uu.seUppsala University Publications
Change search
Refine search result
273274275276277278279 13751 - 13800 of 13955
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 13751.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Aspects of Progression in Breast Carcinoma: from ductal carcinoma in situ to invasive cancer2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown.

    In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

    In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade.

    In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

    In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

    List of papers
    1. Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution
    Open this publication in new window or tab >>Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution
    Show others...
    2009 (English)In: Molecular Oncology, ISSN 1574-7891, Vol. 3, no 3, p. 214-219Article in journal (Refereed) Published
    Abstract [en]

    In breast cancer, previous studies have suggested that somatic TP53 mutations are likely to be an early event. However, there are controversies regarding the cellular origin and linear course of breast cancer. The purpose of this study was to investigate tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. The entire coding sequence of TP53 was sequenced in a cohort of pure ductal carcinoma in situ (DCIS), pure invasive cancer (</=15mm) and mixed lesions (i.e. invasive cancer with an in situ component). Of 118 tumor samples, 19 were found to harbor a TP53 mutation; 5 (15.6%) of the pure DCIS, 4 (10.5%) of the pure invasive cancers and 10 (20.8%) of the mixed lesions. In the mixed lesions, both the invasive and the DCIS components showed the same mutation in all 5 cases where the two components were successfully microdissected. Presence of the same mutation in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

    Keywords
    TP53 mutation, Breast cancer, DCIS
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-113745 (URN)10.1016/j.molonc.2009.03.001 (DOI)000266853200004 ()19403344 (PubMedID)
    Available from: 2010-02-03 Created: 2010-02-03 Last updated: 2012-02-15Bibliographically approved
    2. Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study
    Open this publication in new window or tab >>Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study
    Show others...
    2010 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 10, p. 653-Article in journal (Refereed) Published
    Abstract [en]

    Background: Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort. Methods: All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Vastmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results: IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS. Conclusions: Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-142827 (URN)10.1186/1471-2407-10-653 (DOI)000285299300001 ()21118480 (PubMedID)
    Available from: 2011-01-17 Created: 2011-01-17 Last updated: 2017-12-11Bibliographically approved
    3. Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ
    Open this publication in new window or tab >>Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ
    Show others...
    2012 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArticle in journal (Other academic) Submitted
    Abstract [en]

    Introduction:

    About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

    Methods:

    Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

    Results:

    One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

    Conclusions:

    Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

    Keywords
    tumor markers, recurrence type, DCIS
    National Category
    Cancer and Oncology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-166365 (URN)
    Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2017-12-08Bibliographically approved
    4. Breast carcinoma with neoductgenesis: a new subgroup of breast cancer
    Open this publication in new window or tab >>Breast carcinoma with neoductgenesis: a new subgroup of breast cancer
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: A new subgroup of breast cancer has been proposed: breast carcinoma with neoductgenesis. Cases presenting with casting type calcifications on the mammogram, histologically high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction and lymphocyte infiltration has been suggested to represent a more aggressive form of breast cancer. Treatment decision based on traditional histopathology showing DCIS might be challenged if neoductgenesis is diagnosed. We evaluated a histological classification system proposed for neoductgenesis and studied tumor biology in cases with and without neoductgenesis.

     

    Material and Method: Seventy-four tumors with DCIS grade 2-3, with or without an invasive component, were blocked in TMAs. A classification system based on a pathological evaluation and Tenascin-C (Tn-C) expression was used to categorize tumors as showing neoductgenesis or not. Immunohistochemical staining for known tumor markers and correlation with mammographic features was performed. Logistic regression model was use to evaluate the correlation between breast carcinoma with neoductgenesis and molecular- and mammographic features.

     

    Results: Four pathologists could categorize cases as “possible neoductgenesis” with an overall correlation of 72% and a kappa value of 0.44. Adding Tn-C staining resulted in a group with neoductgenesis (n=37) and one without (n=31). Neoductgenesis correlated significantly with mammographic casting- and crushed stone microcalcifications and estrogen receptor status (p-values 0.04 and 0.03, respectively). High nuclear grade, HER2 positivity, progesterone receptor negativity and high proliferation were also more often seen in the group with neoductgenesis, but this was not statistically significant (0.10, 0.07, 0.20 and 0.29).

     

    Discussion: We developed reproducible histologic criteria for a new entity: breast carcinoma with neoductgenesis. The system seemed to be useful in receiving reproducibility between pathologists making the diagnosis. Neoductgenesis was related to more aggressive tumor biology and to the mammographic features. Our findings have to be repeated and the relation to prognosis further studied. However, we can already predict a potential benefit for women earlier considered having a pure DCIS but now diagnosed as breast carcinoma with neoductgenesis and a need to develop appropriate treatment regiments.

    Keywords
    breast carcinoma, neoductgenesis
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-166704 (URN)
    Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2012-02-15
  • 13752.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jirström, Karin
    Department of Clinical Sciences, Pathology, Lund University.
    Ringberg, Anita
    Department of Plastic and Reconstructive Surgery, Malmö Hospital.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArticle in journal (Other academic)
    Abstract [en]

    Introduction:

    About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

    Methods:

    Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

    Results:

    One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

    Conclusions:

    Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

  • 13753.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sollie, Thomas
    Univ Örebro, Dept Pathol, Örebro, Sweden..
    Tot, Tibor
    Falun Cent Hosp, Dept Pathol, Falun, Sweden..
    Blomqvist, Carl
    Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland..
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Liljegren, Göran
    Univ Örebro, Dept Surg, Örebro, Sweden..
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort2017In: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, article id 4351319Article in journal (Refereed)
    Abstract [en]

    Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabar. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER-and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13-1.08) and 0.82 (0.29-2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41-1.95) and 1.60 (0.75-3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.

  • 13754.
    Zhou, Wenjing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tot, Tibor
    Department of Pathology, Falun Central Hospital.
    Tabár, László
    Department of Mammography, Falun Central Hospital.
    Pinder, Sarah
    Department of Pathology, King´s College, London.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Gunilla, Christensson
    Department of Surgery, Falun Central Hospital.
    Abdsaleh, Shahin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Sollie, Thomas
    Department of Pathology, Örebro University.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Breast carcinoma with neoductgenesis: a new subgroup of breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A new subgroup of breast cancer has been proposed: breast carcinoma with neoductgenesis. Cases presenting with casting type calcifications on the mammogram, histologically high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction and lymphocyte infiltration has been suggested to represent a more aggressive form of breast cancer. Treatment decision based on traditional histopathology showing DCIS might be challenged if neoductgenesis is diagnosed. We evaluated a histological classification system proposed for neoductgenesis and studied tumor biology in cases with and without neoductgenesis.

     

    Material and Method: Seventy-four tumors with DCIS grade 2-3, with or without an invasive component, were blocked in TMAs. A classification system based on a pathological evaluation and Tenascin-C (Tn-C) expression was used to categorize tumors as showing neoductgenesis or not. Immunohistochemical staining for known tumor markers and correlation with mammographic features was performed. Logistic regression model was use to evaluate the correlation between breast carcinoma with neoductgenesis and molecular- and mammographic features.

     

    Results: Four pathologists could categorize cases as “possible neoductgenesis” with an overall correlation of 72% and a kappa value of 0.44. Adding Tn-C staining resulted in a group with neoductgenesis (n=37) and one without (n=31). Neoductgenesis correlated significantly with mammographic casting- and crushed stone microcalcifications and estrogen receptor status (p-values 0.04 and 0.03, respectively). High nuclear grade, HER2 positivity, progesterone receptor negativity and high proliferation were also more often seen in the group with neoductgenesis, but this was not statistically significant (0.10, 0.07, 0.20 and 0.29).

     

    Discussion: We developed reproducible histologic criteria for a new entity: breast carcinoma with neoductgenesis. The system seemed to be useful in receiving reproducibility between pathologists making the diagnosis. Neoductgenesis was related to more aggressive tumor biology and to the mammographic features. Our findings have to be repeated and the relation to prognosis further studied. However, we can already predict a potential benefit for women earlier considered having a pure DCIS but now diagnosed as breast carcinoma with neoductgenesis and a need to develop appropriate treatment regiments.

  • 13755.
    Zhou, Yunting
    et al.
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Wei
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Zhou, Junming
    Nanjing Univ, Jingling Hosp, Dept Outpatient, Army Engn Univ, Nanjing, Jiangsu, Peoples R China.
    Chen, Juan
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Wang, Xiaohang
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Cai, Min
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Fengfei
    Nanjing Med Univ, Nanjing Hosp 1, Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Xu, Wei
    Kings Coll London, Sch Life Course Sci, Dept Diabet, Guys Campus, London, England.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sun, Zilin
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Lipotoxicity reduces beta cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules2019In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 380, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background: Islet stellate cells (ISCs) activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood.

    Methods: In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD) induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA) using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets.

    Results: HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated a-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures.

    Conclucions: These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.

