsala University, Sweden.
    Halvardson, Jonatan
    Uppsala University, Sweden.
    Zander, Cecilia S.
    Uppsala University, Sweden.
    Zaghlool, Ammar
    Uppsala University, Sweden.
    Georgii-Hemming, Patrik
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Mansson, Else
    Örebro University Hospital, Sweden.
    Brandberg, Göran
    Pediat Clin, Falun, Sweden.
    Savmarker, Helena E.
    Gävle Central Hospital, Sweden.
    Frykholm, Carina
    Uppsala University, Sweden.
    Kuchinskaya, Ekaterina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Thuresson, Ann-Charlotte
    Uppsala University, Sweden.
    Feuk, Lars
    Uppsala University, Sweden.
    Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability2018Ingår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, nr 1, s. 10-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

  • 5664.
    Zhao, Juan
    et al.
    Peking University, Peoples R China.
    Han, Zhenhui
    Kaifeng Childrens Hospital, Peoples R China.
    Zhang, Xi
    Kaifeng Childrens Hospital, Peoples R China.
    Du, Shuxu
    Capital Medical University, Peoples R China.
    Dong Liu, Angie
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Holmberg, Lukas
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Li, Xueying
    Peking University, Peoples R China.
    Lin, Jing
    Peking University, Peoples R China.
    Xiong, Zhenyu
    Kaifeng Childrens Hospital, Peoples R China.
    Gai, Yong
    Kaifeng Childrens Hospital, Peoples R China.
    Yang, Jinyan
    Peking University, Peoples R China.
    Liu, Ping
    Peking University, Peoples R China.
    Tang, Chaoshu
    Peking University, Peoples R China.
    Du, Junbao
    Peking University, Peoples R China; Minist Educ, Peoples R China.
    Jin, Hongfang
    Peking University, Peoples R China.
    A cross-sectional study on upright heart rate and BP changing characteristics: basic data for establishing diagnosis of postural orthostatic tachycardia syndrome and orthostatic hypertension2015Ingår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, nr 6, artikel-id e007356Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: We aimed to determine upright heart rate and blood pressure (BP) changes to suggest diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) and orthostatic hypertension (OHT) in Chinese children. Methods: In this cross-sectional study, 1449 children and adolescents aged 6-18 years were randomly recruited from two cities in China, Kaifeng in Henan province and Anguo in Hebei province. They were divided into two groups: 844 children aged 6-12 years (group I) and 605 adolescents aged 13-18 years (group II). Heart rate and BP were recorded during an active standing test. Results: 95th percentile (P-95) of delta heart rate from supine to upright was 38 bpm, with a maximum upright heart rate of 130 and 124 bpm in group I and group II, respectively. P-95 of delta systolic blood pressure (SBP) increase was 18 mm Hg and P-95 of upright SBP was 132 mm Hg in group I and 138 mm Hg in group II. P-95 of delta diastolic blood pressure (DBP) increase was 24 mm Hg in group I and 21 mm Hg in group II, and P-95 of upright DBP was 89 mm Hg in group I and 91 mm Hg in group II. Conclusions: POTS is suggested when delta heart rate is greater than= 38 bpm (for easy memory, greater than= 40 bpm) from supine to upright, or maximum heart rate greater than= 130 bpm (children aged 6-12 years) and greater than= 125 bpm (adolescents aged 13-18 years), associated with orthostatic symptoms. OHT is suggested when delta SBP (increase) is greater than= 20 mm Hg, and/or delta DBP (increase) greater than= 25 mm Hg (in children aged 6-12 years) or greater than= 20 mm Hg (in adolescents aged 13-18 years) from supine to upright; or upright BP greater than= 130/90 mm Hg (in children aged 6-12 years) or greater than= 140/90 mm Hg (in adolescents aged 13-18 years).

  • 5665.
    Zhao, Lue Ping
    et al.
    Fred Hutchinson Canc Res Ctr, WA 98104 USA.
    Papadopoulos, George K.
    Technol Educ Inst Epirus, Greece; Univ Ioannina, Greece.
    Kwok, William W.
    Benaroya Res Inst Virginia Mason, WA USA.
    Xu, Bryan
    Univ Calif Berkeley, CA 94720 USA.
    Kong, Matthew
    Carnegie Mellon Univ, PA 15213 USA.
    Moustakas, Antonis K.
    Ionian Univ, Greece.
    Bondinas, George P.
    Technol Educ Inst Epirus, Greece; Univ Ioannina, Greece.
    Carlsson, Annelie
    Lund Univ, Sweden.
    Elding-Larsson, Helena
    Lund Univ, Sweden.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Marcus, Claude
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Persson, Martina
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Samuelsson, Ulf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wang, Ruihan
    Fred Hutchinson Canc Res Ctr, WA 98104 USA.
    Pyo, Chul-Woo
    Fred Hutchinson Canc Res Ctr, WA 98104 USA.
    Nelson, Wyatt C.
    Fred Hutchinson Canc Res Ctr, WA 98104 USA.
    Geraghty, Daniel E.
    Fred Hutchinson Canc Res Ctr, WA 98104 USA.
    Lernmark, Ake
    Lund Univ, Sweden.
    Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes2019Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, nr 8, s. 1692-1704Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Next-generation targeted sequencing of HLA-DRB1 and HLA-DRB3, -DRB4, and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity as a result of high polymorphisms and extended linkage disequilibrium among the DR loci, we applied a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease-associated DR sequences and identifies 11 residues of DRB1, sequences of which retain all significant associations observed by DR genes. Furthermore, all 11 residues locate under/adjoining the peptide-binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. The 15 residues of DRB345, located respectively in the beta 49-55 homodimerization patch and on the face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds that DRB1 residues significantly associated with ZnT8A and DRB345 residues with GADA. The strongest association is between four residues (beta 14, beta 25, beta 71, and beta 73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15, P = 10(-18)), and another sequence, ERKG, confers a protective association (odds ratio 0.59, P = 10(-11)), despite a difference of only one amino acid. Because motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.

  • 5666.
    Zhao, Mingduo
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    Bone conduction hearing in the Guinea pig and the effect of artificially induced middle ear lesions2019Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 379, s. 21-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although human bone conduction (BC) hearing is well investigated, there is a lack of information about BC hearing in most other species. In humans, the amount of conductive loss is estimated as the difference between the air conduction (AC) and BC thresholds. Similar estimations for animals are difficult since in most species, the normal BC hearing thresholds have not been established. In the current study, the normal BC thresholds in the frequency range between 2 kHz and 20 kHz are investigated for the Guinea pig. Also, the effect of a middle ear lesion, here modelled by severing the ossicles (ossicular discontinuity) and gluing the ossicles to the bone (otosclerosis), is investigated for both AC and BC. The hearing thresholds in the Guinea pigs were estimated by a regression of the amplitude of the compound action potential (CAP) with stimulation level and was found robust and gave a high resolution of the threshold level. The reference for the BC thresholds was the cochlear promontory bone velocity. This reference enables comparison of BC hearing in animals, both intra and inter species, which is independent on the vibrator and stimulation position. The vibration was measured in three orthogonal directions where the dominating vibration directions was in line with the stimulation direction, here the ventral direction. The BC thresholds lay between -10 and 3 dB re 1 mu m/s. The slopes of CAP growth function were similar for AC and BC at low and high frequencies, but slightly lower for BC than AC at frequencies between 8 and 16 kHz. This was attributed to differences in the stimulus levels used for the slope estimation and not a real difference in CAP slopes between the stimulation modalities. Two kinds of middle ear lesions, ossicular discontinuity and stapes glued to the surrounding bone, gave threshold shifts of between 23 and 53 dB for AC while it was below 16 dB when the stimulation was by BC. Statistically different threshold shifts between the two types of lesions were found where the AC threshold shifts for a glued stapes at 2 and 4 kHz were 9-18 dB greater than for a severed ossicular chain, and the BC threshold shifts for a glued stapes at 4 and 12 kHz were 8-9 dB greater than fora severed ossicular chain. (C) 2019 Elsevier B.V. All rights reserved.

    Publikationen är tillgänglig i fulltext från 2020-04-17 07:26
  • 5667.
    Zhao, Senlin
    et al.
    Shanghai Jiao Tong University, Peoples R China.
    Sun, Hongcheng
    Shanghai Jiao Tong University, Peoples R China.
    Jiang, Weiliang
    Shanghai Jiao Tong University, Peoples R China.
    Mi, Yushuai
    Shanghai Jiao Tong University, Peoples R China.
    Zhang, Dongyuan
    Shanghai Jiao Tong University, Peoples R China.
    Wen, Yugang
    Shanghai Jiao Tong University, Peoples R China.
    Cheng, Dantong
    Shanghai Jiao Tong University, Peoples R China.
    Tang, Huamei
    Shanghai Jiao Tong University, Peoples R China.
    Wu, Shaohan
    Jiaxing Coll, Peoples R China.
    Yu, Yang
    Shanghai Jiao Tong University, Peoples R China.
    Liu, Xisheng
    Shanghai Jiao Tong University, Peoples R China.
    Cui, Weiyingqi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Zhang, Meng
    Fudan University, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Zhou, Zongguang
    Sichuan University, Peoples R China.
    Peng, Zhihai
    Shanghai Jiao Tong University, Peoples R China.
    Yan, Dongwang
    Shanghai Jiao Tong University, Peoples R China.
    miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGF beta-mediated epithelial to mesenchymal transition2017Ingår i: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 16, artikel-id 12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Despite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression. Methods: qPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGF beta pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC. Results: miR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGF beta signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/ Smad7/TGF beta in vitro and in vivo. Conclusion: miR-4775 promotes CRC metastasis and recurrence in a Smad7/TGF beta signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.

  • 5668.
    Zhong, Liang
    et al.
    Natl Heart Ctr Singapore, Singapore; Natl Univ Singapore, Singapore.
    Schrauben, Eric M.
    Hosp Sick Children, Canada.
    Garcia, Julio
    Univ Calgary, Canada.
    Uribe, Sergio
    Pontificia Univ Catolica Chile, Chile.
    Grieve, Stuart M.
    Univ Sydney, Australia; Royal Prince Alfred Hosp, Australia.
    Elbaz, Mohammed S. M.
    Northwestern Univ, IL 60611 USA.
    Barker, Alex J.
    Univ Colorado, CO 80202 USA.
    Geiger, Julia
    Univ Childrens Hosp Zurich, Switzerland.
    Nordmeyer, Sarah
    German Heart Ctr, Germany; Charite, Germany.
    Marsden, Alison
    Stanford Univ, CA 94305 USA.
    Carlsson, Marcus
    Lund Univ, Sweden.
    Tan, Ru-San
    Natl Heart Ctr Singapore, Singapore; Natl Univ Singapore, Singapore.
    Garg, Pankaj
    Univ Sheffield, England.
    Westenberg, Jos J. M.
    Leiden Univ, Netherlands.
    Markl, Michael
    Northwestern Univ, IL 60611 USA.
    Ebbers, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Ödeshög. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Intracardiac 4D Flow MRI in Congenital Heart Disease: Recommendations on Behalf of the ISMRM Flow & Motion Study Group2019Ingår i: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019.

  • 5669.
    Zhou, Xin
    et al.
    Sichuan Univ, Peoples R China.
    Shang, Yan-Na
    Sichuan Univ, Peoples R China.
    Lu, Ran
    Sichuan Univ, Peoples R China.
    Fan, Chuanwen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Sichuan Univ, Peoples R China; Sichuan Univ, Peoples R China.
    Mo, Xian-Ming
    Sichuan Univ, Peoples R China.
    High ANKZF1 expression is associated with poor overall survival and recurrence-free survival in colon cancer2019Ingår i: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 15, nr 18, s. 2093-2106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: To investigate the association and prognostic value of ANKZF1 gene for survival in colorectal cancer, the mechanism of ANKZF1 level alteration and correlated signaling pathways ANKZF1 is involved. Patients amp; methods: The Cancer Genome Atlas COREAD dataset was analyzed by bioinformatical investigation. Results: High ANKZF1 expression is associated with poor overall survival (hazard ratio [HR]: 2.094; 95% CI: 1.188-3.689; p=0.011) and recurrence-free survival (HR: 1.762; 95% CI: 1.021-3.042; p=0.042) in colon cancer. Bioinformatical analysis showed ANKZF1 was upregulated by amplification and exon expression. ANKZF1 was associated with angiogenesis and cancer signaling pathways. Conclusion: High ANKZF1 is an independent factor of poor survival (overall survival and recurrence-free survival) in colon cancer by taking part in angiogenesis and some cancer signaling pathways.

  • 5670.
    Zhou, Yin
    et al.
    Sichuan University, Peoples R China.
    Li, Yibo
    Sichuan University, Peoples R China.
    Zhou, Bin
    Sichuan University, Peoples R China.
    Chen, Keling
    Sichuan University, Peoples R China.
    Lyv, Zhaoying
    Sichuan University, Peoples R China.
    Huang, Dongmei
    Sichuan University, Peoples R China.
    Liu, Bin
    Sichuan University, Peoples R China.
    Xu, Zhicheng
    Sichuan University, Peoples R China.
    Xiang, Bo
    Sichuan University, Peoples R China.
    Jin, Shuguang
    Sichuan University, Peoples R China.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Li, Yuan
    Sichuan University, Peoples R China.
    Inflammation and Apoptosis: Dual Mediator Role for Toll-like Receptor 4 in the Development of Necrotizing Enterocolitis2017Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, nr 1, s. 44-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Necrotizing enterocolitis (NEC) is the leading cause of neonatal gastrointestinal mortality; effective interventions are lacking with limited understanding of the pathogenesis of NEC. The importance of Toll-like receptor 4 (TLR4) signaling in NEC is well documented; however, the potential mechanisms that regulate enterocyte inflammation and apoptosis remain unclear. The aim of this study was to characterize the role of TLR4-mediated inflammation and apoptosis in the development of NEC and to determine the major apoptotic pathways and regulators in the process. Methods: TLR4-deficient C57BL/10ScNJ mice and lentivirus-mediated stable TLR4-silent cell line (IEC-6) were used. NEC was induced by formula gavage, cold, hypoxia, combined with lipopolysaccharide in vivo or lipopolysaccharide stimulation in vitro. Enterocyte apoptosis was evaluated by TUNEL or Annexin analysis. The expression of TLR4, caspase3, caspase8, caspase9, Bip, Bax, Bcl-2, and RIP was detected by Western blot and immunofluorescence. Inflammatory factors such as tumor necrosis factor-a and interleukin-2 were examined by Luminex. Results: Defect of TLR4 led to suppressed enterocytes apoptosis both in vitro and in vivo; the expression of caspase3, caspase8, Bip, and Bax was decreased; and caspase9 and Bcl-2 were increased. NEC severity was attenuated in TLR4-deficient mice compared with wild-type counterparts, and enterocytes apoptosis was correlated with NEC severity. RIP and cytokine level of tumor necrosis factor-a and interleukin-2 were also decreased. Conclusions: TLR4-induced inflammation and apoptosis play a critical role in the pathogenesis of NEC. TLR4 inhibition, combined with extrinsic (caspase8) and/or endoplasmic reticulum stress (Bip) apoptosis signaling blockade could serve as a potential effective treating strategy for NEC.

  • 5671.
    Zhou, Yuan
    et al.
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Wang, Cong
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Qiu, Xuefeng
    Nanjing University, Peoples R China.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    Yin, Xiaoqin
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Xiang, Zou
    University of Gothenburg, Sweden.
    Li, Dongmei
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Han, Xiaodong
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity2015Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 287, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system.

  • 5672.
    Zhou, Zien
    et al.
    Univ New South Wales, Australia; Shanghai Jiao Tong Univ, Peoples R China.
    Lindley, Richard I.
    George Inst Global Hlth, Australia; Univ Sydney, Australia.
    Rådholm, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Ödeshög. George Inst Global Hlth, Australia; Univ Sydney, Australia.
    Jenkins, Bronwyn
    Royal North Shore Hosp, Australia.
    Watson, John
    Univ New South Wales, Australia.
    Perkovic, Vlado
    Univ New South Wales, Australia; Univ Sydney, Australia; Royal North Shore Hosp, Australia.
    Mahaffey, Kenneth W.
    Stanford Univ, CA 94305 USA.
    de Zeeuw, Dick
    Univ Groningen, Netherlands.
    Fulcher, Greg
    Univ Sydney, Australia; Royal North Shore Hosp, Australia.
    Shaw, Wayne
    Janssen Res and Dev LLC, NJ USA.
    Oh, Richard
    Janssen Res and Dev LLC, NJ USA.
    Desai, Mehul
    Janssen Res and Dev LLC, NJ USA.
    Matthews, David R.
    Univ Oxford, England; Univ Oxford, England.
    Neal, Bruce
    Univ New South Wales, Australia; Univ New South Wales, Australia; Univ Sydney, Australia; Imperial Coll London, England.
    Canagliflozin and Stroke in Type 2 Diabetes Mellitus Results From the Randomized CANVAS Program Trials2019Ingår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 50, nr 2, s. 396-404Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Purpose-This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Methods-The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria. Results-There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all Pamp;lt;0.001) compared with those without such a history. There were 309 participants with stroke events during followup (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.691.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20-0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48-2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline. Conclusions-There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation.