  • 13756.
    Zhu, Wei
    et al.
    Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Orthoped, Beijing 100730, Peoples R China;Peking Union Med Coll, Beijing 100730, Peoples R China.
    Ma, Qi
    Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Orthoped, Beijing 100730, Peoples R China;Peking Union Med Coll, Beijing 100730, Peoples R China.
    Borg, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Öhman Mägi, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Weng, Xisheng
    Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Orthoped, Beijing 100730, Peoples R China;Peking Union Med Coll, Beijing 100730, Peoples R China.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Cemented injectable multi-phased porous bone grafts for the treatment of femoral head necrosis2019In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 7, no 18, p. 2997-3006Article in journal (Refereed)
    Abstract [en]

    Femoral head necrosis (FHN) can induce musculoskeletal disability. It presents a challenge from diagnostic and therapeutic points of view. Open surgery for the treatment of FHN is not an optimal route. To minimize the surgery window, an injectable material with a porous structure and bioactive nature is preferred. The fabrication of an injectable porous bone graft via a simple route was the aim of our study. Therefore, cemented multi-phased calcium phosphate porous granules have been studied with varied phase compositions, pore sizes and porosities, and degradation rates. Granules templated by PEG 100-600 mu m were chosen for cell toxicity and in vitro osteogenic potential testing. Rabbits, making up a femoral head necrosis model, were implanted with granule A. Mature cancellous bone tissue was observed in the femoral head defect after 2 months implantation. The results indicate that the newly formed injectable bioactive porous grafts could be a good candidate for the treatment of femoral head necrosis.

  • 13757.
    Zhu, Yanping
    et al.
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Qi, Xiaoying
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yu, Cuicui
    Qing Dao Univ, Affiliated Yantai Yuhuangding Hosp, Dept Anesthesiol, 20 Yudong Rd, Yantai S264009, Shandong, Peoples R China.
    Yu, Shoujun
    Binzhou Med Univ, Yantai Affiliated Hosp, Dept Ultrasound, 717 Jinfu Rd, Binzhou 264100, Shandong, Peoples R China.
    Zhang, Chao
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Yuan
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Liu, Xiuxiu
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Xu, Yuxue
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yang, Chunhua
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Jiang, Wenguo
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Tian, Geng
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Li, Xuri
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Jiandi
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China;Yantai Zestern Biotech Co LTD, 39 Keji Ave Bioasis, Yantai, Peoples R China.
    Wang, Lei
    Harbin Med Univ, Affiliated Hosp 1, Dept Thorac Surg, 23 Youzheng St, Harbin 150000, Heilongjiang, Peoples R China.
    Mi, Jia
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Identification of prothymosin alpha (PTMA) as a biomarker for esophageal squamous cell carcinoma (ESCC) by label-free quantitative proteomics and Quantitative Dot Blot (QDB)2019In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 16, article id 12Article in journal (Refereed)
    Abstract [en]

    Background: Esophageal cancer (EC) is one of the malignant tumors with a poor prognosis. The early stage of EC is asymptomatic, so identification of cancer biomarkers is important for early detection and clinical practice.

    Methods: In this study, we compared the protein expression profiles in esophageal squamous cell carcinoma (ESCC) tissues and adjacent normal esophageal tissues from five patients through high-resolution label-free mass spectrometry. Through bioinformatics analysis, we found the differentially expressed proteins of ESCC. To perform the rapid identification of biomarkers, we adopted a high-throughput protein identification technique of Quantitative Dot Blot (QDB). Meanwhile, the QDB results were verified by classical immunohistochemistry.

    Results: In total 2297 proteins were identified, out of which 308 proteins were differentially expressed between ESCC tissues and normal tissues. By bioinformatics analysis, the four up-regulated proteins (PTMA, PAK2, PPP1CA, HMGB2) and the five down-regulated proteins (Caveolin, Integrin beta-1, Collagen alpha-2(VI), Leiomodin-1 and Vinculin) were selected and validated in ESCC by Western Blot. Furthermore, we performed the QDB and IHC analysis in 64 patients and 117 patients, respectively. The PTMA expression was up-regulated gradually along the progression of ESCC, and the PTMA expression ratio between tumor and adjacent normal tissue was significantly increased along with the progression. Therefore, we suggest that PTMA might be a potential candidate biomarker for ESCC.

    Conclusion: In this study, label-free quantitative proteomics combined with QDB revealed that PTMA expression was up-regulated in ESCC tissues, and PTMA might be a potential candidate for ESCC. Since Western Blot cannot achieve rapid and high-throughput screening of mass spectrometry results, the emergence of QDB meets this demand and provides an effective method for the identification of biomarkers.

  • 13758.
    Zhu, Yingyan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Analysis of Spinal Fusion Versus Nonsurgical Treatment for Chronic Low Back Pain Based on Elisabeth Svensson’s Method2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The utility of spinal fusion for patients with chronic low back pain is controversial. The aim ofthe current study is to find out whether spinal fusion benefits the patients or not. Additionally,two outcome scales, the Balanced Inventory for Spinal Disorders (BIS) and Oswestry Low BackPain Disability Index (ODI), are compared to detect which one is preferable. A prospectiverandomized study concerning spinal fusion has recently been performed in Sweden. 74 patientsaged 18 to 65 with low back pain lasting longer than one year were randomized into twotreatment groups: a fusion group and a non-fusion group. Evaluation of the physical sensationsbased on several outcome scales were conducted both before and one year after the treatment.Elisabeth Svensson’s Method, which measures the level of changes both from systematic andindividual aspects, was applied to analyse the effect of spinal fusion. Measures of disorder(D) and order consistency (MA) were calculated when comparing the two outcome scales. Theconclusions are that spinal fusion has shown significant advantages over non-surgical treatmentmethods, and that BIS is recommended over ODI.

  • 13759. Zhukova, Nataliya
    et al.
    Ramaswamy, Vijay
    Remke, Marc
    Martin, Dianna C
    Castelo-Branco, Pedro
    Zhang, Cindy H
    Fraser, Michael
    Tse, Ken
    Poon, Raymond
    Shih, David J H
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ray, Peter N
    Bouffet, Eric
    Dirks, Peter
    von Bueren, Andre O
    Pfaff, Elke
    Korshunov, Andrey
    Jones, David T W
    Northcott, Paul A
    Kool, Marcel
    Pugh, Trevor J
    Pomeroy, Scott L
    Cho, Yoon-Jae
    Pietsch, Torsten
    Gessi, Marco
    Rutkowski, Stefan
    Bognar, Laszlo
    Cho, Byung-Kyu
    Eberhart, Charles G
    Conter, Cecile Faure
    Fouladi, Maryam
    French, Pim J
    Grajkowska, Wieslawa A
    Gupta, Nalin
    Hauser, Peter
    Jabado, Nada
    Vasiljevic, Alexandre
    Jung, Shin
    Kim, Seung-Ki
    Klekner, Almos
    Kumabe, Toshihiro
    Lach, Boleslaw
    Leonard, Jeffrey R
    Liau, Linda M
    Massimi, Luca
    Pollack, Ian F
    Ra, Young Shin
    Rubin, Joshua B
    Van Meir, Erwin G
    Wang, Kyu-Chang
    Weiss, William A
    Zitterbart, Karel
    Bristow, Robert G
    Alman, Benjamin
    Hawkins, Cynthia E
    Malkin, David
    Clifford, Steven C
    Pfister, Stefan M
    Taylor, Michael D
    Tabori, Uri
    WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma2014In: Acta neuropathologica communications, ISSN 2051-5960, Vol. 2, article id 174Article in journal (Refereed)
    Abstract [en]

    TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

  • 13760.
    Zhulina, Y.
    et al.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Cao, Y.
    Univ Orebro, Clin Epidemiol & Biostat, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Amcoff, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala Univ, Dept Med Sci, Gastroenterol Res Grp, Uppsala, Sweden..
    Tysk, C.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Halfvarson, J.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Prognostic significance of serial faecal calprotectin in inflammatory bowel disease2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, p. S315-S318Article in journal (Other academic)
  • 13761.
    Zhulina, Y.
    et al.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Cao, Y.
    Univ Orebro, Clin Epidemiol & Biostat, Sch Med Sci, Orebro, Sweden.;Karolinska Inst, Unit Biostat, Inst Environm Med, Stockholm, Sweden..
    Amcoff, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Tysk, C.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Halfvarson, J.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    The prognostic significance of faecal calprotectin in patients with inactive inflammatory bowel disease2016In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 44, no 5, p. 495-504Article in journal (Refereed)
    Abstract [en]

    BackgroundFaecal calprotectin, an established biomarker used to assess mucosal inflammation, has been shown to correlate with endoscopic activity in inflammatory bowel disease (IBD). Longitudinal monitoring of faecal calprotectin, however, has rarely been employed beyond assessment of therapy response and post hoc analyses of clinical trials. AimTo study whether consecutive measurements of faecal calprotectin every third month are useful for monitoring patients with IBD in clinical remission. MethodsPatients aged 18 years or older, with a known diagnosis of IBD in clinical remission, were prospectively studied. Patients provided faecal samples every third month and were prospectively followed until the first clinical relapse or the end of the 2-year follow-up period. Measurements (EK-CAL, Buhlmann Lab. AG, Switzerland) were done at the end of the study. A Cox model with time-dependent covariates was used for analysis. ResultsAmong 104 patients, Crohn's disease (n = 49) and ulcerative colitis (n = 55), 37 had a relapse. A doubling of faecal calprotectin level between two consecutively collected samples was associated with a 101% increased risk of relapse (HR: 2.01; 95% CI: 1.53-2.65; P < 0.001). The relative risk of relapse attenuated with time (HR: 0.80; 95% CI: 0.75-0.86; P < 0.001), by a 20% decrease in risk of relapse per 3-month period since the sample was obtained. ConclusionsBy consecutively measuring faecal calprotectin every third month, we quantified the risk of relapse related to faecal calprotectin change and observed attenuation of the risk across time. Our data suggest that longitudinal monitoring of faecal calprotectin is informative in predicting relapse in IBD.

  • 13762. Zickert, A.
    et al.
    Amoudruz, P.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Malmström, V.
    Gunnarsson, I.
    Cytokines in lupus nephritis, levels of IL-17 and IL-23 in association to histopathology and response to treatment2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A4-A5Article in journal (Other academic)
  • 13763.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A comprehensive understanding of how the body and all its components function is essential when this knowledge is exploited for medical purposes. The achievements in biological and medical research during last decades has provided us with the complete human genome and identified signaling pathways that governs the cellular processes that facilitates the development and maintenance of higher order organisms. This has brought about the realization that diseases such as cancer is a consequence of genomic aberrations that effects these signaling pathways, endowing cancer cells with the capacity to circumvent homeostasis by acquiring features like self-sustained proliferation and insensitivity to apoptosis. The increased understanding of biology and medicine has been made possible by the development of advanced methods to carry out biological and clinical analyses. The demands of a method often differ regarding in what context it will be applied. It may be acceptable for method to be laborious and time consuming if it is used in basic research, but for medical purposes molecular methods need to be fast and straightforward to perform. Innovative technologies should preferentially address the demands of both researchers and clinicians and provide data not possible to obtain by other methods. An example of such a method is the in situ proximity ligation assay (in situ PLA). In this thesis I have used this method to determine the activity status, at the single-cell level, of the transforming growth factor-β (TGF-β) signaling pathway and activating protein-1 (AP-1) family of transcription factors.  Both of these pathways are frequently involved in cancer development and progression. In addition to this research I herein also present further modifications of in situ PLA, and analyses thereof, to increase the utility and resolution of this assay.

    List of papers
    1. Intercellular variation in signaling through the TGF-β pathway and its relation to cell densityand cell cycle phase
    Open this publication in new window or tab >>Intercellular variation in signaling through the TGF-β pathway and its relation to cell densityand cell cycle phase
    Show others...
    2012 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, no 7, article id M111.013482Article in journal (Refereed) Published
    Abstract [en]

    Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work we have characterized the intercellular variability of transforming growth factor β-induced Smad interactions, providing essential information about TGF-β signaling and its dependence on the density of cell populations and the cell-cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single-cell analysis of TGF-β signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples, and to evaluate their susceptibility to drug treatment.

    Place, publisher, year, edition, pages
    American Society for Biochemistry and Molecular Biology, 2012
    National Category
    Cell Biology
    Research subject
    Molecular Cellbiology
    Identifiers
    urn:nbn:se:uu:diva-171949 (URN)10.1074/mcp.M111.013482 (DOI)000306411300017 ()22442258 (PubMedID)
    Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
    2. Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion
    Open this publication in new window or tab >>Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion
    Show others...
    2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 31, p. 3606-3615Article in journal (Refereed) Published
    Abstract [en]

    Deregulation of the transforming growth factor β (TGFβ) signal transduction cascade is functionally linked to cancer. In early phases, TGFβ acts as a tumor suppressor by inhibiting tumor cell proliferation, whereas in late phases, it can act as a tumor promoter by stimulating tumor cell invasion and metastasis. Smad transcriptional effectors mediate TGFβ responses, but relatively little is known about the Smad-containing complexes that are important for epithelial-mesenchymal transition and invasion. In this study, we have tested the hypothesis that specific members of the AP-1 transcription factor family determine TGFβ signaling specificity in breast cancer cell invasion. Using a 3D model of collagen-embedded spheroids of MCF10A-MII premalignant human breast cancer cells, we identified the AP-1 transcription factor components c-Jun, JunB, c-Fos and Fra1 as essential factors for TGFβ-induced invasion and found that various mesenchymal and invasion-associated TGFβ-induced genes are co-regulated by these proteins. In situ proximity ligation assays showed that TGFβ signaling not only induces complexes between Smad3 and Smad4 in the nucleus but also complexes between Smad2/3 and Fra1, whereas complexes between Smad3, c-Jun and JunB could already be detected before TGFβ stimulation. Finally, chromatin immunoprecipitations showed that c-Jun, JunB and Fra1, but not c-Fos, are required for TGFβ-induced binding of Smad2/3 to the mmp-10 and pai-1 promoters. Together these results suggest that in particular formation of Smad2/3-Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGFβ-induced invasion program.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-180124 (URN)10.1038/onc.2012.370 (DOI)000322638400005 ()22926518 (PubMedID)
    Note

    Agata Zieba & Eleftheria Vasilaki contributed equally to this work.

    Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2017-12-07Bibliographically approved
    3. A detailed analysis of 3D subcellular signal localization
    Open this publication in new window or tab >>A detailed analysis of 3D subcellular signal localization
    Show others...
    2009 (English)In: Cytometry Part A, ISSN 1552-4922, Vol. 75A, no 4, p. 319-328Article in journal (Refereed) Published
    Abstract [en]

    Detection and localization of fluorescent signals in relation to other subcellular structures is an important task in various biological studies. Many methods for analysis of fluorescence microscopy image data are limited to 2D. As cells are in fact 3D structures, there is a growing need for robust methods for analysis of 3D data. This article presents an approach for detecting point-like fluorescent signals and analyzing their subnuclear position. Cell nuclei are delineated using marker-controlled (seeded) 3D watershed segmentation. User-defined object and background seeds are given as input, and gradient information defines merging and splitting criteria. Point-like signals are detected using a modified stable wave detector and localized in relation to the nuclear membrane using distance shells. The method was applied to a set of biological data studying the localization of Smad2-Smad4 protein complexes in relation to the nuclear membrane. Smad complexes appear as early as 1 min after stimulation while the highest signal concentration is observed 45 min after stimulation, followed by a concentration decrease. The robust 3D signal detection and concentration measures obtained using the proposed method agree with previous observations while also revealing new information regarding the complex formation.

    Keywords
    3D image analysis, fluorescence signal segmentation, subcellular positioning, Smad detection
    National Category
    Computer and Information Sciences
    Identifiers
    urn:nbn:se:uu:diva-98014 (URN)10.1002/cyto.a.20663 (DOI)000264513800006 ()
    Available from: 2009-02-05 Created: 2009-02-05 Last updated: 2018-01-13Bibliographically approved
    4. Bright-Field Microscopy Visualization of Proteins and Protein Complexes by In Situ Proximity Ligation with Peroxidase Detection
    Open this publication in new window or tab >>Bright-Field Microscopy Visualization of Proteins and Protein Complexes by In Situ Proximity Ligation with Peroxidase Detection
    Show others...
    2010 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 56, no 1, p. 99-110Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    The in situ proximity ligation assay (PLA) allows a protein or protein complex to be represented as an amplifiable DNA molecule. Recognition is mediated by proximity probes consisting of antibodies coupled with oligonucleotides. Upon dual binding of the proximity probes, the oligonucleotides direct the formation of a circular DNA molecule, which is then amplified by rolling-circle replication. The localized concatemeric product is then detected with fluorescent probes. The in situ PLA enables localized detection of individual native proteins or interacting protein pairs in fixed cells or tissue sections, thus providing an important tool for basic and clinical research.

    METHODS:

    We used horseradish peroxidase (HRP)conjugated oligonucleotides to couple in situ PLA with enzymatic visualization of the localized detection event.

    RESULTS:

    We demonstrate the detection of protein complexes, both in cells and in tissue sections, and show that we can quantify the complexes with image-analysis software specially developed for recognizing HRP signals in bright-field microscopy images. We show that fluorescence and HRP signals produce equivalent results, both ill cultured cells and in tissue samples.

    CONCLUSIONS:

    The combination of in situ PLA with bright-field detection and automated image analysis allows the signals present to be Counted in an automated fashion and thus provides a sensitive and specific method for quantification of proteins and protein complexes with bright-field microscopy. With this approach, in situ PLA can be used without the requirement for expensive fluorescence microscopes, thereby avoiding problems with nonspecific fluorescence while maintaining compatibility with conventional histologic staining.

    National Category
    Medical Genetics Bioinformatics and Systems Biology
    Research subject
    Clinical Genetics; Computerized Image Analysis
    Identifiers
    urn:nbn:se:uu:diva-111499 (URN)10.1373/clinchem.2009.134452 (DOI)000273466300016 ()
    Available from: 2009-12-15 Created: 2009-12-15 Last updated: 2018-01-12Bibliographically approved
  • 13764. Ziemssen, Tjalf
    et al.
    Bajenaru, Ovidiu A
    Carrá, Adriana
    de Klippel, Nina
    de Sá, João C
    Edland, Astrid
    Frederiksen, Jette L
    Heinzlef, Olivier
    Karageorgiou, Klimentini E
    Lander Delgado, Rafael H
    Landtblom, Anne-Marie
    Department of Neurology and Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden .
    Macías Islas, Miguel A
    Tubridy, Niall
    Gilgun-Sherki, Yossi
    A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial2014In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 261, no 11, p. 2101-2111Article in journal (Refereed)
    Abstract [en]

    Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p < 0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p < 0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.