  • 5673.
    Zhu, Mingzhu
    et al.
    Peking University, Peoples R China.
    Du, Junbao
    Peking University, Peoples R China; Minist Educ, Peoples R China.
    Chen, Siyao
    Peking University, Peoples R China.
    Dong Liu, Angie
    Holmberg, Lukas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Chen, Yonghong
    Peking University, Peoples R China.
    Zhang, Chunyu
    Peking University, Peoples R China.
    Tang, Chaoshu
    Minist Educ, Peoples R China; Peking University, Peoples R China.
    Jin, Hongfang
    Peking University, Peoples R China.
    L-Cystathionine Inhibits the Mitochondria-Mediated Macrophage Apoptosis Induced by Oxidized Low Density Lipoprotein2014Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 15, nr 12, s. 23059-23073Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study was designed to investigate the regulatory role of L-cystathionine in human macrophage apoptosis induced by oxidized low density lipoprotein (ox-LDL) and its possible mechanisms. THP-1 cells were induced with phorbol 12-myristate 13-acetate (PMA) and differentiated into macrophages. Macrophages were incubated with ox-LDL after pretreatment with L-cystathionine. Superoxide anion, apoptosis, mitochondrial membrane potential, and mitochondrial permeability transition pore (MPTP) opening were examined. Caspase-9 activities and expression of cleaved caspase-3 were measured. The results showed that compared with control group, ox-LDL treatment significantly promoted superoxide anion generation, release of cytochrome c (cytc) from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and cell apoptosis, in addition to reduced mitochondrial membrane potential as well as increased MPTP opening. However, 0.3 and 1.0 mmol/L L-cystathionine significantly reduced superoxide anion generation, increased mitochondrial membrane potential, and markedly decreased MPTP opening in ox-LDL + L-cystathionine macrophages. Moreover, compared to ox-LDL treated-cells, release of cytc from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and apoptosis levels in L-cystathionine pretreated cells were profoundly attenuated. Taken together, our results suggested that L-cystathionine could antagonize mitochondria-mediated human macrophage apoptosis induced by ox-LDL via inhibition of cytc release and caspase activation.

  • 5674.
    Zhu, Mingzhu
    et al.
    Peking University, Peoples R China.
    Du, Junbao
    Peking University, Peoples R China; Minist Educ, Peoples R China; Peking University, Peoples R China.
    Dong Liu, Angie
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Holmberg, Lukas
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Chen, Selena Y.
    University of Calif San Diego, CA 92093 USA.
    Bu, Dingfang
    Peking University, Peoples R China.
    Tang, Chaoshu
    Minist Educ, Peoples R China; Peking University, Peoples R China.
    Jin, Hongfang
    Peking University, Peoples R China.
    L-cystathionine inhibits oxidized low density lipoprotein-induced THP-1-derived macrophage inflammatory cytokine monocyte chemoattractant protein-1 generation via the NF-kappa B pathway2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 10453Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to explore whether and how L-cystathionine had any regulatory effect on the inflammatory response in THP-1-derived macrophages cultured in vitro under oxidized low-density lipoprotein (ox-LDL) stimulation. The human monocyte line THP-1 cell was cultured in vitro and differentiated into macrophages after 24 hours of PMA induction. Macrophages were pretreated with L-cystathionine and then treated with ox-LDL. The results showed that compared with the controls, ox-LDL stimulation significantly upregulated the expression of THP-1-derived macrophage MCP-1 by enhancing NF-kappa B p65 phosphorylation, nuclear translocation and DNA binding with the MCP-1 promoter. Compared with the ox-LDL group, 0.3 mmol/L and 1.0 mmol/L L-cystathionine significantly inhibited the expression of THP-1-derived macrophage MCP-1. Mechanistically, 0.3 mmol/L and 1.0 mmol/L L-cystathionine suppressed phosphorylation and nuclear translocation of the NF-kappa B p65 protein, as well as the DNA binding activity and DNA binding level of NF-kappa B with the MCP-1 promoter, which resulted in a reduced THP-1-derived macrophage MCP-1 generation. This study suggests that L-cystathionine could inhibit the expression of MCP-1 in THP-1-derived macrophages induced by ox-LDL via inhibition of NF-kappa B p65 phosphorylation, nuclear translocation, and binding of the MCP-1 promoter sequence after entry into the nucleus.

  • 5675.
    Ziegelasch, Michael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Diagnostic and prognostic potential of joint imaging in patients with anti-citrullinated protein antibodies2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The introduction of novel therapeutic strategies set new goals for the patients’ outcome, which aims to achieve remission. This goal requires early diagnosis of RA and prompt efficient pharmacotherapy. The introduction of anti-citrullinated protein antibodies (ACPA) two decades ago allowed an earlier RA diagnosis. However, there are indications that ACPA positivity is still associated with higher rates of radiographic damage. As the small joints in hands and feet commonly are the first involved sites of inflammation, the role of different imaging modalities were studied regarding their diagnostic and prognostic impact for assessment of arthritis in RA. Further, ultrasound (US) and radiography were used to study the association between RA-specific antibodies and the occurrence of arthritis and joint damage in systemic lupus erythematosus (SLE).

    The use of US allows assessment of soft tissue like joint capsules, tendons and bursae. Used for a live scanning, it is easy to detect effusions and edema. Doppler indicates vasoproliferation were inflammation is present. Also, US seems to be more sensitive than radiography to detect minimal structural changes located at bone surfaces. We wanted to investigate whether US findings in a pre-RA stage can predict development of arthritis.

    Digital X-ray radiogrammetry (DXR) is a technique based on computerized analyses of standard hand radiographs to calculate peripheral bone mineral density (BMD) of the three middle metacarpal bones (DXR-BMD). In order for early treatment decisions, we aimed to study whether changes in DXR-BMD loss after 3 months can predict radiographic damage in early RA.

    In conclusion, the studies showed that ACPA-positivity is still associated with a higher risk of radiographic damage regardless of early treatment decisions. Therefore, close radiographic monitoring and readiness to intensive treatment is warranted in ACPA-positive patients. This thesis also shows that erosions detected by US in ACPA-positive patients with arthralgia predict development of clinical arthritis. Also, the magnitude of DXR-BMD loss helps identify patients at higher risk for future radiographic damage, and may therefore help to improve early treatment decisions. Finally, US and radiography confirm a higher rate of arthritis and erosions also in SLE patients who are positive for RA-specific antibodies.

    Delarbeten
    1. Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts.
    Öppna denna publikation i ny flik eller fönster >>Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts.
    Visa övriga...
    2016 (Engelska)Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 1Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.

    METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.

    RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.

    CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.

    Ort, förlag, år, upplaga, sidor
    BioMed Central, 2016
    Nationell ämneskategori
    Reumatologi och inflammation
    Identifikatorer
    urn:nbn:se:liu:diva-133852 (URN)10.1186/s13075-016-1192-x (DOI)000390276600002 ()27912793 (PubMedID)
    Anmärkning

    Funding agencies: County Council of Ostergotland; Swedish Society for Medical Research; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz foundation; King Gustaf V 80-year foundation; Dutch Arthritis Foundation; IMI JU project, BeTheCure [

    Tillgänglig från: 2017-01-12 Skapad: 2017-01-12 Senast uppdaterad: 2019-01-04
    2. Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year
    Öppna denna publikation i ny flik eller fönster >>Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year
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    2017 (Engelska)Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 195Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid arthritis (RA), but cannot be accurately quantified using conventional radiography. Digital X-ray radiogrammetry (DXR) is a computerized technique to estimate bone mineral density (BMD) from hand radiographs. The aim of this study was to evaluate whether decrease in BMD of the hands (BMD loss), as determined by DXR 3 months after diagnosis, predicts radiographic joint damage after 1 and 2 years in patients with early RA. Methods: Patients (n = 176) with early RA (amp;lt; 12 months after onset of symptoms) from three different Swedish rheumatology centers were consecutively included in the study, and 167 of these patients were included in the analysis. Medication was given in accordance with Swedish guidelines, and the patients were followed for 2 years. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) were measured at baseline, and 28-joint Disease Activity Score (DAS28) was assessed at each visit. Radiographs of the hands and feet were obtained at baseline, 3 months (hands only) and 1 and 2 years. Baseline and 1-year and 2-year radiographs were evaluated by the Larsen score. Radiographic progression was defined as a difference in Larsen score above the smallest detectable change. DXR-BMD was measured at baseline and after 3 months. BMD loss was defined as moderate when the decrease in BMD was between 0.25 and 2.5 mg/cm(2)/month and as severe when the decrease was greater than 2.5 mg/cm(2)/month. Multivariate regression was applied to test the association between DXR-BMD loss and radiographic damage, including adjustments for possible confounders. Results: DXR-BMD loss during the initial 3 months occurred in 59% of the patients (44% moderate, 15% severe): 32 patients (19%) had radiographic progression at 1 year and 45 (35%) at 2 years. In multiple regression analyses, the magnitude of DXR-BMD loss was significantly associated with increase in Larsen score between baseline and 1 year (p = 0.033, adjusted R-squared = 0.069). Conclusion: DXR-BMD loss during the initial 3 months independently predicted radiographic joint damage at 1 year in patients with early RA. Thus, DXR-BMD may be a useful tool to detect ongoing joint damage and thereby to improve individualization of therapy in early RA.