  • 13765.
    Zimerman, Andre
    et al.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Lopes, Renato D.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Stebbins, Amanda L.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Guimaraes, Patricia O.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Haque, Ghazala
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Melloni, Chiara
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Trollinger, Kathleen
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Tricoci, Pierluigi
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Roe, Matthew T.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Ohman, Erik Magnus
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Mahaffey, Kenneth W.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tinga, Brian
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Pieper, Karen S.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Alexander, Karen P.
    Duke Med, Duke Clin Res Inst, Durham, NC USA..
    Pooled analysis of adverse event collection from 4 acute coronary syndrome trials2016In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 174, p. 60-67Article in journal (Refereed)
    Abstract [en]

    Background: Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.

    Methods: Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.

    Results: In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.

    Conclusions: Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

  • 13766.
    Zimmer, A. D.
    et al.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Kim, G. J.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Hotz, A.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Bourrat, E.
    St Louis Hosp, AP HP, Dept Dermatol, Reference Ctr Rare Skin Dis MAGEC, Paris, France..
    Hausser, I.
    Univ Clin Heidelberg, Inst Pathol IPH, Heidelberg, Germany..
    Has, C.
    Univ Freiburg, Fac Med, Med Ctr, Dept Dermatol, Freiburg, Germany..
    Oji, V.
    Univ Hosp Munster, Dept Dermatol, Munster, Germany..
    Stieler, K.
    Charite Univ Med Berlin, Child Dermatol & Hair Competence Ctr, Dept Dermatol, Berlin, Germany..
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Kunde, V.
    Christian Childrens Hosp, Dept Neonatol, Osnabruck, Germany..
    Weber, B.
    Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland..
    Radner, F. P. W.
    Karl Franzens Univ Graz, Inst Mol Biosci, Graz, Austria..
    Leclerc-Mercier, S.
    Hop Necker Enfants Malad, Reference Ctr Rare Skin Dis MAGEC, Dept Dermatol & Pathol, Paris, France..
    Schlipf, N.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Demmer, P.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Kuesel, J.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Fischer, J.
    Univ Freiburg, Fac Med, Med Ctr, Inst Human Genet, Freiburg, Germany..
    Sixteen novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function2017In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 177, no 2, p. 445-455Article in journal (Refereed)
    Abstract [en]

    Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause nonsyndromic forms of ARCI. To date, only 10 distinct pathogenic mutations in PNPLA1 have been reported. Objectives To identify new causative PNPLA1 mutations. Methods We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis. Results Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA1 mutations that are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. Conclusions We estimate the frequency of PNPLA1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs.

  • 13767. Zimmermann, Stefan
    et al.
    Flachskampf, Frank A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Alff, Anna
    Schneider, Reinhard
    Dechant, Katharina
    Klinghammer, Lutz
    Stumpf, Christian
    Zopf, Yurdaguel
    Loehr, Thomas
    Brand, Georg
    Ludwig, Josef
    Daniel, Werner G
    Achenbach, Stephan
    Out-of-hospital cardiac arrest and percutaneous coronary intervention for ST-elevation myocardial infarction: Long-term survival and neurological outcome2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 166, no 1, p. 236-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion.

    METHODS:

    We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale.

    RESULTS:

    PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p=0.87). One-year mortality was 34.7% vs. 9.5% (p<0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status ≤2 (median 1min, range 0-11min) compared to non-survivors or survivors with CPC status >2 (median 8min, range 0-13min), p<0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after >6min' as independent predictors of negative long-term outcome (death or CPC >2).

    CONCLUSIONS:

    Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1year, especially if advanced life support had been started within ≤6min and PCI was successful.

  • 13768. Zindovic, Igor
    et al.
    Sjögren, Johan
    Bjursten, Henrik
    Björklund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Herou, Erik
    Ingemansson, Richard
    Nozohoor, Shahab
    Predictors and impact of massive bleeding in acute type A aortic dissection.2017In: Interactive Cardiovascular and Thoracic Surgery, ISSN 1569-9293, E-ISSN 1569-9285, Vol. 24, no 4, p. 498-505Article in journal (Refereed)
    Abstract [en]

    Objectives: Bleeding complications associated with acute type A aortic dissection (aTAAD) are a well-known clinical problem. Here, we evaluated predictors of massive bleeding related to aTAAD and associated surgery and assessed the impact of massive bleeding on complications and survival.

    Methods: This retrospective study of 256 patients used Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) criteria to define massive bleeding, which was met by 66 individuals (Group I) who were compared to the remaining patients (Group II). Multivariable logistic regression was used to identify independent predictors of massive bleeding and in-hospital mortality, Kaplan-Meier estimates for analysis of late survival, and Cox regression analysis to evaluate independent predictors of late mortality.

    Results: Independent predictors of massive bleeding included symptom duration (odds ratio [OR], 0.974 per hour increment; 95% confidence interval [CI], 0.950-0.999; P  =   0.041) and DeBakey type 1 dissection (OR, 2.652; 95% CI, 1.004-7.008; P  =   0.049). In-hospital mortality was higher in Group I (30.3% vs 8.0%, P  <0.001). Kaplan-Meier estimates of survival indicated poorer survival for Group I at 1, 3 and 5 years (68.8 ± 5.9% vs 92.8 ± 1.9%; 65.2 ± 6.2% vs 85.3 ± 2.7%; 53.9 ± 6.9% vs 82.1 ± 3.3 %, respectively; log rank P  <   0.001). Re-exploration for bleeding was an independent predictor of in-hospital (OR, 3.109; 95% CI, 1.044-9.256; P  =   0.042) and late mortalities (hazard ratio, 3.039; 95% CI, 1.605-5.757; P  =   0.001).

    Conclusions: Massive bleeding in patients with aTAAD is prompted by shorter symptom duration and longer extent of dissection and has deleterious effects on outcomes of postoperative complications as well as in-hospital and late mortalities.

  • 13769. Zingales, Bianca
    et al.
    Rondinelli, Edson
    Degrave, Wim
    da Silveira, José Franco
    Levin, Mariano
    Le Paslier, Denis
    Modabber, F
    Dobrokhotov, Boris
    Swindle, John
    Kelly, John
    Åslund, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hoheisel, Jörg
    Ruiz, Andres
    Cazzulo, Juan José
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frasch, Alberto
    The Trypanosoma cruzi genome initiative1997In: Parasitology Today, ISSN 0169-4758, E-ISSN 1873-1473, Vol. 13, no 1, p. 16-22Article in journal (Refereed)
    Abstract [en]

    An initiative was launched in 1994 by the Special Programme for Research and Training in Tropical Diseases (TDR) of the WHO to analyse the genomes of the parasites Filaria, Schistosoma, Leishmania, Trypanosoma brucei and Trypanosoma cruzi. Five networks were established through wide publicity, holding meetings of key laboratories and developing proposals which were then reviewed by the Steering Committee of Strategic Research for financial support. The aim of the Programme was to use the platform of these networks to: (1) train scientists from tropical disease-endemic countries; (2) transfer technology and share material and expertise, thereby reducing costs and increasing efficiency; and (3) provide an information system that is accessible globally as soon as the results become available. The initial target was to produce a low-resolution genome map for each of the parasites, but it soon became evident that by using rapidly developing technologies, it might be feasible to complete DNA-sequence analysis for some of the parasites in the next decade, as discussed here by Alberto Carlos Frasch and colleagues, with particular focus on the T. cruzi genome initiative.

  • 13770.
    Zingmark, Per-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, E. Niclas
    Karlsson, Mats O.
    Comparing the differential drug effect model to the proportional odds modelManuscript (Other academic)
  • 13771. Zippelius, Alfred
    et al.
    Batard, Pascal
    Rubio-Godoy, Verena
    Bioley, Gilles
    Liénard, Danielle
    Lejeune, Ferdy
    Rimoldi, Donata
    Guillaume, Philippe
    Meidenbauer, Norbert
    Mackensen, Andreas
    Rufer, Nathalie
    Lubenow, Norbert
    Department of Transfusion Medicine, Greifswald University, Germany.
    Speiser, Daniel
    Cerottini, Jean-Charles
    Romero, Pedro
    Pittet, Mikaël J
    Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 8, p. 2865-73Article in journal (Refereed)
    Abstract [en]

    Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.

  • 13772.
    Zirakzadeh, A. Ali
    et al.
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Kinn, Johan
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Krantz, David
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Rosenblatt, Robert
    Umeå Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden; Karolinska Inst, Stockholm South Gen Hosp, Dept Urol, Stockholm, Sweden.
    Winerdal, Malin E.
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Hu, Jin
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Hartana, Ciputra Adijaya
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Lundgren, Christian
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Bergman, Emma Ahlén
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Johansson, Markus
    Sundsvall Hosp, Dept Urol, Sundsvall, Sweden.
    Holmström, Benny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Hansson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Sidikii, Alexander
    Länssjukhuset Ryhov, Dept Urol, Region Jonköping, Sweden.
    Vasko, Janos
    Umeå Univ, Dept Med Biosci, Pathol, Umeå, Sweden.
    Marits, Per
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Sherif, Amir
    Umeå Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Winqvist, Ola
    Karolinska Inst, Unit Immunol & Allergy, Dept Med, Stockholm, Sweden.
    Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer2017In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 176, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-alpha. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.

  • 13773. Zirkzee, Elisabeth J. M.
    et al.
    Checa, Cesar Magro
    Steup-Beekman, Gerda M.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cluster Analysis of an Array of Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus2014In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 41, no 8, p. 1720-+Article in journal (Refereed)
  • 13774.
    Zoega, Gunnar Mar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Arnarsson, Arsaell
    Neuroscience Research, University of Akureyri, Akureyri, Iceland.
    Sasaki, Hiroshi
    Dept. of Ophthalmology, Kanazawa Medical University, Uchinada, Japan.
    Söderberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Jonasson, Fridbert
    Dept. of Ophthalmology, University of Iceland, Reykjavik, Iceland.
    The 7-year cumulative incidence of cornea guttata and morphological changes in the corneal endothelium in the Reykjavik Eye Study2013In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 91, no 3, p. 212-218Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine the corneal endothelium and establish the 7-year cumulativeincidence of cornea guttata (CG).

    Methods: Population-based prospective cohort study with 573 participants(third wave of the Reykjavik Eye Study (RES) in 2008). Four hundred and thirty-seven subjects had either right or left eyes available for analysis after excluding confounding eye conditions. The baseline for eyes at risk for developing CG is the second wave of the RES in 2001. Participants underwent specular microscopy and a standardized eye examination.

    Results: The cumulative 7-year incidence of CG in either eye was estimated as a 95% confidence interval for the expected value for both genders combined (15–23%), for males (8–18%) and for females (19–29%). In right eye only, the 7-year cumulative incidence for both genders combined was estimated to be 6–11%. For genders combined and for males only, the data indicated no correlation between 7-year cumulated incidence and age at baseline. In women, however, the change of 7-year incidence for CG in at least one eye appeared to be correlated to age at baseline. Reduction of endothelial cell density for corneas with CG at baseline was found [CI (0.95))132 ± 94].

    Conclusion: The cumulative 7-year incidence of primary central CG for a middle-aged and older Caucasian population without history of potentially confounding eye disease has been established. Women tend to have higher incidence if onset occurs at middle age. If CG is present, the cell density and the cell size variation decrease within a 7-year period.

  • 13775.
    Zoerner, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Department of Operative- and Intensive Care Medicine, Hallands Hospital Halmstad, Halmstad, Sweden.
    Novel Interventions in Cardiac Arrest: Targeted Temperature Management, Methylene Blue, S-PBN, Amiodarone, Milrinone and Esmolol,  Endothelin and Nitric Oxide In Porcine Resuscitation Models2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB).

    In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM.

    The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM.

    The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only.

    In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.

    List of papers
    1. Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
    Open this publication in new window or tab >>Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
    Show others...
    2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 8, p. 1073-1082Article in journal (Refereed) Published
    Abstract [en]

    Background

    Induced mild hypothermia and administration of methylene blue (MB) have proved to have neuroprotective effects in cardiopulmonary resuscitation (CPR); however, induction of hypothermia takes time. We set out to determine if MB administered during CPR could add to the histologic neuroprotective effect of hypothermia.

    Methods

    A piglet model of extended cardiac arrest (12 min of untreated cardiac arrest and 8 min of CPR) was used to assess possible additional neuroprotective effects of MB when administered during CPR before mild therapeutic hypothermia induced 30 min after restoration of spontaneous circulation (ROSC). Three groups were compared: C group (n = 8) received standard CPR; PH group (n = 8) received standard CPR but 30 min after ROSC these piglets were cooled to 34°C; the PH+MB group (n = 8) received an MB infusion 1 min after commencement of CPR and the same cooling protocol as the PH group. Three hours later, the animals were killed. Immediately after death, the brains were harvested pending histological and immunohistological analysis.

    Results

    Circulatory variables were similar in the groups except that cardiac output was greater in the PH+MB group 2–3 h after ROSC. Cerebral cortical neuronal injury and blood–brain barrier disruption was greatest in the C group and least in the MB group. The neuroprotective effect of MB and hypothermia was significantly greater than that of delayed hypothermia alone.

    Conclusion

    Administration of MB during CPR added to the short term neuroprotective effects of induced mild hypothermia induced 30 min after ROSC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-199854 (URN)10.1111/aas.12106 (DOI)000323075000017 ()23577658 (PubMedID)
    Available from: 2013-05-17 Created: 2013-05-17 Last updated: 2017-12-06Bibliographically approved
    2. Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
    Open this publication in new window or tab >>Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e64792-Article in journal (Refereed) Published
    Abstract [en]

    Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-200585 (URN)10.1371/journal.pone.0064792 (DOI)000319435600076 ()23717659 (PubMedID)
    Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
    3. Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
    Open this publication in new window or tab >>Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
    2014 (English)In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. METHODS: Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. RESULTS: Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. CONCLUSION: Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

    Keywords
    Amiodarone, cardiac arrest, ventricular fibrillation, hemorrhage, pigs
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-228547 (URN)10.1097/TA.0000000000000243 (DOI)000337145500011 ()
    Available from: 2014-07-17 Created: 2014-07-16 Last updated: 2015-02-03Bibliographically approved
    4. Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
    Open this publication in new window or tab >>Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    Methods: Twenty-six immature male piglets were subjected to 12 min VF followed by 8 min CPR. The treatment group (n=13) received i.v. boluses vasopressin 0.4 U∙kg−1, esmolol 250 μg∙kg−1 and milrinone 25 μg∙kg−1 after 13 min, followed by i.v. boluses esmolol 375 μg∙kg−1 and milrinone 25 μg∙kg−1 after 18 min and continuous esmolol 15 μg∙kg−1∙h−1 infusion during 180 min reperfusion, while controls (n=13) received equal amounts of vasopressin and saline. A 200J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200J defibrillation and bolus vasopressin 0.4 U∙kg−1 were administered in both groups. DC shocks at 360J were applied as one shot min−1 over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    Results: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (p<0.05). The treatment group received less norepinephrine (p<0.01) and had greater diuresis (p<0.01). There was no difference in survival between groups.

    Conclusions: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. 

    Keywords
    Cardiac arrest, resumption of spontaneous circulation, ROSC, milrinone, vasopressin, esmolol, I/R injury, reperfusion injury, cardioprotection, myocardial ischemia, epinephrine, resuscitation
    National Category
    Anesthesiology and Intensive Care Medical and Health Sciences
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-237869 (URN)
    Available from: 2014-12-06 Created: 2014-12-06 Last updated: 2015-06-11
  • 13776.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrestManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    Methods: Twenty-six immature male piglets were subjected to 12 min VF followed by 8 min CPR. The treatment group (n=13) received i.v. boluses vasopressin 0.4 U∙kg−1, esmolol 250 μg∙kg−1 and milrinone 25 μg∙kg−1 after 13 min, followed by i.v. boluses esmolol 375 μg∙kg−1 and milrinone 25 μg∙kg−1 after 18 min and continuous esmolol 15 μg∙kg−1∙h−1 infusion during 180 min reperfusion, while controls (n=13) received equal amounts of vasopressin and saline. A 200J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200J defibrillation and bolus vasopressin 0.4 U∙kg−1 were administered in both groups. DC shocks at 360J were applied as one shot min−1 over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    Results: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (p<0.05). The treatment group received less norepinephrine (p<0.01) and had greater diuresis (p<0.01). There was no difference in survival between groups.

    Conclusions: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. 

  • 13777.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest2015In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 4, p. 465-474Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    METHODS: A total of 26 immature male piglets were subjected to 12-min VF followed by 8-min CPR. The treatment group (n = 13) received i.v. (intravenous) boluses vasopressin 0.4 U/kg, esmolol 250 μg/kg and milrinone 25 μg/kg after 13 min, followed by i.v. boluses esmolol 375 μg/kg and milrinone 25 μg/kg after 18 min and continuous esmolol 15 μg/kg/h infusion during 180 min reperfusion, whereas controls (n = 13) received equal amounts of vasopressin and saline. A 200 J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200 J defibrillation and bolus vasopressin 0.4 U/kg would be administered in both groups. Direct current shocks at 360 J were applied as one shot per minute over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    RESULTS: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (P < 0.05). The treatment group received less norepinephrine (P < 0.01) and had greater diuresis (P < 0.01). There was no difference in survival between groups.

    CONCLUSION: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone.

  • 13778. Zoerner, Frank
    et al.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs2014In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. METHODS: Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. RESULTS: Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. CONCLUSION: Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

  • 13779.
    Zoerner, Frank
    et al.
    Department of Operative and Intensive Care Medicine, Hallands Hospital Halmstad, Halmstad, Sweden.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs2014In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, E-ISSN 2163-0763, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets.

    METHODS:

    Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation.

    RESULTS:

    Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group.