    Ort, förlag, år, upplaga, sidor
    BIOMED CENTRAL LTD, 2017
    Nyckelord
    Digital X-ray radiogrammetry; Bone mineral density; Disease progression; Early rheumatoid arthritis
    Nationell ämneskategori
    Reumatologi och inflammation
    Identifikatorer
    urn:nbn:se:liu:diva-141121 (URN)10.1186/s13075-017-1403-0 (DOI)000409495000002 ()28865482 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Rheumatism Association; Norrbacka-Eugenia foundation; King Gustav V 80-year Foundation; Swedish Medical Society; ALF Grants from Region Ostergotland; Linkoping University Hospital Research Fund; Foundation for Assistance to Disabled People in Skane (Stiftelsen for Bistand at Rorelsehindrade i Skane)

    Tillgänglig från: 2017-09-27 Skapad: 2017-09-27 Senast uppdaterad: 2019-01-04
  • 5676.
    Ziegelasch, Michael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Forslind, Kristina
    Helsingborg Hospital, Sweden; Lund University, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Riklund, Katrine
    Umeå University Hospital, Sweden.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Berglin, Ewa
    Umeå University Hospital, Sweden.
    Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year2017Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid arthritis (RA), but cannot be accurately quantified using conventional radiography. Digital X-ray radiogrammetry (DXR) is a computerized technique to estimate bone mineral density (BMD) from hand radiographs. The aim of this study was to evaluate whether decrease in BMD of the hands (BMD loss), as determined by DXR 3 months after diagnosis, predicts radiographic joint damage after 1 and 2 years in patients with early RA. Methods: Patients (n = 176) with early RA (amp;lt; 12 months after onset of symptoms) from three different Swedish rheumatology centers were consecutively included in the study, and 167 of these patients were included in the analysis. Medication was given in accordance with Swedish guidelines, and the patients were followed for 2 years. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) were measured at baseline, and 28-joint Disease Activity Score (DAS28) was assessed at each visit. Radiographs of the hands and feet were obtained at baseline, 3 months (hands only) and 1 and 2 years. Baseline and 1-year and 2-year radiographs were evaluated by the Larsen score. Radiographic progression was defined as a difference in Larsen score above the smallest detectable change. DXR-BMD was measured at baseline and after 3 months. BMD loss was defined as moderate when the decrease in BMD was between 0.25 and 2.5 mg/cm(2)/month and as severe when the decrease was greater than 2.5 mg/cm(2)/month. Multivariate regression was applied to test the association between DXR-BMD loss and radiographic damage, including adjustments for possible confounders. Results: DXR-BMD loss during the initial 3 months occurred in 59% of the patients (44% moderate, 15% severe): 32 patients (19%) had radiographic progression at 1 year and 45 (35%) at 2 years. In multiple regression analyses, the magnitude of DXR-BMD loss was significantly associated with increase in Larsen score between baseline and 1 year (p = 0.033, adjusted R-squared = 0.069). Conclusion: DXR-BMD loss during the initial 3 months independently predicted radiographic joint damage at 1 year in patients with early RA. Thus, DXR-BMD may be a useful tool to detect ongoing joint damage and thereby to improve individualization of therapy in early RA.

  • 5677.
    Ziegelasch, Michael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    van Delft, Myrthe A M
    Leiden University Medical Center, Leiden, The Netherlands.
    Wallin, Philip
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Magro-Checa, César
    Leiden University Medical Center, Leiden, The Netherlands.
    Steup-Beekman, Gerda M
    Leiden University Medical Center, Leiden, The Netherlands.
    Trouw, Leendert A
    Leiden University Medical Center, Leiden, The Netherlands.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts.2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.

    METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.

    RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.

    CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.

  • 5678.
    Ziegler, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Improving Assessments of Hemodynamics and Vascular Disease2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Blood vessels are more than simple pipes, passively enabling blood to pass through them. Their form and function are dynamic, changing with both aging and disease. This process involves a feedback loop wherein changes to the shape of a blood vessel affect the hemodynamics, causing yet more structural adaptation. This feedback loop is driven in part by the hemodynamic forces generated by the blood flow, and the distribution and strength of these forces appear to play a role in the initiation, progression, severity, and the outcome of vascular diseases.

    Magnetic Resonance Imaging (MRI) offers a unique platform for investigating both the form and function of the vascular system. The form of the vascular system can be examined using MR-based angiography, to generate detailed geometric analyses, or through quantitative techniques for measuring the composition of the vessel wall and atherosclerotic plaques. To complement these analyses, 4D Flow MRI can be used to quantify the functional aspect of the vascular system, by generating a full time-resolved three-dimensional velocity field that represents the blood flow.

    This thesis aims to develop and evaluate new methods for assessing vascular disease using novel hemodynamic markers generated from 4D Flow MRI and quantitative MRI data towards the larger goal of a more comprehensive non-invasive examination oriented towards vascular disease. In Paper I, we developed and evaluated techniques to quantify flow stasis in abdominal aortic aneurysms to measure this under-explored aspect of aneurysmal hemodynamics. In Paper II, the distribution and intensity of turbulence in the aorta was quantified in both younger and older men to understand how aging changes this aspect of hemodynamics. A method to quantify the stresses generated by turbulence that act on the vessel wall was developed and evaluated using simulated flow data in Paper III, and in Paper V this method was utilized to examine the wall stresses of the carotid artery. The hemodynamics of vascular disease cannot be uncoupled from the anatomical changes the vessel wall undergoes, and therefore Paper IV developed and evaluated a semi-automatic method for quantifying several aspects of vessel wall composition. These developments, taken together, help generate more valuable information from imaging data, and can be pooled together with other methods to form a more comprehensive non-invasive examination for vascular disease.

    Delarbeten
    1. Visualizing and quantifying flow stasis in abdominal aortic aneurysms in men using 4D flow MRI
    Öppna denna publikation i ny flik eller fönster >>Visualizing and quantifying flow stasis in abdominal aortic aneurysms in men using 4D flow MRI
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    2019 (Engelska)Ingår i: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 57, s. 103-110Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: To examine methods for visualizing and quantifying flow stasis in abdominal aortic aneurysms (AAA) using 4D Flow MRI. Methods: Three methods were investigated: conventional volumetric residence time (VRT), mean velocity analysis (MVA), and particle travel distance analysis (TDA). First, ideal 4D Flow MRI data was generated using numerical simulations and used as a platform to explore the effects of noise and background phase-offset errors, both of which are common 4D Flow MRI artifacts. Error-free results were compared to noise or offset affected results using linear regression. Subsequently, 4D Flow MRI data for thirteen (13) subjects with AAA was acquired and used to compare the stasis quantification methods against conventional flow visualization. Results: VRT (R-2 = 0.69) was more sensitive to noise than MVA (R-2 = 0.98) and TDA (R-2 = 0.99) at typical noncontrast signal-to-noise ratio levels (SNR = 20). VRT (R-2 = 0.14) was more sensitive to background phase-offsets than MVA (R-2 = 0.99) and TDA (R-2 = 0.96) when considering a 95% effective background phase-offset correction. Qualitatively, TDA outperformed MVA (Wilcoxon p amp;lt; 0.005, mean score improvement 1.6/5), and had good agreement (median score 4/5) with flow visualizations. Conclusion: Flow stasis can be quantitatively assessed using 4D Flow MRI. While conventional residence time calculations fail due to error accumulation as a result of imperfect measured velocity fields, methods that do not require lengthy particle tracking perform better. MVA and TDA are less sensitive to measurement errors, and TDA generates results most similar to those obtained using conventional flow visualization.

    Ort, förlag, år, upplaga, sidor
    ELSEVIER SCIENCE INC, 2019
    Nyckelord
    Abdominal aortic aneurysm; Hemodynamics; 4D flow MRI; Flow stasis
    Nationell ämneskategori
    Medicinsk laboratorie- och mätteknik
    Identifikatorer
    urn:nbn:se:liu:diva-154524 (URN)10.1016/j.mri.2018.11.003 (DOI)000458096100012 ()30445146 (PubMedID)
    Tillgänglig från: 2019-02-20 Skapad: 2019-02-20 Senast uppdaterad: 2019-04-17
    2. Age-Related Vascular Changes Affect Turbulence in Aortic Blood Flow
    Öppna denna publikation i ny flik eller fönster >>Age-Related Vascular Changes Affect Turbulence in Aortic Blood Flow
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    2018 (Engelska)Ingår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, artikel-id 36Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Turbulent blood flow is implicated in the pathogenesis of several aortic diseases but the extent and degree of turbulent blood flow in the normal aorta is unknown. We aimed to quantify the extent and degree of turbulece in the normal aorta and to assess whether age impacts the degree of turbulence. 22 young normal males (23.7 +/- 3.0 y.o.) and 20 old normal males (70.9 +/- 3.5 y.o.) were examined using four dimensional flow magnetic resonance imaging (4D Flow MRI) to quantify the turbulent kinetic energy (TKE), a measure of the intensity of turbulence, in the aorta. All healthy subjects developed turbulent flow in the aorta, with total TKE of 3-19 mJ. The overall degree of turbulence in the entire aorta was similar between the groups, although the old subjects had about 73% more total TKE in the ascending aorta compared to the young subjects (young = 3.7 +/- 1.8 mJ, old = 6.4 +/- 2.4 mJ, p amp;lt; 0.001). This increase in ascending aorta TKE in old subjects was associated with age-related dilation of the ascending aorta which increases the volume available for turbulence development. Conversely, age-related dilation of the descending and abdominal aorta decreased the average flow velocity and suppressed the development of turbulence. In conclusion, turbulent blood flow develops in the aorta of normal subjects and is impacted by age-related geometric changes. Non-invasive assessment enables the determination of normal levels of turbulent flow in the aorta which is a prerequisite for understanding the role of turbulence in the pathophysiology of cardiovascular disease.

    Ort, förlag, år, upplaga, sidor
    FRONTIERS MEDIA SA, 2018
    Nyckelord
    turbulent kinetic energy (TKE); turbulent blood flow; aortic blood flow; aortic dilation; normal values; 4D flow MRI; phase contrast MRI
    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:liu:diva-145129 (URN)10.3389/fphys.2018.00036 (DOI)000423400000001 ()29422871 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [2013-6077, 2014-6191]; Swedish Heart and Lung foundation [20140398]; Kangwon National University [D1001179-01-01]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2016R1A6A3A03006337]

    Tillgänglig från: 2018-02-19 Skapad: 2018-02-19 Senast uppdaterad: 2019-04-17
    3. Assessment of Turbulent Flow Effects on the Vessel Wall Using Four-Dimensional Flow MRI
    Öppna denna publikation i ny flik eller fönster >>Assessment of Turbulent Flow Effects on the Vessel Wall Using Four-Dimensional Flow MRI
    2017 (Engelska)Ingår i: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 77, nr 6, s. 2310-2319Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Purpose: To explore the use of MR-estimated turbulence quantities for the assessment of turbulent flow effects on the vessel wall. Methods: Numerical velocity data for two patient-derived models was obtained using computational fluid dynamics (CFD) for two physiological flow rates. The four-dimensional (4D) Flow MRI measurements were simulated at three different spatial resolutions and used to investigate the estimation of turbulent wall shear stress (tWSS) using the intravoxel standard deviation (IVSD) of velocity and turbulent kinetic energy (TKE) estimated near the vessel wall. Results: Accurate estimation of tWSS using the IVSD is limited by the spatial resolution achievable with 4D Flow MRI. TKE, estimated near the wall, has a strong linear relationship to the tWSS (mean R(2=)0.84). Near-wall TKE estimates from MR simulations have good agreement to CFD-derived ground truth (mean R-2=0.90). Maps of near-wall TKE have strong visual correspondence to tWSS. Conclusion: Near-wall estimation of TKE permits assessment of relative maps of tWSS, but direct estimation of tWSS is challenging due to limitations in spatial resolution. Assessment of tWSS and near-wall TKE may open new avenues for analysis of different pathologies. (C) 2016 International Society for Magnetic Resonance in Medicine

    Ort, förlag, år, upplaga, sidor
    WILEY, 2017
    Nyckelord
    phase contrast magnetic resonance imaging; wall shear stress; turbulence; turbulent kinetic energy; aorta
    Nationell ämneskategori
    Medicinsk bildbehandling
    Identifikatorer
    urn:nbn:se:liu:diva-138232 (URN)10.1002/mrm.26308 (DOI)000401270900022 ()27350049 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council; National Supercomputer Centre [SNIC2014-11-22]

    Tillgänglig från: 2017-06-14 Skapad: 2017-06-14 Senast uppdaterad: 2019-04-17
  • 5679.
    Ziegler, Magnus
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Lantz, Jonas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Ebbers, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dyverfeldt, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Assessment of Turbulent Flow Effects on the Vessel Wall Using Four-Dimensional Flow MRI2017Ingår i: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 77, nr 6, s. 2310-2319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To explore the use of MR-estimated turbulence quantities for the assessment of turbulent flow effects on the vessel wall. Methods: Numerical velocity data for two patient-derived models was obtained using computational fluid dynamics (CFD) for two physiological flow rates. The four-dimensional (4D) Flow MRI measurements were simulated at three different spatial resolutions and used to investigate the estimation of turbulent wall shear stress (tWSS) using the intravoxel standard deviation (IVSD) of velocity and turbulent kinetic energy (TKE) estimated near the vessel wall. Results: Accurate estimation of tWSS using the IVSD is limited by the spatial resolution achievable with 4D Flow MRI. TKE, estimated near the wall, has a strong linear relationship to the tWSS (mean R(2=)0.84). Near-wall TKE estimates from MR simulations have good agreement to CFD-derived ground truth (mean R-2=0.90). Maps of near-wall TKE have strong visual correspondence to tWSS. Conclusion: Near-wall estimation of TKE permits assessment of relative maps of tWSS, but direct estimation of tWSS is challenging due to limitations in spatial resolution. Assessment of tWSS and near-wall TKE may open new avenues for analysis of different pathologies. (C) 2016 International Society for Magnetic Resonance in Medicine

  • 5680.
    Ziegler, Magnus
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Welander, Martin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Lantz, Jonas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Lindenberger, Marcus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Bjarnegård, Niclas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Matts
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanisk värmeteori och strömningslära. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Ebbers, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dyverfeldt, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Visualizing and quantifying flow stasis in abdominal aortic aneurysms in men using 4D flow MRI2019Ingår i: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 57, s. 103-110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To examine methods for visualizing and quantifying flow stasis in abdominal aortic aneurysms (AAA) using 4D Flow MRI. Methods: Three methods were investigated: conventional volumetric residence time (VRT), mean velocity analysis (MVA), and particle travel distance analysis (TDA). First, ideal 4D Flow MRI data was generated using numerical simulations and used as a platform to explore the effects of noise and background phase-offset errors, both of which are common 4D Flow MRI artifacts. Error-free results were compared to noise or offset affected results using linear regression. Subsequently, 4D Flow MRI data for thirteen (13) subjects with AAA was acquired and used to compare the stasis quantification methods against conventional flow visualization. Results: VRT (R-2 = 0.69) was more sensitive to noise than MVA (R-2 = 0.98) and TDA (R-2 = 0.99) at typical noncontrast signal-to-noise ratio levels (SNR = 20). VRT (R-2 = 0.14) was more sensitive to background phase-offsets than MVA (R-2 = 0.99) and TDA (R-2 = 0.96) when considering a 95% effective background phase-offset correction. Qualitatively, TDA outperformed MVA (Wilcoxon p amp;lt; 0.005, mean score improvement 1.6/5), and had good agreement (median score 4/5) with flow visualizations. Conclusion: Flow stasis can be quantitatively assessed using 4D Flow MRI. While conventional residence time calculations fail due to error accumulation as a result of imperfect measured velocity fields, methods that do not require lengthy particle tracking perform better. MVA and TDA are less sensitive to measurement errors, and TDA generates results most similar to those obtained using conventional flow visualization.