    CONCLUSION:

    Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

  • 13780.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cecile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e64792-Article in journal (Refereed)
    Abstract [en]

    Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

  • 13781. Zohari, Siamak
    et al.
    Gyarmati, Péter
    Ejdersund, Anneli
    Berglöf, Ulla
    Thorén, Peter
    Ehrenberg, Maria
    Czifra, György
    Belák, Sándor
    Waldenström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berg, Mikael
    Phylogenetic analysis of the non-structural (NS) gene of influenza A viruses isolated from mallards in Northern Europe in 20052008In: Virology Journal, ISSN 1743-422X, Vol. 5, p. 147-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the important role of the non-structural 1 (NS) gene of influenza A in virulence of the virus is well established, our knowledge about the extent of variation in the NS gene pool of influenza A viruses in their natural reservoirs in Europe is incomplete. In this study we determined the subtypes and prevalence of influenza A viruses present in mallards in Northern Europe and further analysed the NS gene of these isolates in order to obtain a more detailed knowledge about the genetic variation of NS gene of influenza A virus in their natural hosts. RESULTS: A total number of 45 influenza A viruses of different subtypes were studied. Eleven haemagglutinin- and nine neuraminidase subtypes in twelve combinations were found among the isolated viruses. Each NS gene reported here consisted of 890 nucleotides; there were no deletions or insertions. Phylogenetic analysis clearly shows that two distinct gene pools, corresponding to both NS allele A and B, were present at the same time in the same geographic location in the mallard populations in Northern Europe. A comparison of nucleotide sequences of isolated viruses revealed a substantial number of silent mutations, which results in high degree of homology in amino acid sequences. The degree of variation within the alleles is very low. In our study allele A viruses displays a maximum of 5% amino acid divergence while allele B viruses display only 2% amino acid divergence. All the viruses isolated from mallards in Northern Europe possessed the typical avian ESEV amino acid sequence at the C-terminal end of the NS1 protein. CONCLUSION: Our finding indicates the existence of a large reservoir of different influenza A viruses in mallards population in Northern Europe. Although our phylogenetic analysis clearly shows that two distinct gene pools, corresponding to both NS allele A and B, were present in the mallards populations in Northern Europe, allele B viruses appear to be less common in natural host species than allele A, comprising only about 13% of the isolates sequenced in this study.

  • 13782. Zoltowska Nilsson, Anna Maria
    et al.
    Lei, Ying
    Adner, Mikael
    Nilsson, G P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden .
    Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma2018In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 3, p. L484-L492Article in journal (Refereed)
    Abstract [en]

    Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated to the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM) induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh+MC-WT) or ST2 deficient bone marrow derived mast cells (Wsh+MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh+MC-ST2KO compared to Wsh+MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in BALF and lung, the aggravated AHR in Wsh+MC-ST2KO mice, seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in bronchoalveolar lavage fluid. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role in the development of AHR.

  • 13783.
    Zorzan, Eleonora
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Sissi, Claudia
    Univ Padua, Dept Pharmaceut & Pharmacol Sci, Padua, Italy.
    Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17107Article in journal (Refereed)
    Abstract [en]

    G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 mu M) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds.

  • 13784.
    Zorzet, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersen, Jytte Mark
    Nilsson, Annika I
    Møller, Niels Frimodt
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Compensatory mutations in agrC partly restore fitness in vitro to peptide deformylase inhibitor-resistant Staphylococcus aureus2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 8, p. 1835-1842Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    To determine how the fitness cost of deformylase inhibitor resistance conferred by fmt mutations can be genetically compensated.

    METHODS

    Resistant mutants were isolated and characterized with regard to their growth rates in vitro and in neutropenic mice, MIC and DNA sequence. Faster-growing compensated mutants were isolated by serial passage in culture medium, and for a subset of the resistant and compensated mutants whole-genome sequencing was performed.

    RESULTS

    Staphylococcus aureus mutants resistant to the peptide deformylase inhibitor actinonin had mutations in the fmt gene that conferred high-level actinonin resistance and reduced bacterial growth rate. Compensated mutants that remained fully resistant to actinonin and showed increased growth rates appeared within 30-60 generations of growth. Whole-genome sequencing and localized DNA sequencing of mutated candidate genes showed that alterations in the gene agrC were present in the majority of compensated strains. Resistant and compensated mutants grew at similar rates as the wild-type in a mouse thigh infection model.

    CONCLUSIONS

    Resistance to deformylase inhibitors due to fmt mutations reduces bacterial growth rates, but these costs can be reduced by mutations in the agrC gene. Mutants defective in fmt (with or without compensatory agrC mutations) grew well in an animal model, implying that they can also cause infection in a host.

  • 13785.
    Zubarev, Roman Alexandrovich
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Nuclear and Particle Physics.
    Mass spectrometry of biopolymers based on ion-induced desorption1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Various aspects of biopolymer molecular characterization by their molecular masses havebeen studied, with emphasis on ion-induced desorption and time-of-flight mass Spectrometry(TOF MS). Limitations of the average-isotopic mass concept, as well as the utility ofaccurate monoisotopic mass measurements for deriving amino-acid and elementalcompositions, are discussed. A new sufficiency criterion of mass accuracy for peptidecharacterization is formulated. Experimentally achievable mass accuracy in TOF MS basedon MeV-ion induced desorption is studied. A new method of deriving peptide structuralinformation using partial acid hydrolysis and accurately measured hydrolysis fragmentmasses is developed.

    Secondary ion formation mechanisms in ion-induced desorption have been studiedusing keV and MeV atomic and polyatomic projectiles. In the MeV-atomic-ion mode, kineticenergies and formation times of secondary ions have been investigated. The results suggestdelayed (10-10-10-9s) formation of target-specific ions in the gas phase. A concept ofexothermic matrices has been tested experimentally. A new effective matrix for peptides andproteins, HMX, has been found. In the keV-atomic-ion mode, target-specific ions are foundto possess kinetic energy distributions that are characteristic for gas-phase ion formation. Thissuggests that the ion-formation mechanisms may be similar in both MeV and keV modes.Polyatomic ion-induced desorption has been studied using multiply-charged proteinprojectiles. The total negative ion yield is found to depend primarily on the surface density ofthe deposited energy. The utility of these findings for mass determination of mixturecomponents from complicated electrospray-ionization spectra is demonstrated.

  • 13786.
    Zucca, Emanuele
    et al.
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland;Inst Oncol Res, Bellinzona, Switzerland;Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Rondeau, Stephanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vanazzi, Anna
    European Inst Oncol IRCCS, Clin Hematooncol, Milan, Italy.
    Ostenstad, Bjorn
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Mey, Ulrich J. M.
    Kantonsspital Graubunden, Med Oncol & Hematol, Chur, Switzerland.
    Rauch, Daniel
    Spital Thun Simmenthal, Div Oncol, Thun, Switzerland.
    Wahlin, Bjorn E.
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Hitz, Felicitas
    Kantonsspital St Gallen, Oncol Hematol, St Gallen, Switzerland.
    Hernberg, Micaela
    Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Oncol, Helsinki, Finland.
    Johansson, Ann-Sofie
    Norrlands Univ Sjukhus, Dept Oncol, Umea, Sweden.
    Brown, Peter de Nully
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ferreri, Andres J. M.
    IRCCS San Raffaele Sci Inst, Unit Lymphoid Malignancies, Milan, Italy.
    Lohri, Andreas
    Med Univ Clin, Dept Oncol Hematol, Liestal, Switzerland.
    Novak, Urban
    Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Zander, Thilo
    Luzerner Kantonsspital, Dept Oncol, Luzern, Switzerland.
    Bersvendsen, Hanne
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway.
    Bargetzi, Mario
    Kantonsspital Aarau, Div Hematol Oncol, Aarau, Switzerland.
    Mingrone, Walter
    Kantonsspital Olten, Dept Med Oncol, Olten, Switzerland.
    Krasniqi, Fatime
    Univ Hosp Basel, Dept Oncol, Basel, Switzerland.
    Dirnhofer, Stefan
    Univ Hosp Basel, Inst Pathol, Basel, Switzerland.
    Hayoz, Stefanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Hawle, Hanne
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vilei, Simona Berardi
    SAKK Coordinating Ctr, Bern, Switzerland.
    Ghielmini, Michele
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland.
    Kimby, Eva
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Caspar, Clemens
    Koberle, Dieter
    Zenhausern, Reinhard
    Jost, Lorenz M.
    Mach, Nicolas
    Voegeli, Michele
    Tscherry, Georg
    Fischer, Natalie
    Burkhard, Roger
    Schmid, Mathias
    Panagiotis, Samaras
    Munksgaard, Lars
    Vasala, Kaija
    Lehtinen, Tuula
    Jyrkkio, Sirkku
    Ekanger, Roald
    Rolke, Jurgen
    Meyer, Peter
    Maisenholder, Martin
    Eidem, Monika
    Radlund, Anders
    Lagerlof, Ingemar
    Brandefors, Lena
    Ola, Linde Prime N.
    Arnljots, Kristina
    Strandberg, Maria
    Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy2019In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 134, no 4, p. 353-362Article in journal (Refereed)
    Abstract [en]

    The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m(2) IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (>= 90%). Toxicity grade >= 3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored.