  • 5681.
    Ziemssen, Tjalf
    et al.
    Neurol University of Klin Klinikum Carl Gustav Carus, Germany.
    Bajenaru, Ovidiu A.
    Carol Davila University of Medical and Pharm, Romania.
    Carra, Adriana
    Hospital Britanico Buenos Aires, Argentina.
    de Klippel, Nina
    Virga Jessaziekenhuis, Belgium.
    Correia de Sa, Joao
    Hospital Santa Maria, Portugal.
    Edland, Astrid
    Central Hospital Buskerud, Norway.
    Frederiksen, Jette L.
    University of Copenhagen, Denmark.
    Heinzlef, Olivier
    Tenon Hospital, France.
    Karageorgiou, Klimentini E.
    Gen Hospital Athens, Greece.
    Delgado, Rafael H. Lander
    Landtblom, Anne-Marie
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Macias Islas, Miguel A.
    Central University of Guadalajara, Mexico.
    Tubridy, Niall
    Dublin University, Ireland.
    Gilgun-Sherki, Yossi
    Teva Pharmaceut Ind Ltd, Israel.
    Erratum to: A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial2015Ingår i: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 262, nr 1, s. 248-248Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 5682.
    Zilg, B.
    et al.
    Karolinska Institute, Sweden.
    Alkass, K.
    Karolinska Institute, Sweden.
    Berg, Sören
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Druid, H.
    Karolinska Institute, Sweden.
    Interpretation of postmortem vitreous concentrations of sodium and chloride2016Ingår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 263, s. 107-113Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitreous fluid can be used to analyze sodium and chloride levels in deceased persons, but it remains unclear to what extent such results can be used to diagnose antemortem sodium or chloride imbalances. In this study we present vitreous sodium and chloride levels from more than 3000 cases. We show that vitreous sodium and chloride levels both decrease with approximately 2.2 mmol/L per day after death. Since potassium is a well-established marker for postmortem interval (PMI) and easily can be analyzed along with sodium and chloride, we have correlated sodium and chloride levels with the potassium levels and present postmortem reference ranges relative the potassium levels. We found that virtually all cases outside the reference range show signs of antemortem hypo- or hypernatremia. Vitreous sodium or chloride levels can be the only means to diagnose cases of water or salt intoxication, beer potomania or dehydration. We further show that postmortem vitreous sodium and chloride strongly correlate and in practice can be used interchangeably if analysis of one of the ions fails. It has been suggested that vitreous sodium and chloride levels can be used to diagnose drowning or to distinguish saltwater from freshwater drowning. Our results show that in cases of freshwater drowning, vitreous sodium levels are decreased, but that this mainly is an effect of postmortem diffusion between the eye and surrounding water rather than due to the drowning process, since the decrease in sodium levels correlates with immersion time. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 5683.
    Zilg, B.
    et al.
    Karolinska Institute, Sweden.
    Bernard, S.
    University of Lyon 1, France.
    Alkass, K.
    Karolinska Institute, Sweden.
    Berg, Sören
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Druid, H.
    Karolinska Institute, Sweden.
    A new model for the estimation of time of death from vitreous potassium levels corrected for age and temperature2015Ingår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 254, s. 158-166Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analysis of potassium concentration in the vitreous fluid of the eye is frequently used by forensic pathologists to estimate the postmortem interval (PMI), particularly when other methods commonly used in the early phase of an investigation can no longer be applied. The postmortem rise in vitreous potassium has been recognized for several decades and is readily explained by a diffusion of potassium from surrounding cells into the vitreous fluid. However, there is no consensus regarding the mathematical equation that best describes this increase. The existing models assume a linear increase, but different slopes and starting points have been proposed. In this study, vitreous potassium levels, and a number of factors that may influence these levels, were examined in 462 cases with known postmortem intervals that ranged from 2 h to 17 days. We found that the postmortem rise in potassium followed a non-linear curve and that decedent age and ambient temperature influenced the variability by 16% and 5%, respectively. A long duration of agony and a high alcohol level at the time of death contributed less than 1% variability, and evaluation of additional possible factors revealed no detectable impact on the rise of vitreous potassium. Two equations were subsequently generated, one that represents the best fit of the potassium concentrations alone, and a second that represents potassium concentrations with correction for decedent age and/or ambient temperature. The former was associated with narrow confidence intervals in the early postmortem phase, but the intervals gradually increased with longer PMIs. For the latter equation, the confidence intervals were reduced at all PMIs. Therefore, the model that best describes the observed postmortem rise in vitreous potassium levels includes potassium concentration, decedent age, and ambient temperature. Furthermore, the precision of these equations, particularly for long PMIs, is expected to gradually improve by adjusting the constants as more reference data are added over time. A web application that facilitates this calculation process and allows for such future modifications has been developed. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

  • 5684.
    Zimdahl Kahlin, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Helander, Sara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden2019Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 164, s. 263-272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

    Publikationen är tillgänglig i fulltext från 2020-04-18 07:47
  • 5685.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland.
    Cecconi, Virginia
    Univ Zurich, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Univ Zurich, Switzerland.
    Restivo, Gaetana
    Univ Hosp Zurich, Switzerland.
    Hafner, Jurg
    Univ Hosp Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    van den Broek, Maries
    Univ Zurich, Switzerland.
    WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma2018Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, nr 27, s. 3753-3762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

  • 5686.
    Zinner, Christoph
    et al.
    University of Wurzburg, Germany; Mid Sweden University, Sweden.
    Morales-Alamo, David
    University of Las Palmas Gran Canaria, Spain; University of Las Palmas Gran Canaria, Spain.
    Ortenblad, Niels
    Mid Sweden University, Sweden; University of Southern Denmark, Denmark.
    Larsen, Filip J.
    Swedish School Sport and Health Science, Sweden.
    Schiffer, Tomas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Willis, Sarah J.
    Mid Sweden University, Sweden.
    Gelabert-Rebato, Miriam
    University of Las Palmas Gran Canaria, Spain; University of Las Palmas Gran Canaria, Spain.
    Perez-Valera, Mario
    University of Las Palmas Gran Canaria, Spain; University of Las Palmas Gran Canaria, Spain.
    Boushel, Robert
    University of British Columbia, Canada.
    Calbet, Jose A. L.
    University of Las Palmas Gran Canaria, Spain; University of Las Palmas Gran Canaria, Spain; University of British Columbia, Canada.
    Holmberg, Hans-Christer
    Mid Sweden University, Sweden; University of British Columbia, Canada; UiT Arctic University of Norway, Norway.
    The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans2016Ingår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, nr 426Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 x 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO(2)peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO(2)peak and Wmax increased 3-11% after training, with a more pronounced change in the arms (P amp;lt; 0.05). Gross efficiency improved for the arms (+8.8%, P amp;lt; 0.05), but not the legs (-0.6%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6% for the arms and legs, respectively (P amp;lt; 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44%, P amp;lt; 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, V-E, and V-t were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O-2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.

  • 5687.
    Zook, Erin C.
    et al.
    University of Chicago, IL 60637 USA.
    Ramirez, Kevin
    University of Chicago, IL 60637 USA.
    Guo, Xiaohuan
    University of Chicago, IL 60637 USA.
    van der Voort, Grant
    University of Chicago, IL 60637 USA.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Svensson, Eric C.
    University of Chicago, IL 60637 USA.
    Fu, Yang-Xin
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Kee, Barbara L.
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC22016Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 213, nr 5, s. 687-696Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Group 2 innate lymphoid cells ( ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33-induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.

  • 5688.
    Zou, Huiyun
    et al.
    Shandong Univ, Peoples R China.
    Zheng, Beiwen
    Zhejiang Univ, Peoples R China.
    Sun, Mingli
    Ctr Dis Prevent and Control, Peoples R China.
    Ottoson, Jakob
    Natl Food Agcy, Sweden.
    Li, Yubo
    Ctr Dis Prevent and Control, Peoples R China.
    Berglund, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Zhejiang Univ, Peoples R China.
    Chi, Xiaohui
    Shandong Univ, Peoples R China.
    Ji, Xiang
    Shandong Univ, Peoples R China.
    Li, Xuewen
    Shandong Univ, Peoples R China.
    Lundborg, Cecilia Stalsby
    Karolinska Inst, Sweden.
    Nilsson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Evaluating Dissemination Mechanisms of Antibiotic-Resistant Bacteria in Rural Environments in China by Using CTX-M-Producing Escherichia coli as an Indicator2019Ingår i: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is becoming increasingly recognized that the environment plays an important role both in the emergence and in dissemination of antibiotic-resistant bacteria (ARB), Mechanisms and factors facilitating this development are, however, not yet well understood. The high detection rate of CTX-M genes in environmental sources provides an opportunity to explore this issue. In this study, 88 CTX-M-producing Escherichia coli were isolated from 30 pig feces samples from 30 pig farms and 201 environmental samples. CTX-M-producing E. coli was detected with the following frequencies in the different types of samples: pig feces, 73%; river water, 64%; river sediment, 52%; wastewater, 31%; drinking water, 23%; outlet sediment, 21%; soil, 17%; and vegetables, 4.4%. Dissemination of CTX-M-producing E. coli to different environmental matrices was evaluated by analyzing the genetic relatedness of isolates from different environmental sources, and putative transmission routes through bird feces, pig feces, drinking water, river sediment, river water, and wastewater were hypothesized. Dissemination through these routes is likely facilitated by anthropogenic activities and environmental factors. Wild birds as potential vectors for dissemination of CTX-M-producing E. coli have the capacity to spread ARB across long distances. Regional dissemination between different environmental matrices of CTX-M-producing E. coli increases the exposure risk of humans and animals in the area.

    Publikationen är tillgänglig i fulltext från 2020-05-22 08:00
  • 5689.
    Zsigmond, Peter
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurokirurgiska kliniken US.
    Hemm-Ode, Simone
    School of Life Sciences FHNW Institute for Medical and Analytical Technologies.
    Wårdell, Karin
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Optical Measurements during Deep Brain Stimulation Lead Implantation: Safety Aspects2017Ingår i: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 95, nr 6, s. 392-399Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Intracerebral hemorrhage (ICH) is the most feared complication in deep brain stimulation (DBS) surgery. The aim of the study was to evaluate patient safety and outcome using laser Doppler flowmetry (LDF) as guidance tool during DBS implantations.

    METHODS: An LDF probe adapted for the stereotactic system was used as guide for creation of the trajectory. The microcirculation along 83 preplanned trajectories was measured with the guide during DBS surgery for movement disorders. The microvascular blood flow levels were investigated for all measurement positions. Medical record and postoperative radiology were retrospectively reviewed.

    RESULTS: Of 2,963 measurement positions, 234 (7.9%) showed at least a doubled blood flow compared to the surrounding tissue. Of these 2.2% had a more than 5 times higher blood flow in front of the probe tip. Along 1 trajectory, a small ICH was detected during surgery. Increased blood flow was more common close to sulci and verticals.

    CONCLUSION: Real-time LDF measurement of the microcirculation using a forward-looking probe during DBS surgery can detect blood flow peaks and further minimize the risk of developing ICH. No separate guide tube is necessary as the probe also creates the trajectory for the DBS lead.

  • 5690.
    Zurkirchen, Luis
    et al.
    Univ Zurich, Switzerland.
    Varum, Sandra
    Univ Zurich, Switzerland.
    Giger, Sonja
    Univ Zurich, Switzerland.
    Klug, Annika
    Univ Zurich, Switzerland.
    Hausel, Jessica
    Univ Zurich, Switzerland.
    Bossart, Raphael
    Univ Zurich, Switzerland.
    Zemke, Martina
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Univ Zurich, Switzerland.
    Atak, Zeynep Kalender
    Katholieke Univ Leuven, Belgium.
    Zamboni, Nicola
    Swiss Fed Inst Technol, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Sommer, Lukas
    Univ Zurich, Switzerland.
    Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 2192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.

  • 5691.
    Zötterman, Johan
    et al.
    Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper.
    Bergkvist, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Iredahl, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Tesselaar, Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Farnebo, Simon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Monitoring of partial and full venous outflow obstruction in a porcine flap model using laser speckle contrast imaging2016Ingår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 69, nr 7, s. 936-943Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In microsurgery, there is a demand for more reliable methods of postoperative monitoring of free flaps, especially with regard to tissue-threatening obstructions of the feeding arteries and draining veins. In this study, we evaluated laser speckle contrast imaging (LSCI) and laser Doppler flowmetry (LDF) to assess their possibilities to detect partial and full venous outflow obstruction, as well as full arterial occlusion, in a porcine flap model. Methods: Cranial gluteal artery perforator flaps (CGAPs) were raised, and arterial and venous blood flow to and from the flaps was monitored using ultrasonic flow probes. The venous flow was altered with an inflatable cuff to simulate partial and full (50% and 100%) venous obstruction, and arterial flow was completely obstructed using clamps. The flap microcirculation was monitored using LSCI and LDF. Results: Both LDF and the LSCI detected significant changes in flap perfusion. After partial (50%) venous occlusion, perfusion decreased from baseline, LSCI: 63.5 +/- 12.9 PU (p = 0.01), LDF 31.3 +/- 15.7 (p = 0.64). After 100% venous occlusion, a further decrease in perfusion was observed: LSCI 54.6 +/- 14.2 PU (p amp;lt; 0.001) and LDF 16.7 +/- 12.8 PU (p amp;lt; 0.001). After release of the venous cuff, LSCI detected a return of the perfusion to a level slightly, but not significantly, below the baseline level 70.1 +/- 11.5 PU (p=0.39), while the LDF signal returned to a level not significant from the baseline 36.1 +/- 17.9 PU (p amp;gt; 0.99). Perfusion during 100% arterial occlusion decreased significantly as measured with both methods, LSCI: 48.3 +/- 7.7 (PU, pamp;lt;0.001) and LDF: 8.5 +/- 4.0 PU (pamp;lt;0.001). During 50% and 100% venous occlusion, LSCI showed a 20% and 26% inter-subject variability (CV%), respectively, compared to 50% and 77% for LDF. Conclusions: LSCI offers sensitive and reproducible measurements of flap microcirculation and seems more reliable in detecting decreases in blood perfusion caused by venous obstruction. It also allows for perfusion measurements in a relatively large area of flap tissue. This may be useful in identifying areas of the flap with compromised microcirculation during and after surgery. (C) 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  • 5692.
    Zötterman, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Elmasry, Moustafa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Olofsson, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Braskaminer kan orsaka svåra brännskador hos små barn2017Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 2017, nr 19, s. 873-873Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    [No abstract available]

  • 5693.
    Zötterman, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Mirdell, Robin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Horsten, Sandra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Farnebo, Simon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Tesselaar, Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Methodological concerns with laser speckle contrast imaging in clinical evaluation of microcirculation2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 3, artikel-id e0174703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Laser Speckle Contrast Imaging (LSCI) is a non-invasive and fast technique for measuring microvascular blood flow that recently has found clinical use for burn assessment and evaluation of flaps. Tissue motion caused by for example breathing or patient movements may however affect the measurements in these clinical applications, as may distance between the camera and the skin and tissue curvature. Therefore, the aims of this study were to investigate the effect of frame rate, number of frames/image, movement of the tissue, measuring distance and tissue curvature on the measured perfusion. Methods Methyl nicotinate-induced vasodilation in the forearm skin was measured using LSCI during controlled motion at different speeds, using different combinations of frame rate and number of frames/image, and at varying camera angles and distances. Experiments were made on healthy volunteers and on a cloth soaked in a colloidal suspension of polystyrene microspheres. Results Measured perfusion increased with tissue motion speed. The relation was independent of the absolute perfusion in the skin and of frame rate and number of frames/image. The measured perfusion decreased with increasing angles (16% at 60, p = 0.01). Measured perfusion did not vary significantly between measurement distances from 15 to 40 cm (p = 0.77, %CV 0.9%). Conclusion Tissue motion increases and measurement angles beyond 45 decrease the measured perfusion in LSCI. These findings have to be taken into account when LSCI is used to assess moving or curved tissue surfaces, which is common in clinical applications.

  • 5694.
    Zötterman, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Steinvall, Ingrid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Elmasry, Moustafa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US. Surgery Department, Plastic Surgery Unit, Suez Canal University, Egypt.
    Better Protection of Glass-Fronted Stoves Is Needed in Sweden Because of the Increase in the Number of Contact Burns Among Small Children2018Ingår i: Journal of Burn Care & Research, ISSN 1559-047X, E-ISSN 1559-0488, Vol. 39, nr 4, s. 618-622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The impression among the attending physicians at their Burn Centre is that the number of contact burns caused by glass-fronted stoves is increasing, particularly in the youngest group of patients. It is an interesting subgroup, as these injuries are preventable. The authors’ aim of this study was to find out whether the incidence of burns after contact with glass-fronted stoves has increased.