  • 13787. Zucchelli, Giulio
    et al.
    Di Cori, Andrea
    Segreti, Luca
    Laroche, Cécile
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Kutarski, Andrzej
    Regoli, François
    Butter, Christian
    Defaye, Pascal
    Pasquié, Jean Luc
    Auricchio, Angelo
    Maggioni, Aldo P
    Bongiorni, Maria Grazia
    Major cardiac and vascular complications after transvenous lead extraction: acute outcome and predictive factors from the ESC-EHRA ELECTRa (European Lead Extraction ConTRolled) registry2019In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 21, no 5, p. 771-780Article in journal (Refereed)
    Abstract [en]

    Aims: We aimed at describing outcomes and predictors of cardiac avulsion or tear (CA/T) with tamponade and vascular avulsion or tear (VA/T) after transvenous lead extraction (TLE) in the ESC-EHRA European Lead Extraction ConTRolled (ELECTRa) registry.

    Methods and results: A total of 3555 consecutive patients of whom 3510 underwent TLE at 73 centres in 19 European countries were enrolled. Among 58 patients (1.7%) with procedure-related major complications, 49 (84.5%) patients (30 CA/T and 19 VA/T) presented cardiovascular complications requiring pericardiocentesis, chest tube positioning and/or surgical repair. The mortality was 20% in patients with tamponade due to CA/T and 31.6% in patients with VA/T. Pericardiocentesis as first manoeuvre followed by rescue surgical repair was highly effective in case of CA/T (93.8%). At multivariate analysis, CA/T with tamponade was more common in RIATA lead extraction, female patients, leads with a mean dwelling time more than 10 years, and when ≥3 leads were extracted or multiple sheaths required. Occlusion or critical stenosis of superior venous access and the leads mean dwelling time more than 10 years were independent predictors for VA/T, while mechanical dilatation was an independent predictor of a lower incidence of this complication as compared to the use of powered sheaths.

    Conclusions: In the ELECTRa registry, RIATA lead extraction and superior venous access occlusion/thrombosis are two new independent predictors for cardiac tamponade and major vascular complications, respectively. The use of mechanical sheaths seems to be associated with a lower incidence of VA/T. A strategy of pericardiocentesis followed by a rescue surgical approach seems to be reasonable in order to treat a CA/T with tamponade.

  • 13788.
    Zupancic, Tina
    et al.
    National Institute of Chemistry, Ljubljana.
    Sersa, Gregor
    Institute of Oncology, Ljubljana.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lane, Ellen Birgitte
    A*Star Institute of Medical Biology, Singapore.
    Herrmann, Harald
    German Cancer Research Center (DKFZ), B065 Functional Architecture of the Cell.
    Komel, Radovan
    University of Ljubljana, Faculty of Medicine, Medical Centre for Molecular Biology.
    Liovic, Mirjana
    University of Ljubljana, Faculty of Medicine, Medical Centre for Molecular Biology.
    Keratin gene mutations influence the keratinocyte response to DNA damage and cytokine induced apoptosis2017In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 309, no 7, p. 587-593Article in journal (Refereed)
    Abstract [en]

    The keratin filament cytoskeleton is vital to the normal function of epithelial cells. It provides structural support and regulates different aspects of cell metabolism. Mutations in keratins 5 and 14 cause a skin fragility disorder, epidermolysis bullosa simplex (EBS). Patients with severe EBS have an increased cumulative risk for basal cell carcinoma. In this study, we tested how keratin 5 and 14 mutant EBS patient-derived keratinocytes behave in the face of two different types of stressors that are able to induce cell death: ionizing radiation and cytokines TNF-alpha and TRAIL. The data point out to a substantial difference between how normal and keratin mutant keratinocytes deal with such stresses. When case of DNA damage, the ATM/Chk2-pathway is one of the two main tracks that can prevent the progression of mitosis and so allow repair. This was altered in all investigated keratin mutants with a particular down-regulation of the activated form of checkpoint kinase 2 (pChk2). Keratin mutants also appear less sensitive than normal cells to treatment with TNF-alpha or TRAIL, and this may be linked to the up-regulation of two pro-survival proteins, Bcl-2 and FLIP. Such changes are likely to have a profound effect on mutant keratinocytes ability to survive and withstand stress, and in theory this may be also a contributing factor to cell transformation.

  • 13789. Zwang, Julien
    et al.
    D'Alessandro, Umberto
    MRC Unit, Banjul, Gambia;London Sch Hyg & Trop Med, London, England;Inst Trop Med, Antwerp, Belgium.
    Ndiaye, Jean-Louis
    Cheikh Anta Diop Univ, Dept Parasitol, Fac Med, Dakar, Senegal.
    Djimde, Abdoulaye A.
    Univ Sci Tech & Technol Bamako, Fac Pharm, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Karema, Corine
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland;Univ Basel, Basel, Switzerland.
    Olliaro, Piero L.
    Special Programme Res & Training Trop Dis WHO TDR, 20 Ave Appia, CH-1211 Geneva, Switzerland;Univ Oxford, Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford OX3 7LJ, England;Univ Basel, Basel, Switzerland.
    Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa2017In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 17, article id 443Article in journal (Refereed)
    Abstract [en]

    Background: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. Methods: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. Results: Eight thousand eight hundred ninety-seven patients (77.0% < 5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5' s had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 mu l) than older subjects (2784 mu l). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5' s the estimated nadir was similar to 35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach + 13.8% compared to baseline. Severe anaemia (< 5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. Conclusion: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment.

  • 13790.
    Ängeby, Karin
    et al.
    Cty Council Varmland, Womens Dept, Karlstad, Sweden.;Cty Council Varmland, Clin Res Ctr, Karlstad, Sweden.;Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden..
    Wilde-Larsson, Bodil
    Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden.;Inland Norway Univ Appl Sci, Fac Publ Hlth, Dept Nursing, Elverum, Norway..
    Hildingsson, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Mid Sweden Univ, Dept Nursing Sci, Sundsvall, Sweden..
    Sandin-Bojo, Ann-Kristin
    Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden..
    Prevalence of Prolonged Latent Phase and Labor Outcomes: Review of Birth Records in a Swedish Population2018In: Journal of midwifery & women's health, ISSN 1526-9523, E-ISSN 1542-2011, Vol. 63, no 1, p. 33-44Article, review/survey (Refereed)
    Abstract [en]

    IntroductionThe prevalence of a prolonged latent phase of labor has been described as ranging from 5% to 6.5% in previous research. The aim of this study was to describe the prevalence of the prolonged latent phase of 18 hours or more, based on women's report, in women intending vaginal birth and who had spontaneous onset of labor. An additional aim was to compare the incidence of obstetric interventions, and the labor and neonatal outcomes in women with and without a prolonged latent phase. MethodsA descriptive and comparative study was performed in a mid-sized hospital in western Sweden. The sample consisted of 1343 birth records of women who intended vaginal births and who had spontaneous onset of labor at 37 or more weeks' gestation during a one-year period (2013-2014). Background characteristics, obstetric interventions, and labor and neonatal outcomes were compared between women with latent phases lasting less than 18 hours and 18 hours or more, based on women's self-report. Odds ratios with 95% confidence intervals were calculated for the different exposure variables. ResultsA prolonged latent phase lasting 18 hours or more occurred in 23% of all births analyzed (n = 1343). A prolonged latent phase was more common among nulliparous women (29.2%) but also common for multiparous women (17%). Nulliparous and multiparous women who experienced a prolonged latent phase were more often exposed to amniotomy during latent phase. For nulliparous women, the adjusted odds ratio (aOR) was 11.57 (95% confidence interval [CI], 5.25-25.51) and for multiparous women the aOR was 18.73 (95% CI, 9.06-38.69). Similarly, amniotomy during active phase was more common for both nulliparous and multiparous women who experienced a prolonged latent phase (aOR, 4.05; 95% CI, 2.53-6.47 and aOR, 3.93; 95% CI, 2.43-6.37, respectively). Women with latent phases of 18 hours or more, more often experienced augmentation of labor during all phases, especially during latent phase. For nulliparous women, the aOR was 10.13 (95% CI, 2.82-36.39) and for multiparous women, aOR was11.9 (95% CI, 3.69-38.71). A prolonged latent phase was associated with more instrumental vaginal births for multiparas (aOR, 2.58; 95% CI, 1.27-5.26) and emergency cesarean regardless of parity (nulliparous women: aOR, 3.21; 95% CI, 1.08-9.50 and multiparous women: aOR, 3.93; 95% CI, 1.67-9.26). DiscussionBased on women's self-report, the prevalence of a prolonged latent phase in women at term who planned a vaginal birth and had spontaneous onset of labor was higher than previously reported. Women with a prolonged latent phase were more likely to receive obstetric interventions. Assisted vaginal birth was more common for nulliparous women with prolonged latent phase and emergency cesarean occurred more frequently for both nulliparous women and multiparous women with a prolonged latent phase.

  • 13791.
    Ärfström, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Determining genetic relatedness in honey bees, Apis mellifera, using microsatellite analysis2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The world population is growing and becoming more connected whereby disease transmission is becoming an increasingly important issue. To learn more about disease spread, honey bees (Apis mellifera) could provide an animal-model system for network transmission. The honey bees have both an individual and a social defense against pathogens, their diseases are well studied and they enable studies on hundreds of individuals. The genetic relatedness is believed to be one of many important factors for disease transmission. A hypothesis is that the more closely related the honey bees are the more interactions will occur. In this study, the genetic relatedness in honey bees was analyzed by the use of microsatellite-DNA primers, in a multiplex PCR. Of the 18 microsatellite-DNA primers that were evaluated, the loci HB-C16-05, A007, AC006, HB-C16-02, AP043 and UN351 showed the highest variation. However, when applied on a larger material, the PCR-products did not yield any chromatograms that were possible to score. Many factors possibly affecting the result are discussed and further efforts will be made to improve the method and thereby determine genetic relatedness.