    The authors included all patients aged between 0 and 3.9 years who presented to the National Burn Centre during the period 2008–2015 with contact burn injuries caused by glass-fronted stoves. The change in incidence over time was calculated from national records and analyzed with simple linear regression.

    Fifty-six patients were included, of whom 20 were treated during the past 2 years of the study. Thirty-seven of the 56 were boys (66%), median (10–90 percentiles) age was 1.1 (0.7–2.5) years, percentage total body surface area burned was 0.6% (0.1–2.0), 12 were admitted for overnight stay in hospital, and seven needed operations. The incidence was 0.34/100 000 children-years during the first 2 years, and it was three times as high during the past 2 years. The increase in incidence was 0.24/100 000 children-years by each 2-year period (P = .02).

    The authors’ results indicate that contact burns among children caused by glass-fronted stoves are increasing in Sweden. The authors propose that there should be a plan for their prevention put in place.

  • 5695.
    Zötterman, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Tesselaar, Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Farnebo, Simon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    The use of laser speckle contrast imaging to predict flap necrosis: An experimental study in a porcine flap model2019Ingår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 72, nr 5, s. 771-777Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: We evaluated the use of laser speckle contrast imaging (LSCI) in the perioperative planning in reconstructive flap surgery. The aim of the study was to investigate whether LSCI can predict regions with a high risk of developing postoperative necrosis. Our hypothesis was that, perioperatively, such regions have perfusion values below a threshold value and show a negative perfusion trend. Methods: A porcine flap model based on the cranial gluteal artery perforator was used. Images were acquired before surgery, immediately after surgery (t = 0), after 30 min (t =30 min), and after 72h (t = 72 h). Regions of interest (ROIs) were chosen along the central axis of the flap. Clinical evaluation of the flap was made during each time point. Results: At t = 72 h, a demarcation line could be seen at a distance of 15.8 +/- 0.4 cm away from the proximal border of the flaps. At t =0, perfusion decreased gradually from the proximal to the distal ROI. At t =30 min, perfusion was significantly lower in the ROI distal to the final demarcation line than that at t = 0, and in all flaps, these ROIs had a perfusion amp;lt;25 PU. At t= 72 h, perfusion in the ROI proximal to this line returned to baseline levels, whereas perfusion in the distal ROI remained low. Conclusions: In our model, a decrease in perfusion during the first 30 min after surgery and a perfusion amp;lt;25 PU at t = 30 min was a predictor for tissue morbidity 72 h after surgery, which indicates that LSCI is a promising technique for perioperative monitoring in reconstructive flap surgery. (C) 2018 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.

    Publikationen är tillgänglig i fulltext från 2020-01-03 12:28
  • 5696.
    Álvarez-Rodríguez, Manuel
    et al.
    Autonomous University of Barcelona Cerdanyola del Vallès, Barcelona, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Guerrero-Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Transgenerational and Epigenetic Impacts of Environmental Exposures in Male Reproduction2018Ingår i: Encyclopedia of Reproduction (Second Edition) / [ed] Michael K. Skinner, Elsevier, 2018, s. 634-641Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    The vertebrate zygote results from the merging of two highly specialized gamete cells, namely the oocyte and the spermatozoon, and has the outstanding potential of creating all cells in the future developing embryo. For this to occur, however, the genome of the gametes is mostly striped of “epigenetic marks,” or proteins and methyl groups attached to the DNA. Epigenetic marks in the genome constitute the so-called epigenome and have the potential for long term regulation of gene expression. Environmental insults during the highly susceptible and delicate period of germ cell development could, by altering the epigenome of spermatozoa, affect the phenotype of future generations (transgenerational epigenetic inheritance). A brief review of how epigenetics can act transgenerationally through the male germline is hereby presented.

  • 5697.
    Ängerud, Karin H
    et al.
    Umeå University, Sweden.
    Sederholm Lawesson, Sofia
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Isaksson, Rose-Marie
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Department of Research, Norrbotten County Council, Sweden.
    Thylén, Ingela
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Swahn, Eva
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Differences in symptoms, first medical contact and pre-hospital delay times between patients with ST- and non-ST-elevation myocardial infarction2019Ingår i: European heart journal. Acute cardiovascular care., ISSN 2048-8726, Vol. 8, nr 3, s. 201-207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: In ST-elevation myocardial infarction, time to reperfusion is crucial for the prognosis. Symptom presentation in myocardial infarction influences pre-hospital delay times but studies about differences in symptoms between patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction are sparse and inconclusive. The aim was to compare symptoms, first medical contact and pre-hospital delay times in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction.

    METHODS AND RESULTS: This multicentre, observational study included 694 myocardial infarction patients from five hospitals. The patients filled in a questionnaire about their pre-hospital experiences within 24 h of hospital admittance. Chest pain was the most common symptom in ST-elevation myocardial infarction and non-ST-elevation myocardial infarction (88.7 vs 87.0%, p=0.56). Patients with cold sweat (odds ratio 3.61, 95% confidence interval 2.29-5.70), jaw pain (odds ratio 2.41, 95% confidence interval 1.04-5.58), and nausea (odds ratio 1.70, 95% confidence interval 1.01-2.87) were more likely to present with ST-elevation myocardial infarction, whereas the opposite was true for symptoms that come and go (odds ratio 0.58, 95% confidence interval 0.38-0.90) or anxiety (odds ratio 0.52, 95% confidence interval 0.29-0.92). Use of emergency medical services was higher among patients admitted with ST-elevation myocardial infarction. The pre-hospital delay time from symptom onset to first medical contact was significantly longer in non-ST-elevation myocardial infarction (2:05 h vs 1:10 h, p=0.001).

    CONCLUSION: Patients with ST-elevation myocardial infarction differed from those with non-ST-elevation myocardial infarction regarding symptom presentation, ambulance utilisation and pre-hospital delay times. This knowledge is important to be aware of for all healthcare personnel and the general public especially in order to recognise symptoms suggestive of ST-elevation myocardial infarction and when to decide if there is a need for an ambulance.

  • 5698.
    Ågren, Axel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Medicinska fakulteten.
    Äldres ensamhet i media: mellan "epidemi" och individuell upplevelse2019Ingår i: Mind, ISSN 2002-4282, nr 2, s. 4s. 36-39Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
    Abstract [sv]

    Ensamhet är idag en fråga som berör och får stor uppmärksamhet i massmedia. I ny forskning riktas blicken mot hur äldres ensamhet beskrivs i svensk dagspress idag, vilken bland annat visat att ensamhet främst kopplas till äldre samt att fokus ligger vid äldreomsorg och inte ensamhet i sig.

  • 5699.
    Ågren, Susanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Eriksson, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Hollman Frisman, Gunilla
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Anestesi- och intensivvårdskliniken VIN.
    Orwelius, Lotti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Anestesi- och intensivvårdskliniken US.
    The health promoting conversations intervention for families with a critically ill relative: A pilot study2019Ingår i: Intensive & Critical Care Nursing, ISSN 0964-3397, E-ISSN 1532-4036, Vol. 50, s. 103-110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: After intensive care unit treatment, patients often have prolonged impairments that affect their physical, cognitive and mental health. Family members can face overwhelming and emotionally challenging situations and their concerns and needs must be addressed. Objective: We investigated the outcomes of pilot randomised control trial, a nurse-led family intervention, Health Promoting Conversations, which focused on family functioning and wellbeing in families with a critically ill member. Study design: This randomised controlled pilot study used a pre-test, post-test design with intervention and control groups to investigate the outcomes of the nurse-led intervention in 17 families. Outcome measures: The Health Promoting Conversations intervention was evaluated using validated instruments that measure family functioning and family wellbeing: the General Functioning sub-scale from the McMaster Family Assessment Device; the Family Sense of Coherence, the Herth Hope Index, and the Medical Outcome Short-Form Health Survey. Descriptive and analytical statistical methods were used to analyse the data. Results: After 12 months, the intervention group reported better family functioning than the control group. The intervention group also had better social functioning and mental health after 12 months. Conclusion: This intervention may improve family wellbeing by improving family function, reducing stress, and promoting better mental health. (C) 2018 Elsevier Ltd. All rights reserved.

  • 5700.
    Ågren, Susanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Ivarsson, Bodil
    Department of Clinical Sciences, Lund University, Lund, Sweden.
    Psychosocial impact in family members before and up to two years after heart or lung transplantation.2015Konferensbidrag (Övrigt vetenskapligt)
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