  • 13792. Ärlestig, Lisbeth
    et al.
    Mullazehi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kokkonen, Heidi
    Rocklöv, Joacim
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rantapää Dahlqvist, Solbritt
    Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 825-829Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.

    OBJECTIVE:

    To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.'

    METHODS:

    51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

    RESULTS:

    The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

    CONCLUSIONS:

    All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

  • 13793.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cathepsin S as a biomarker: where are we now and what are the future challenges?2012In: Biomarkers in medicine, ISSN 1752-0371, Vol. 6, no 1, p. 9-11Article in journal (Refereed)
  • 13794.
    Ärnlöv, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Left Ventricular Function in Elderly Men: Metabolic, Hormonal, Genetic and Prognostic Implications2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry.

    Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years.

    In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

  • 13795.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Tobias E
    Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community2013In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 83, no 1, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Fibroblast growth factor-23 (FGF23), a regulator of mineral metabolism, has been linked to cardiovascular disease in chronic kidney disease. As community-based data of the longitudinal association between FGF23 and cardiovascular events are lacking, we investigated a possible relationship in 727 men of the Uppsala Longitudinal Study of Adult Men population-based cohort (mean age 77 years). During a median follow-up of 9.7 years, 110 participants died of cardiovascular causes. In Cox regression models adjusted for age and established cardiovascular risk factors, higher serum FGF23 was associated with a significantly increased risk for cardiovascular mortality (hazard ratio (HR) per increased s.d. of 1.36). This relationship remained significant, albeit attenuated, after adjustment for glomerular filtration rate (GFR) (HR 1.21). FGF23 was also associated with all-cause mortality, although the association was weaker than that with cardiovascular mortality, and it was nonsignificant in fully adjusted multivariate models. Spline analysis suggested a log-linear relationship between FGF23 and outcome. Participants with a combination of high FGF23 (>60 pg/ml), low GFR (<60 ml/min), and micro-/macro-albuminuria (albumin/creatinine ratio above 3 mg/ml) had an almost eightfold increased risk compared with participants without these abnormalities. Thus, a higher FGF23 level is associated with an increased cardiovascular mortality risk in the community. Clinical trials are needed to determine whether FGF23 is a modifiable risk factor.

  • 13796.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carrero, J. J.
    Karolinska Inst, Stockholm, Sweden..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stenemo, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carlsson, A. C.
    Karolinska Inst, Stockholm, Sweden..
    Discovery and replication of new risk markers for 5-year kidney function decline using a targeted multiplex proteomics chip2016Conference paper (Refereed)
  • 13797.
    Åberg, Anna Cristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gender comparisons of function-related dependence pain and insecurity in geriatric rehabilitation2006In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 38, no 1, p. 73-79Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate possible gender differences regarding the effect of intervention in geriatric rehabilitation, expressed in terms of change in function-related dependence, pain and insecurity. DESIGN: Comparative study. PARTICIPANTS: A total of 110 women and 44 men undergoing geriatric rehabilitation. METHODS: Performance-based assessments with use of the General Motor Function assessment scale. Non-parametric statistics were mainly used. RESULTS: The women showed higher degrees of function-related dependence, pain and insecurity on admission than the men. Both women and men displayed significant improvement in all 3 variables during the rehabilitation period. However, the positive changes regarding pain and insecurity were according to the analyses of systematic group changes, at a low degree among the men, probably because of the low levels on admission. Gender comparisons of proportions with positive intervention outcome indicated that a significantly larger proportion of the women showed a positive treatment effect after intervention, with a difference in recovery of 19% in dependence, 23% in pain and 33% in insecurity (p<0.05). CONCLUSIONS: Gender differences in disability, with higher degrees of function-related dependence, pain and insecurity among women on admission for geriatric rehabilitation, can be diminished during the rehabilitation period. These promising results may have relevance for the public health of the elderly population.

  • 13798.
    Åberg, Anna Cristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ehrenberg, Anna
    Dalarna Univ, Sch Educ Hlth & Social Studies, S-79188 Falun, Sweden.;Orebro Univ, Sch Hlth Sci, Orebro, Sweden..
    Inpatient geriatric care in Sweden-Important factors from an inter-disciplinary team perspective2017In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 72, p. 113-120Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to describe factors of importance for the quality of inpatient geriatric care from an inter-disciplinary team perspective, an area that has not been previously studied to our knowledge. The study design was qualitative descriptive with data being collected from focus-group interviews with members of geriatric care teams. The data collection was conducted at a Swedish university hospital with 69 beds for geriatric care. It comprised five group interviews with a total of 32 staff members, including representatives of all the seven professions working with geriatric care. Data was analysed using qualitative content analysis and a thematic framework approach. Three main themes were identified as being perceived as characterising important factors essential for quality geriatric care: Interactive assessment processes, A holistic care approach, and Proactive non-hierarchical interaction. Aspects of Time and Goal-Orientation were additionally running like common threads through these themes and informed them. Accessibility, open communication, and staff continuity were experienced as prerequisites for well-functioning teamwork. Including patients and relatives in care planning and implementation was seen as essential for good care, but was at risk due to budget cuts that imposed shortened hospital stays. To meet the care demands of the growing population of older frail people, more specialised team-based care according to the concept of Comprehensive Geriatric Assessment - which is possibly best provided by older-friendly hospitals - appears as a constructive solution for reaching high degrees of both staff and patient satisfaction in geriatric care. More research is needed in this area.

  • 13799.
    Åberg, Anna Cristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sidenvall, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Hepworth, Mike
    O'Reilly, Karen
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    On loss of activity and independence, adaptation improves life satisfaction in old age: a qualitative study of patients' perceptions2005In: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 14, no 4, p. 1111-1125Article in journal (Refereed)
    Abstract [en]

    The purpose was to improve the understanding of factors are perceived by elderly people as important for their life satisfaction, during and after rehabilitation. Fifteen persons aged 80-94 years were interviewed while in hospital and on two follow-up occasions after discharge. Assessment of motor function using the General Motor Function assessment scale was used for descriptive purposes. Three themes emerged as important for life satisfaction: activity, independence and adaptation. Activity and independence were considered significant for life satisfaction. Basic activity preferences were related to care of one's own body and to social contacts. Control and influence over help and services were regarded as important. Different strategies for adaptation to the consequences of disease were used: reorganisation, interaction with caregivers, mental adaptation and mental activities (used as pastime and escape). Those with declined motor functions limited their activity preferences. A key finding was that pleasant past memories were actively recalled in an effort to achieve current life satisfaction. This adaptation strategy created a sense of life satisfaction, however with a potential risk for concealing dissatisfaction with conditions that might otherwise be correctable. Strategies for improving life satisfaction among old people in rehabilitation are suggested.

  • 13800.
    Åberg, Joakim
    et al.
    Orebro Univ, Sch Med Sci, S-70185 Orebro, Sweden.
    Hasselgren, Mikael
    Orebro Univ, Sch Med Sci, S-70185 Orebro, Sweden.
    Montgomery, Scott
    Orebro Univ, Clin Epidemiol & Biostat, S-70182 Orebro, Sweden;Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden;UCL, Dept Epidemiol & Publ Hlth, London, England.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Sundh, Josefin
    Orebro Univ, Sch Med Sci, Dept Resp Med, S-70185 Orebro, Sweden.
    Sex-related differences in management of Swedish patients with a clinical diagnosis of chronic obstructive pulmonary disease2019In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 14, p. 961-969Article in journal (Refereed)
    Abstract [en]

    Purpose: Women with chronic obstructive pulmonary disease (COPD) have more symptoms, more exacerbations, lower health status scores, and more comorbidity. However, it is unclear whether management of COPD differs by sex. The aim of the study was to investigate differences by sex in the care of patients with COPD. Patients and methods: The population included 1329 primary and secondary care patients with a doctor ' s diagnosis of COPD in central Sweden. Data were obtained from patient questionnaires and included patient characteristics and data on achieved COPD care. Analyses included cross-tabulations, chi-squared test and multiple logistic regression using several measures in COPD management as dependent variables, female sex as independent variable, and with adjustment for age groups, previous exacerbations, COPD Assessment Test, level of dyspnea assessed by the modified Medical Research Council scale, comorbid conditions, self-rated moderate/severe disease, level of education and body mass index. Results: Women were more likely to receive triple therapy (OR 1.86 (95% CI 1.38-2.51)), to have any maintenance treatment (OR 1.82 (95% CI 1.31-2.55)), to be on sick leave (OR 2.16 (95% CI 1.19-3.93)), to have received smoking cessation support (OR 1.80 (95% CI 1.18-2.75)) and to have had pneumococcal vaccination (OR 1.82 (95% CI 1.37-2.43)), all independently of age, severity of disease or other potential confounders. Conclusion: Management of COPD differs by sex, with women being more actively managed than men. It is unclear whether this is due to patient-or care-related factors.

273274275276277278279 13751 - 13800 of 13955
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf