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  • 1.
    Abdalla, Maie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal University, Egypt.
    Landerholm, Kalle
    Ryhov County Hospital, Sweden.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Andersson, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov County Hospital, Sweden.
    Myrelid, Pär
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Risk of Rectal Cancer After Colectomy for Patients With Ulcerative Colitis: A National Cohort Study2017In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 15, no 7, p. 1055-1060, article id e2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND amp; AIMS: Patients with ulcerative colitis (UC) have an increased risk of rectal cancer, therefore reconstruction with an ileal pouch-anal anastomosis (IPAA) generally is preferred to an ileorectal anastomosis (IRA) after subtotal colectomy. Similarly, completion proctectomy is recommended for patients with ileostomy and a diverted rectum, although this approach has been questioned because anti-inflammatory agents might reduce cancer risk. We performed a national cohort study in Sweden to assess the risk of rectal cancer in patients with UC who have an IRA, IPAA, or diverted rectum after subtotal colectomy.

    METHODS: We collected data from the Swedish National Patient Register for a cohort of 5886 patients with UC who underwent subtotal colectomy with an IRA, IPAA, or diverted rectum from 1964 through 2010. Patients who developed rectal cancer were identified from the Swedish National Cancer Register. The risk of rectal cancer was compared between this cohort and the general population by standardized incidence ratio analysis.

    RESULTS: Rectal cancer occurred in 20 of 1112 patients (1.8%) who received IRA, 1 of 1796 patients (0.06%) who received an IPAA, and 25 of 4358 patients (0.6%) with a diverted rectum. Standardized incidence ratios for rectal cancer were 8.7 in patients with an IRA, 0.4 in patients with an IPAA, and 3.8 in patients with a diverted rectum. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio, 6.12), and colonic severe dysplasia or cancer before subtotal colectomy in patients with a diverted rectum (hazard ratio, 3.67).

    CONCLUSIONS: In an analysis of the Swedish National Patient Register, we found that the risk for rectal cancer after colectomy in patients with UC is low, in relative and absolute terms, after reconstruction with an IPAA. An IRA and diverted rectum are associated with an increased risk of rectal cancer, compared with the general population, but the absolute risk is low. Patients and their health care providers should consider these findings in making decisions to leave the rectum intact, perform completion proctectomy, or reconstruct the colon with an IRA or IPAA.

  • 2.
    Abdelrahman, Islam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Validation of the burn intervention score in a National Burn Centre2018In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, no 5, p. 1159-1166Article in journal (Refereed)
    Abstract [en]

    The Linköping burn score has been used for two decades to calculate the cost to the hospital of each burned patient. Our aim was to validate the Burn Score in a dedicated Burn Centre by analysing the associations with burn-specific factors: percentage of total body surface area burned (TBSA%), cause of injury, patients referred from other (non-specialist) centres, and survival, to find out which of these factors resulted in higher scores. Our second aim was to analyse the variation in scores of each category of care (surveillance, respiration, circulation, wound care, mobilisation, laboratory tests, infusions, and operation).

    We made a retrospective analysis of all burned patients admitted during the period 2000–15. Multivariable regression models were used to analyse predictive factors for an increased daily burn score, the cumulative burn score (the sum of the daily burn scores for each patient) and the total burn score (total sum of burn scores for the whole group throughout the study period) in addition to sub-analysis of the different categories of care that make up the burn score.

    We retrieved 22 301 daily recordings for inpatients. Mobilisation and care of the wound accounted for more than half of the total burn score during the study. Increased TBSA% and age over 45 years were associated with increased cumulative (model R2 0.43, p < 0.001) and daily (model R2 0.61, p < 0.001) burn scores. Patients who died had higher daily burn scores, while the cumulative burn score decreased with shorter duration of hospital stay (p < 0.001).

    To our knowledge this is the first long term analysis and validation of a system for scoring burn interventions in patients with burns that explores its association with the factors important for outcome. Calculations of costs are based on the score, and it provides an indicator of the nurses’ workload. It also gives important information about the different dimensions of the care provided from thorough investigation of the scores for each category.

  • 3.
    Abdelrahman, Islam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Olofsson, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Division of overall duration of stay into operative stay and postoperative stay improves the overall estimate as a measure of quality of outcome in burn care.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174579Article in journal (Refereed)
    Abstract [en]

    Patients and Methods: Surgically managed burn patients admitted between 2010-14 were included. Operative stay was defined as the time from admission until the last operation, postoperative stay as the time from the last operation until discharge. The difference in variation was analysed with F-test. A retrospective review of medical records was done to explore reasons for extended postoperative stay. Multivariable regression was used to assess factors associated with operative stay and postoperative stay.less thanbr /greater thanResults: Operative stay/TBSA% showed less variation than total duration/TBSA% (F test = 2.38, pless than0.01). The size of the burn, and the number of operations, were the independent factors that influenced operative stay (R2 0.65). Except for the size of the burn other factors were associated with duration of postoperative stay: wound related, psychological and other medical causes, advanced medical support, and accommodation arrangements before discharge, of which the two last were the most important with an increase of (mean) 12 and 17 days (pless than0.001, R2 0.51).less thanbr /greater thanConclusion: Adjusted operative stay showed less variation than total hospital stay and thus can be considered a more accurate outcome measure for surgically managed burns. The size of burn and number of operations are the factors affecting this outcome measure.

  • 4.
    Abdelrahman, Islam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. a Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Improvement in mortality at a National Burn Centre since 2000: Was it the result of increased resources?2017In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 96, no 25, article id e6727Article in journal (Refereed)
    Abstract [en]

    Abstract The aim of this study was to find out whether the charging costs (calculated using interventional burn score) increased as mortality decreased. During the last 2 decades, mortality has declined significantly in the Linköping Burn Centre. The burn score that we use has been validated as a measure of workload and is used to calculate the charging costs of each burned patient. We compared the charging costs and mortality in 2 time periods (2000–2007 and 2008–2015). A total of 1363 admissions were included. We investigated the change in the burn score, as a surrogate for total costs per patient. Multivariable regression was used to analyze risk-adjusted mortality and burn score. The median total body surface area % (TBSA%) was 6.5% (10–90 centile 1.0–31.0), age 33 years (1.3–72.2), duration of stay/ TBSA% was 1.4 days (0.3–5.3), and 960 (70%) were males. Crude mortality declined from 7.5% in 2000–2007 to 3.4% in 2008–2015, whereas the cumulative burn score was not increased (P=.08). Regression analysis showed that risk-adjusted mortality decreased (odds ratio 0.42, P=.02), whereas the adjusted burn score did not change (P=.14, model R2 0.86). Mortality decreased but there was no increase in the daily use of resources as measured by the interventional burn score. The data suggest that the improvements in quality obtained have been achieved within present routines for care of patients (multidisciplinary/ orientated to patients’ safety).

    Abbreviation: TBSA% = total body surface area %.

  • 5.
    Abdelrahman, Islam Mohamedy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Ismailia, Egypt.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Response to comments on: A prospective randomized cost billing comparison of local fasciocutaneous perforator versus free Gracilis flap reconstruction for lower limb in a developing economy2017In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 70, no 9, p. 1307-1308Article in journal (Other academic)
  • 6.
    Abdelrahman, Islam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Mossaad, Bassem
    Plastic Surgery Unit, Surgery Department Suez, Canal University, Ismailia, Egypt.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Evaluation of Glandular Liposculpture as a Single Treatment for Grades I and II Gynaecomastia2018In: Aesthetic Plastic Surgery, ISSN 0364-216X, E-ISSN 1432-5241, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Background

    Gynaecomastia is a benign enlargement of the male breast, of which the psychological burden on the patient can be considerable, with the increased risk of disorders such as depression, anxiety, and social phobia. Minimal scarring can be achieved by liposuction alone, though it is known to have a limited effect on the dense glandular and fibroconnective tissues. We know of few studies published on “liposuction alone”, so we designed this study to evaluate the outcome of combining liposuction with glandular liposculpturing through two axillary incisions as a single treatment for the management of grades I and II gynaecomastia.

    Methods

    We made a retrospective analysis of 18 patients with grade I or II gynaecomastia who were operated on by combined liposuction and glandular liposculpturing using a fat disruptor cannula, without glandular excision, during the period 2014–2016. Patient satisfaction was assessed using the Breast Evaluation Questionnaire (BEQ), which is a 5-point Likert scale (1 = very dissatisfied; 2 = dissatisfied; 3 = neither; 4 = satisfied; 5 = very satisfied). The post-operative aesthetic appearance of the chest was evaluated by five independent observers on a scale from 1 to 5 (5 = considerable improvement).

    Results

    The patient mean (SD) overall satisfaction score was 4.7 (0.7), in which 92% of the responders were “satisfied” to “very satisfied”. The mean (SD) BEQ for all questions answered increased from 2.1 (0.2) “dissatisfied” preoperatively to 4.1 (0.2) “satisfied” post-operatively. The observers’ mean (SD) rate for the improvement in the shape of the front chest wall was 4.1 (0.7). No haematomas were recorded, one patient developed a wound infection, and two patients complained of remnants of tissue. The median (IQR) body mass index was 27.4 (26.7–29.4), 11 patients had gynaecomastia grade I, and 7 patients grade II. The median (IQR) volume of aspirated fat was 700 ml (650–800), operating time was 67 (65–75) minutes, 14 patients had general anaesthesia, and hospital charges were US$ 538 (481–594).

    Conclusions

    Combined liposuction and liposculpturing using the fat disruptor cannula resulted in satisfied patients and acceptable outcomes according to the observers’ ratings. It could be a useful alternative with an outcome that corresponds to that of more expensive methods.

  • 7.
    Aboelnaga, Ahmed
    et al.
    Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Adly, Osama A.
    Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Elbadawy, Mohamed A.
    Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Abbas, Ashraf H.
    Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Abdelrahman, Islam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Salah, Omar
    Plastic Surgery Unit, Surgery Department, Suez Canal University, Egypt.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Microbial cellulose dressing compared with silver sulphadiazine for the treatment of partial thickness burns: A prospective, randomised, clinical trial2018In: Burns, ISSN 0305-4179, E-ISSN 1879-1409Article in journal (Refereed)
    Abstract [en]

    Background

    The current treatment for partial thickness burns at the trial site is silver sulphadiazine, as it minimises bacterial colonisation of wounds. Its deleterious effect on wound healing, together with the need for repeated, often painful, procedures, has brought about the search for a better treatment. Microbial cellulose has shown promising results that avoid these disadvantages. The aim of this study was therefore to compare microbial cellulose with silver sulphadiazine as a dressing for partial thickness burns.

    Method

    All patients who presented with partial thickness (superficial and deep dermal) burns from October 2014 to October 2016 were screened for this randomised clinical trial. Twenty patients were included in each group: the cellulose group was treated with microbial cellulose sheets and the control group with silver sulphadiazine cream 10 mg/g. The wound was evaluated every third day. Pain was assessed using the Face, Legs, Activity, Cry, Consolability (FLACC) scale during and after each procedure. Other variables recorded were age, sex, percentage total body surface area burned (TBSA%), clinical signs of infection, time for epithelialisation and hospital stay. Linear multivariable regression was used to analyse the significance of differences between the treatment groups by adjusting for the size and depth of the burn, and the patient’s age.

    Results

    Median TBSA% was 9% (IQR 5.5–12.5). The median number of dressing changes was 1 (IQR 1–2) in the cellulose group, which was lower than that in the control group (median 9.5, IQR 6–16) (p < 0.001). Multivariable regression analysis showed that the group treated with microbial cellulose spent 6.3 (95% CI 0.2–12.5) fewer days in hospital (p = 0.04), had a mean score that was 3.4 (95% CI 2.5–4.3) points lower during wound care (p < 0.001), and 2.2 (95% CI 1.6–2.7) afterwards (p < 0.001). Epithelialisation was quicker, but not significantly so.

    Conclusion

    These results suggest that the microbial cellulose dressing is a better first choice for treatment of partial thickness burns than silver sulphadiazine cream. Fewer dressings of the wound were done and, combined with the low pain scores, this is good for both the patients and the health care system. The differences in randomisation of the area of burns is, however, a concern that needs to be included in the interpretation of the results.

  • 8.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Capodanno, Alessandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 54, p. 92134-92142Article in journal (Refereed)
    Abstract [en]

    Women with dense breast tissue on mammography are at higher risk of developing breast cancer but the underlying mechanisms are not well understood. De-regulation of microRNAs (miRNAs) has been associated with the onset of breast cancer. miRNAs in the extracellular space participate in the regulation of the local tissue microenvironment. Here, we recruited 39 healthy postmenopausal women attending their mammography-screen that were assessed having extreme dense or entirely fatty breasts (nondense). Microdialysis was performed in breast tissue and a reference catheter was inserted in abdominal subcutaneous fat for local sampling of extracellular compounds. Three miRNAs, associated with tumor suppression, miR-193b, miR-365a, and miR-452 were significantly down-regulated in dense breast tissue compared with nondense breast tissue. In addition, miR-452 exhibited significant negative correlations with several pro-inflammatory cytokines in vivo, which was confirmed in vitro by overexpression of miR-452 in breast cancer cells. No differences were found of miR-21, -29a, -30c, 146a, -148a, -203, or -451 in breast tissue and no miRs were different in plasma. Extracellular miRNAs may be among factors that should be included in studies of novel prevention strategies for breast cancer.

  • 9.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Equal Pro-inflammatory Profiles of CCLs, CXCLs, and Matrix Metalloproteinases in the Extracellular Microenvironment In Vivo in Human Dense Breast Tissue and Breast Cancer2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1994Article in journal (Refereed)
    Abstract [en]

    The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-a, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.

  • 10.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Increased nutrient availability in dense breast tissue of postmenopausal women in vivo2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 42733Article in journal (Refereed)
    Abstract [en]

    Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

  • 11.
    Adini, B.
    et al.
    Tel Aviv University, Israel.
    Bodas, M.
    Tel Aviv University, Israel.
    Nilsson, Heléne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Disaster Medicine and Traumatology.
    Peleg, K.
    Tel Aviv University, Israel; Gertner Institute Health Policy and Epidemiol, Israel.
    Policies for managing emergency medical services in mass casualty incidents2017In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 48, no 9, p. 1878-1883Article in journal (Refereed)
    Abstract [en]

    Introduction: Diverse decision-making is needed in managing mass casualty incidents (MCIs), by emergency medical services (EMS). The aim of the study was to review consensus among international experts concerning policies of EMS management during MCIs. Methods: Applicability of 21 EMS policies was tested through a 2-cycle modified e-Delphi process, in which 38 multi-disciplinary experts from 10 countries participated. Threshold for approving proposed solutions was defined as consensus of amp;gt;80%. Policies that did not achieve the targeted consensus were reviewed to detect variability according to respondents origin country. Results: 16 policies were endorsed in the first cycle including collaboration between ambulance service providers; implementing a unified mode of operation; preparing criteria for ground versus aerial evacuation; and, developing support systems for caregivers exposed to violence. An additional policy which proposed that senior EMS officers should not necessarily act as on-site MCI commanders was endorsed in the second cycle. Demographic breakdown of views concerning non-consensual policies revealed differences according to countries of origin. Assigning ambulances to off-duty team members was highly endorsed by experts from Israel and South Africa and strongly rejected by European respondents. Avoiding entry to risk areas until declared safe was endorsed by European, Asian and Oceanic experts, but rejected by Israeli, South African and North American experts. Conclusions: Despite uniqueness of countries and EMS agencies, solutions to most dilemmas were applicable to all organizations, regardless of location or affiliation. Cultural diversity was found concerning readiness to implement military-civilian collaboration in MCIs and a rigid separation between work-leisure responsibilities. (C) 2017 Elsevier Ltd. All rights reserved.

  • 12.
    Adolfsson, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Nestorson, Jens
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Scheer, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Extensive soft tissue lesions in redislocated after simple elbow dislocations2017In: Journal of shoulder and elbow surgery, ISSN 1058-2746, E-ISSN 1532-6500, Vol. 26, no 7, p. 1294-1297Article in journal (Refereed)
    Abstract [en]

    Background: The majority of simple elbow dislocations (no associated fractures) can be treated nonoperatively with a short period of immobilization followed by guided aftercare. This case series describes the soft tissue injuries in a rare subset of patients in whom the elbow redislocated despite adequate immobilization. Methods: During a 6-year period, 8 patients were identified. They were all treated with reduction and casting in 90 degrees of flexion or more. At 1 week of follow-up, redislocation had occurred in all patients and open soft tissue repair was performed. The injuries were documented and the patients were followed up clinically and with radiographs. Results: Extensive soft tissue injuries, including both collateral ligament injuries and muscle origin avulsions from either or both sides, were found in all patients. The functional result at follow-up was satisfactory in all patients. Conclusion: Vast soft tissue injuries including both collateral ligaments and muscle origins should be expected in the event of early severe instability of a dislocated elbow joint. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

  • 13.
    Ahle, Margareta
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Drott, Peder
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Elfvin, Anders
    Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Roland E.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Department of Surgery, Ryhov County Hospital, Jönköping, Sweden .
    Maternal, fetal and perinatal factors associated with necrotizing enterocolitis in Sweden: A national case-control study2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, PLoS ONE, ISSN 1932-6203, Vol. 13, no 3, article id e0194352Article in journal (Refereed)
    Abstract [en]

    Objective

    To analyze associations of maternal, fetal, gestational, and perinatal factors with necrotizing enterocolitis in a matched case-control study based on routinely collected, nationwide register data.

    Study design

    All infants born in 1987 through 2009 with a diagnosis of necrotizing enterocolitis in any of the Swedish national health care registers were identified. For each case up to 6 controls, matched for birth year and gestational age, were selected. The resulting study population consisted of 720 cases and 3,567 controls. Information on socioeconomic data about the mother, maternal morbidity, pregnancy related diagnoses, perinatal diagnoses of the infant, and procedures in the perinatal period, was obtained for all cases and controls and analyzed with univariable and multivariable logistic regressions for the whole study population as well as for subgroups according to gestational age.

    Results

    In the study population as a whole, we found independent positive associations with necrotizing enterocolitis for isoimmunization, fetal distress, cesarean section, neonatal bacterial infection including sepsis, erythrocyte transfusion, persistent ductus arteriosus, cardiac malformation, gastrointestinal malformation, and chromosomal abnormality. Negative associations were found for maternal weight, preeclampsia, maternal urinary infection, premature rupture of the membranes, and birthweight. Different patterns of associations were seen in the subgroups of different gestational age.

    Conclusion

    With some interesting exceptions, especially in negative associations, the results of this large, population based study, are in keeping with earlier studies. Although restrained by the limitations of register data, the findings mirror conceivable pathophysiological processes and underline that NEC is a multifactorial disease.

  • 14.
    Alim, Abdul
    et al.
    Uppsala University, Sweden; Karolinska Institute, Sweden; Uppsala University, Sweden.
    Ackermann, Paul W.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Kristiansson, Per
    Uppsala University, Sweden.
    Pejler, Gunnar
    Uppsala University, Sweden; Swedish University of Agriculture Science, Sweden.
    Peterson, Magnus
    Uppsala University, Sweden.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, no 3, p. 451-460Article in journal (Refereed)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

  • 15.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer2018In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, no 4, article id 159.e19Article in journal (Refereed)
    Abstract [en]

    Background

    Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer(UBC) is controversial.

    Methods

    We prospectively studied 103 patients with stage pT1–T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome.

    Results

    The mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02).

    Conclusions

    M2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact.

  • 16.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Solna Stockholm, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology.
    Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.2017In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 120, no 3, p. 329-336Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.

    PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.

    RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).

    CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

  • 17.
    Almroth, Gabriel
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Recidivating thrombocytopenia, renal failure and thymitis2017In: Recidivating thrombocytopenia, renal failure and thymitis, 2017Conference paper (Other academic)
  • 18.
    Almroth, Gabriel
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Recurrent thrombocytopenia, renal failure and thymitis of unknown cause. A case report2017In: Vaskulär medicin, Vol. 33, no 3, p. 24-25Article in journal (Refereed)
    Abstract [en]

    A 45-year old man was admitted to an intensive care unit with flank pain and thrombocytopenia. He was treated for a suspected septicaemia but turned out to have signs of an unknown collagenosis which responded to plasma exchange, thymectomi and corticosteroids. Kidney biopsy revealed an intense tubulointerstitial reaction with suspected microthrombotic lesions in the vessels. The condition reoccurred with thrombocytopenia a couple of months later but responded to plasma exchange, corticosteroids and mycophenolate mofetil. An unknown collagenosis with findings of autoimmune thymitis and tubulointerstitial nephritis is the most probable cause of the condition.

  • 19.
    Amirhosseini, Mehdi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Göran
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Fahlgren, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening2017In: Bone Reports, ISSN 2352-1872, Vol. 7, p. 17-25Article in journal (Refereed)
    Abstract [en]

    Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

  • 20.
    Andersson, Manne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Cty Council Jonkoping, Dept Surg, Ryhov Cty Hosp, Jonkoping, Sweden.
    Kolodziej, B.
    County Council Jonköping, Sweden.
    Andersson, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. County Council Jonköping, Sweden.
    Randomized clinical trial of Appendicitis Inflammatory Response score-based management of patients with suspected appendicitis2017In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 11, p. 1451-1461Article in journal (Refereed)
    Abstract [en]

    BackgroundThe role of imaging in the diagnosis of appendicitis is controversial. This prospective interventional study and nested randomized trial analysed the impact of implementing a risk stratification algorithm based on the Appendicitis Inflammatory Response (AIR) score, and compared routine imaging with selective imaging after clinical reassessment. MethodPatients presenting with suspicion of appendicitis between September 2009 and January 2012 from age 10years were included at 21 emergency surgical centres and from age 5years at three university paediatric centres. Registration of clinical characteristics, treatments and outcomes started during the baseline period. The AIR score-based algorithm was implemented during the intervention period. Intermediate-risk patients were randomized to routine imaging or selective imaging after clinical reassessment. ResultsThe baseline period included 1152 patients, and the intervention period 2639, of whom 1068 intermediate-risk patients were randomized. In low-risk patients, use of the AIR score-based algorithm resulted in less imaging (192 versus 345 per cent; Pamp;lt;0001), fewer admissions (295 versus 428 per cent; Pamp;lt;0001), and fewer negative explorations (16 versus 32 per cent; P=0030) and operations for non-perforated appendicitis (68 versus 97 per cent; P=0034). Intermediate-risk patients randomized to the imaging and observation groups had the same proportion of negative appendicectomies (64 versus 67 per cent respectively; P=0884), number of admissions, number of perforations and length of hospital stay, but routine imaging was associated with an increased proportion of patients treated for appendicitis (534 versus 463 per cent; P=0020). ConclusionAIR score-based risk classification can safely reduce the use of diagnostic imaging and hospital admissions in patients with suspicion of appendicitis. Registration number: NCT00971438 ( ). Reduces imaging and admissions

  • 21.
    Andersson, Peter
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Muhrbeck, Måns
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Veen, Harald
    Int Comm Red Cross, Switzerland.
    Osman, Zaher
    Int Comm Red Cross, Switzerland.
    von Schreeb, Johan
    Karolinska Institute, Sweden.
    Hospital Workload for Weapon-Wounded Females Treated by the International Committee of the Red Cross: More Work Needed than for Males2018In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 42, no 1, p. 93-98Article in journal (Refereed)
    Abstract [en]

    Civilians constitute 33-51% of victims in armed conflicts. Several reports on civilian injuries exist, but few have focused on injuries afflicting females. We analyzed routinely collected data on weapon-related injuries from the International Committee of the Red Cross (ICRC) hospital in northwestern Pakistan in order to define injury patterns and types of surgical treatment for females. A total of 3028 patient files (376 females) from consecutively admitted patients to the ICRC-hospital in Peshawar from February 2009 to May 2012 were included. Information regarding injury-mechanism, time since injury, vital parameters at admission, type of injury, treatment and basic outcome was extracted from the files and analyzed. Comparisons between gender and age-groups were done by cross-table analyses or nonparametric tests. Females were younger than males (20 vs. 25 years), arrived sooner after injury (24 vs. 48 h) (p amp;lt; 0.001 for both) and were victims of bombs and missiles more frequently (64.4 vs. 54.6%) (p amp;lt; 0.001). Vital parameters such as systolic blood pressure (110 vs. 113 mmHg) and pulse rate (100 vs. 86) were more affected at admission (p amp;lt; 0.001 for both). Females were subjected to surgery (83.0 vs. 77.4%) (p amp;lt; 0.05) and were given blood transfusions more often (18.8 vs. 13.6%) (p amp;lt; 0.01). No differences in amputations or in-hospital mortality were found. Females treated at the ICRC-hospital in northwestern Pakistan are markedly affected by indiscriminate weapons such as bombs and missiles. Their average consumption of surgery is greater than for males, and this might be relevant in planning for staffing and facility needs in similar contexts.

  • 22.
    Apellániz-Ruiz, Maria
    et al.
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Tejero, Héctor
    Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
    Inglada-Pérez, Lucía
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
    Sánchez-Barroso, Lara
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Gutiérrez-Gutiérrez, Gerardo
    Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Calvo, Isabel
    Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain. Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Castelo, Beatriz
    Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
    Redondo, Andrés
    Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
    García-Donás, Jesus
    Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Romero-Laorden, Nuria
    Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Sereno, Maria
    Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Merino, María
    Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Currás-Freixes, Maria
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Montero-Conde, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Mancikova, Veronika
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Al-Shahrour, Fatima
    Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
    Cascon, Alberto
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
    Robledo, Mercedes
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain .
    Rodriguez-Antona, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain .
    Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 5, p. 1227-1235Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.

    EXPERIMENTAL DESIGN: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/ gene-based analyses were used to compare variant frequencies among neuropathy groups and Cox regression models were used to analyze neuropathy evolution along treatment.

    RESULTS: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low frequency non-synonymous variants in EPHA6 were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, 95%CI=2.33-91.62, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10(-4)).

    CONCLUSION: This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.

  • 23.
    Ardenfors, Oscar
    et al.
    Stockholm University, Sweden.
    Gudowska, Irena
    Stockholm University, Sweden.
    Flejmer, Anna M.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 μGy.Gy−1 in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 μSv.Gy−1 for the paediatric patient and between 0.2 and 134 μSv.Gy−1 for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 24.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Apropå! En arrogant organisation2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Other academic)
    Abstract [en]

    n/a

  • 25.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Beslut att operera kopplat till ortopeders attityder till kirurgi2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, no 41Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 26.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Placeboeffekten är övervärderad: »Återgång till medelvärdet« kan förklara förbättring efter skenbehandling – men misstolkas ofta2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Refereed)
  • 27.
    Baubeta Fridh, Erik
    et al.
    Ryhov County Hospital, Sweden; University of Gothenburg, Sweden.
    Andersson, Manne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov County Hospital, Sweden.
    Thuresson, Marcus
    Statisticon AB, Sweden.
    Sigvant, Birgitta
    Karlstad Central Hospital, Sweden; Karolinska Institute, Sweden.
    Kragsterman, Björn
    Uppsala University, Sweden.
    Johansson, Saga R.
    AstraZeneca Gothenburg, Sweden.
    Hasvold, Pål
    AstraZeneca Nordic Balt, Sweden.
    Falkenberg, Mårten
    University of Gothenburg, Sweden.
    Nordanstig, Joakim
    Gothenburg University, Sweden; Gothenburg University, Sweden.
    Amputation Rates, Mortality, and Pre-operative Comorbidities in Patients Revascularised for Intermittent Claudication or Critical Limb Ischaemia: A Population Based Study2017In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 54, no 4, p. 480-486Article in journal (Refereed)
    Abstract [en]

    Objectives

    The aims of this population based study were to describe mid- to long-term amputation risk, cumulative incidence of death or amputation, and differences in pre-operative comorbidities in patients revascularised for lower limb peripheral artery disease (PAD).

    Methods

    This was an observational cohort study. Data from the Swedish National Quality Registry for Vascular Surgery (Swedvasc) were combined with mandatory national health care registries and patient medical records. All patients who underwent revascularisation in Sweden between May 2008 and May 2013 for intermittent claudication (IC) or critical limb ischaemia(CLI), aged 50 years and older, were identified through the Swedvasc database. The mandatory national health care registries and medical records provided data on comorbidities, mortality, and major amputations.

    Results

    A total of 16,889 patients with PAD (IC, n = 6272; CLI, n = 10,617) were studied. The incidence of amputations in IC patients was 0.4% (range 0.3%–0.5%) per year. Among CLI patients, the amputation rate during the first 6 months following revascularisation was 12.0% (95% CI 11.3–12.6). Thereafter, the incidence declined to approximately 2% per year. The cumulative combined incidence of death or amputation 3 years after revascularisation was 12.9% (95% CI 12.0–13.9) in IC patients and 48.8% (95% CI 47.7–49.8) in CLI patients. Among CLI patients, compared with IC patients, the prevalence of diabetes, ischaemic stroke, heart failure, and atrial fibrillation was approximately doubled and renal failure was nearly tripled, even after age standardisation.

    Conclusion

    The risk of amputation is particularly high during the first 6 months following revascularisation for CLI. IC patients have a benign course in terms of limb loss. Mortality in both IC and CLI patients is substantial. Revascularised CLI patients have different comorbidities from IC patients.

  • 28.
    Bausch, Birke
    et al.
    Albert Ludwigs University, Germany.
    Schiavi, Francesca
    Ist Ricovero and Cura Carattere Science, Italy.
    Ni, Ying
    Cleveland Clin, OH 44106 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Patocs, Attila
    Semmelweis University, Hungary; Semmelweis University, Hungary.
    Ngeow, Joanne
    National Cancer Centre Singapore, Singapore; Nanyang Technology University, Singapore.
    Wellner, Ulrich
    University of Lubeck, Germany.
    Malinoc, Angelica
    Albert Ludwigs University, Germany.
    Taschin, Elisa
    Ist Ricovero and Cura Carattere Science, Italy.
    Barbon, Giovanni
    Ist Ricovero and Cura Carattere Science, Italy.
    Lanza, Virginia
    Ist Ricovero and Cura Carattere Science, Italy.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Larsson, Catharina
    Karolinska Institute, Sweden.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Chen, Jin-Lian
    Cleveland Clin, OH 44106 USA.
    Marquard, Jessica
    Cleveland Clin, OH 44106 USA.
    Fraenkel, Merav
    Hadassah Hebrew University, Israel.
    Walter, Martin A.
    University Hospital, Switzerland.
    Peczkowska, Mariola
    Institute Cardiol, Poland.
    Prejbisz, Aleksander
    Institute Cardiol, Poland.
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Hasse-Lazar, Kornelia
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Petersenn, Stephan
    Centre Endocrine Tumors, Germany.
    Moeller, Lars C.
    University of Duisburg Essen, Germany.
    Meyer, Almuth
    HELIOS Klin, Germany.
    Reisch, Nicole
    Ludwigs Maximilians University of Munich, Germany.
    Trupka, Arnold
    City Hospital, Germany.
    Brase, Christoph
    University of Erlangen Nurnberg, Germany.
    Galiano, Matthias
    University Hospital Erlangen, Germany.
    Preuss, Simon F.
    University of Cologne, Germany.
    Kwok, Pingling
    University of Regensburg, Germany.
    Lendvai, Nikoletta
    Semmelweis University, Hungary.
    Berisha, Gani
    Albert Ludwigs University, Germany.
    Makay, Ozer
    Ege University, Turkey.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Weryha, Georges
    University of Nancy, France.
    Racz, Karoly
    Semmelweis University, Hungary.
    Januszewicz, Andrzej
    Institute Cardiol, Poland.
    Walz, Martin K.
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Opocher, Giuseppe
    Ist Ricovero and Cura Carattere Science, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs University, Germany.
    Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention2017In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 9, p. 1204-1212Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

  • 29.
    Bednarska, Olga
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Casado-Bedmar, Maite
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Salvo-Romero, Eloisa
    University of Autonoma Barcelona, Spain.
    Vicario, Maria
    University of Autonoma Barcelona, Spain.
    Mayer, Emeran A.
    University of Calif Los Angeles, CA 90095 USA.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome2017In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 4, p. 948-+Article in journal (Refereed)
    Abstract [en]

    BACKGROUND amp; AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P amp;lt;.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

  • 30.
    Behrens, Kira
    et al.
    Leibniz Institute Expt Virol, Germany; Walter and Eliza Hall Institute Medical Research, Australia.
    Maul, Katrin
    Leibniz Institute Expt Virol, Germany.
    Tekin, Nilguen
    Leibniz Institute Expt Virol, Germany; Leibniz Institute Expt Virol, Germany.
    Kriebitzsch, Neele
    Leibniz Institute Expt Virol, Germany.
    Indenbirken, Daniela
    Leibniz Institute Expt Virol, Germany.
    Prassolov, Vladimir
    Engelhardt Institute Molecular Biol, Russia.
    Mueller, Ursula
    Leibniz Institute Expt Virol, Germany.
    Serve, Hubert
    Goethe University of Frankfurt, Germany.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Stocking, Carol
    Leibniz Institute Expt Virol, Germany.
    RUNX1 cooperates with FLT3-ITD to induce leukemia2017In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 3, p. 737-752Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.

  • 31.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Joost, Patrick
    Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Off Medical Serv, Sweden; Lund University, Sweden.
    Backman, Ann-Sofie
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    von Salome, Jenny
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Zagoras, Theofanis
    Sahlgrens University Hospital, Sweden.
    Gebre-Medhin, Samuel
    Lund University, Sweden; Karolinska University Hospital, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 32.
    Berggren, Daniel Moreno
    et al.
    Uppsala Univ, Sweden.
    Folkvaljon, Yasin
    Uppsala Univ Hosp, Sweden.
    Engvall, Marie
    Uppsala Univ, Sweden.
    Sundberg, Johan
    Uppsala Univ, Sweden.
    Lambe, Mats
    Uppsala Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sweden.
    Lorenz, Fryderyk
    Umea Univ, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Rasmussen, Bengt
    Orebro Univ Hosp, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden.
    Hellstrom-Lindberg, Eva
    Karolinska Inst, Sweden.
    Jadersten, Martin
    Karolinska Inst, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 5, p. 614-627Article in journal (Refereed)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (Pamp;lt;0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;05) and for WPSS compared to IPSS (P=0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;07). IPSS-R was superior to both IPSS and WPSS for patients aged 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

  • 33.
    Bergkvist, Max
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Zötterman, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Henricson, Joakim
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Iredahl, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Vascular Occlusion in a Porcine Flap Model: Effects on Blood Cell Concentration and Oxygenation.2017In: Plastic and reconstructive surgery. Global open, ISSN 2169-7574, Vol. 5, no 11, article id e1531Article in journal (Refereed)
    Abstract [en]

    Background: Venous congestion in skin flaps is difficult to detect. This study evaluated the ability of tissue viability imaging (TiVi) to measure changes in the concentration of red blood cells (CRBC), oxygenation, and heterogeneity during vascular provocations in a porcine fasciocutaneous flap model.

    Methods: In 5 pigs, cranial gluteal artery perforator flaps were raised (8 flaps in 5 pigs). The arterial and venous blood flow was monitored with ultrasonic flow probes. CRBC, tissue oxygenation, and heterogeneity in the skin were monitored with TiVi during baseline, 50% and 100% venous occlusion, recovery, 100% arterial occlusion and final recovery, thereby simulating venous and arterial occlusion of a free fasciocutaneous flap. A laser Doppler probe was used as a reference for microvascular perfusion in the flap.

    Results: During partial and complete venous occlusion, increases in CRBC were seen in different regions of the flap. They were more pronounced in the distal part. During complete arterial occlusion, CRBC decreased in all but the most distal parts of the flap. There were also increases in tissue oxygenation and heterogeneity during venous occlusion.

    Conclusions: TiVi measures regional changes in CRBC in the skin of the flap during arterial and venous occlusion, as well as an increase in oxygenated hemoglobin during venous occlusion that may be the result of reduced metabolism and impaired delivery of oxygen to the tissue. TiVi may provide a promising method for measuring flap viability because it is hand-held, easy to-use, and provides spatial information on venous congestion.

  • 34.
    Bernhardsson, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury2018In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 4, p. 457-461Article in journal (Refereed)
    Abstract [en]

    Background and purpose - Fracture healing in the shaft is usually described as a sequence of events, starting with inflammation, which triggers mesenchymal tissue formation in successive steps. Most clinical fractures engage cancellous bone. We here describe fracture healing in cancellous bone, focusing on the timing of inflammatory and mesenchymal cell type appearance at the site of injury. Material and methods - Rats received a proximal tibial drill hole, A subgroup received clodronate-containing liposomes before or after surgery. The tibiae were analyzed with micro-CT and immunohistochemistry 1 to 7 days after injury. Results - Granulocytes (myeloperoxidase) appeared in moderate numbers within the hole at day 1 and then gradually disappeared. Macrophage expression (CD68) was seen on day 1, increased until day 3, and then decreased. Mesenchymal cells (vimentin) had already accumulated in the periphery of the hole on day 1. Mesenchymal cells dominated in the entire lesion on day 3, now producing extracellular matrix. A modest number of preosteoblasts (RUNX2) were seen on day 1 and peaked on day 4. Osteoid was seen on day 4 in the traumatized region, with a distinct border to the uninjured surrounding marrow. Clodronate liposomes given before the injury reduced the volume of bone formation at day 7, but no reduction in macrophage numbers could be detected. Interpretation - The typical sequence of events in shaft fractures was not seen. Mesenchymal cells appeared simultaneously with granulocyte and macrophage arrival. Clodronate liposomes, known to reduce macrophage numbers, seemed to be associated with the delineation of the volume of tissue to be replaced by bone.

  • 35.
    Bernhardsson, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Sandberg, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Ressner, Marcus
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Koziorowski, Jacek
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Medicine and Health Sciences.
    Malmqvist, Jonas
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Shining dead bone-cause for cautious interpretation of [F-18]NaF PET scans2018In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 1, p. 124-127Article in journal (Refereed)
    Abstract [en]

    Background and purpose — [18F]Fluoride ([18F]NaF) PET scan is frequently used for estimation of bone healing rate and extent in cases of bone allografting and fracture healing. Some authors claim that [18F]NaF uptake is a measure of osteoblastic activity, calcium metabolism, or bone turnover. Based on the known affinity of fluoride to hydroxyapatite, we challenged this view.

    Methods — 10 male rats received crushed, frozen allogeneic cortical bone fragments in a pouch in the abdominal wall on the right side, and hydroxyapatite granules on left side. [18F]NaF was injected intravenously after 7 days. 60 minutes later, the rats were killed and [18F]NaF uptake was visualized in a PET/CT scanner. Specimens were retrieved for micro CT and histology.

    Results — MicroCT and histology showed no signs of new bone at the implant sites. Still, the implants showed a very high [18F]NaF uptake, on a par with the most actively growing and remodeling sites around the knee joint.

    Interpretation — [18F]NaF binds with high affinity to dead bone and calcium phosphate materials. Hence, an [18F]NaF PET/CT scan does not allow for sound conclusions about new bone ingrowth into bone allograft, healing activity in long bone shaft fractures with necrotic fragments, or remodeling around calcium phosphate coated prostheses

  • 36.
    Bernhardsson, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tätting, Love
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Sandberg, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Schilcher, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Marrow compartment contribution to cortical defect healing2018In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 1, p. 119-123Article in journal (Refereed)
    Abstract [en]

    Background and purpose - Healing of shaft fractures is commonly described as regards external callus. We wanted to clarify the role of the bone marrow compartment in the healing of stable shaft fractures. Patients and methods - A longitudinal furrow was milled along the longitudinal axis of the femoral shaft in mice. The exposed bone marrow under the furrow was scooped out. The mice were then randomized to no further treatment, or to receiving 2 silicone plugs in the medullary canal distal and proximal to the defect. The plugs isolated the remaining marrow from contact with the defect. Results were studied with histology and flow cytometry. Results - Without silicone plugs, the marrow defect was filled with new bone marrow-like tissue by day 5, and new bone was seen already on day 10. The new bone was seen only at the level of the cortical injury, where it seemed to form simultaneously in the entire region of the removed cortex. The new bone seemed not to invade the marrow compartment, and there was a sharp edge between new bone and marrow. The regenerated marrow was similar to uninjured marrow, but contained considerably more cells. In the specimens with plugs, the marrow compartment was either filled with loose scar tissue, or empty, and there was only minimal bone formation, mainly located around the edges of the cortical injury. Interpretation - Marrow regeneration in the defect seemed to be a prerequisite for normal cortical healing. Shaft fracture treatment should perhaps pay more attention to the local bone marrow.

  • 37.
    Bernink, Jochem H.
    et al.
    University of Amsterdam, Netherlands; Royal Netherlands Academic Arts and Science KNAW, Netherlands.
    Mjösberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Spits, Hergen
    University of Amsterdam, Netherlands.
    Letter: Human ILC1: To Be or Not to Be in IMMUNITY, vol 46, issue 5, pp 756-7572017In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 46, no 5, p. 756-757Article in journal (Other academic)
    Abstract [en]

    n/a

  • 38.
    Björnsson Hallgren, Hanna C
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Adolfsson, Lars E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Johansson, Kajsa
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Öberg, Birgitta
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Petersson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Holmgren, Theresa M
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Specific exercises for subacromial pain: Good results maintained for 5 years2017In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 88, no 6, p. 600-605Article in journal (Refereed)
    Abstract [en]

    Background and purpose — We have previously shown that specific exercises reduced the need for surgery in subacromial painpatients at 1-year follow-up. We have now investigated whetherthis result was maintained after 5 years and compared the outcomesof surgery and non-surgical treatment.Patients and methods — 97 patients were included in the previouslyreported randomized study of patients on a waiting list forsurgery. These patients were randomized to specifi c or unspecifi cexercises. After 3 months of exercises the patients were asked ifthey still wanted surgery and this was also assessed at the present5-year follow-up. The 1-year assessment included Constant–Murley score, DASH, VAS at night, rest and activity, EQ-5D, andEQ-VAS. All these outcome assessments were repeated after 5years in 91 of the patients.Results — At the 5-year follow-up more patients in the specifi cexercise group had declined surgery, 33 of 47 as compared with16 of 44 (p = 0.001) in the unspecifi c exercise group. The meanConstant–Murley score continued to improve between the 1- and5-year follow-ups in both surgically and non-surgically treatedgroups. On a group level there was no clinically relevant changebetween 1 and 5 years in any of the other outcome measuresregardless of treatment.Interpretation — This 5-year follow-up of a previously publishedrandomized controlled trial found that specifi c exercisesreduced the need for surgery in patients with subacromial pain.Patients not responding to specifi c exercises may achieve similargood results with surgery. These fi ndings emphasize that a specifi cexercise program may serve as a selection tool for surgery.

  • 39.
    Blockhuys, S.
    et al.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Celauro, E.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Feizi, A.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fierro-González, J.C.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Wittung-Stafshede, P.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Defining the human copper proteome and analysis of its expression variation in cancers.2017In: Metallomics : integrated biometal science, ISSN 1756-591X, Vol. 9, no 2, p. 112-123Article in journal (Refereed)
    Abstract [en]

    Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

  • 40.
    Blockhuys, Stephanie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Chalmers University of Technology, Sweden.
    Rani Agarwal, Nisha
    Chalmers University of Technology, Sweden; McMaster University, Canada; McMaster University, Canada.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Jarlsfelt, Ingvar
    Ryhov Hospital, Sweden.
    Wittung-Stafshede, Pernilla
    Chalmers University of Technology, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Second harmonic generation for collagen I characterization in rectal cancer patients with and without preoperative radiotherapy2017In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 22, no 10, article id 106006Article in journal (Refereed)
    Abstract [en]

    Rectal cancer is treated with preoperative radiotherapy (RT) to downstage the tumor, reduce local recurrence, and improve patient survival. Still, the treatment outcome varies significantly and new biomarkers are desired. Collagen I (Col-I) is a potential biomarker, which can be visualized label-free by second harmonic generation (SHG). Here, we used SHG to identify Col-I changes induced by RT in surgical tissue, with the aim to evaluate the clinical significance of RT-induced Col-I changes. First, we established a procedure for quantitative evaluation of Col-I by SHG in CDX2-stained tissue sections. Next, we evaluated Col-I properties in material from 31 non-RT and 29 RT rectal cancer patients. We discovered that the Col-I intensity and anisotropy were higher in the tumor invasive margin than in the inner tumor and normal mucosa, and RT increased and decreased the intensity in inner tumor and normal mucosa, respectively. Furthermore, higher Col-I intensity in the inner tumor was related to increased distant recurrence in the non-RT group but to longer survival in the RT group. In conclusion, we present a new application of SHG for quantitative analysis of Col-I in surgical material, and the first data suggest Col-I intensity as a putative prognostic biomarker in rectal cancer. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.

  • 41.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammation and tendon healing2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.

    The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.

    First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.

    In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations. 

    List of papers
    1. A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
    Open this publication in new window or tab >>A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 29824Article in journal (Refereed) Published
    Abstract [en]

    Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and T-reg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and T-reg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the T-reg cell fraction was lower (p amp;lt; 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more T-reg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2016
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-130383 (URN)10.1038/srep29824 (DOI)000379584000001 ()27405922 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

    Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2018-01-10
    2. Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
    Open this publication in new window or tab >>Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
    2017 (English)In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, p. 223-229Article in journal (Refereed) Published
    Abstract [en]

    Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.

    Place, publisher, year, edition, pages
    Rome, Italy: CIC Edizioni Internazionali, 2017
    Keywords
    tendon healing; NSAID; inflammation; rat model; flow cytometry
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-142352 (URN)10.11138/mltj/2017.7.2.223 (DOI)
    Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2018-04-17
    3. Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
    Open this publication in new window or tab >>Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
    2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12468Article in journal (Refereed) Published
    Abstract [en]

    Inflammation initiates tendon healing and then normally resolves more or less completely. Unresolved inflammation might disturb the remodeling process. We hypothesized that suppression of inflammation during the early remodeling phase by systemic dexamethasone treatment can improve healing. 36 rats underwent Achilles tendon transection and were randomized to dexamethasone or saline on days 0-4 after surgery (early inflammatory phase), and euthanasia day 7. Another 54 rats received injections days 5-9 (early remodeling phase) and were euthanized day 12 for mechanical, histological and flow cytometric evaluation. Dexamethasone treatment days 0-4 reduced the cross-sectional area, peak force and stiffness by day 7 to less than half (p amp;lt; 0.001 for all), while material properties (peak stress and elastic modulus) were not significantly affected. In contrast, dexamethasone treatment days 5-9 increased peak force by 39% (p = 0.002) and stiffness by 58% (p amp;lt; 0.001). The cross-sectional area was reduced by 42% (p amp;lt; 0.001). Peak stress and elastic modulus were more than doubled (p amp;lt; 0.001 for both). Semi-quantitative histology at day 12 showed that late dexamethasone treatment improved collagen alignment, and flow cytometry revealed reduced numbers of CD8a(+) cytotoxic T cells in the tendon callus. These results suggest that downregulation of lingering inflammation during the early remodeling phase can improve healing.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2017
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:liu:diva-142175 (URN)10.1038/s41598-017-12657-0 (DOI)000412032600034 ()28963482 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; Ostergotland county (ALF)

    Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-11-16
    4. COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    Open this publication in new window or tab >>COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    2015 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, p. 534-540Article in journal (Refereed) Published
    Abstract [en]

    Early tendon healing can be stimulated by mechanical loading and inhibited by cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs). Therefore, we investigated if impairment of tendon healing by a COX-2 inhibitor (parecoxib) is related to loading. Because loading might infer microdamage, which also stimulates healing, we also investigated if this effect is inhibited by parecoxib. The Achilles tendon was transected in 114 rats. Three degrees of loading were used: full loading, partial unloading, and unloading (no unloading, Botox injections in the plantar flexor muscles, or Botox in combination with tail suspension). For each loading condition, the rats received either parecoxib or saline. In a second experiment, rats were unloaded with Botox, and the tendon was subjected to microdamage by needling combined with either saline or parecoxib. Mechanical testing day 7 showed that there was a significant interaction between loading and parecoxib for peak force at failure (P less than 0.01). However, logarithmic values showed no significant interaction, meaning that we could not exclude that the inhibitory effect of parecoxib was proportionate to the degree of loading. Microbleeding was common in the healing tissue, suggesting that loading caused microdamage. Needling increased peak force at failure (P less than 0.01), and this effect of microdamage was almost abolished by parecoxib (P less than 0.01). Taken together, this suggests that COX-2 inhibition impairs the positive effects of mechanical loading during tendon healing, mainly by reducing the response to microdamage.

    Place, publisher, year, edition, pages
    AMER PHYSIOLOGICAL SOC, 2015
    Keywords
    tendon healing; COX-2; NSAIDs; mechanical stimulation; microdamage
    National Category
    Physiology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-122063 (URN)10.1152/japplphysiol.00239.2015 (DOI)000360694300013 ()26159755 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

    Available from: 2015-12-18 Created: 2015-10-19 Last updated: 2018-02-20
  • 42.
    Blomgran, Parmis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing2017In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, p. 223-229Article in journal (Refereed)
    Abstract [en]

    Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.

  • 43.
    Blomgran, Parmis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammerman, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Systemic corticosteroids improve tendon healing when given after the early inflammatory phase2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12468Article in journal (Refereed)
    Abstract [en]

    Inflammation initiates tendon healing and then normally resolves more or less completely. Unresolved inflammation might disturb the remodeling process. We hypothesized that suppression of inflammation during the early remodeling phase by systemic dexamethasone treatment can improve healing. 36 rats underwent Achilles tendon transection and were randomized to dexamethasone or saline on days 0-4 after surgery (early inflammatory phase), and euthanasia day 7. Another 54 rats received injections days 5-9 (early remodeling phase) and were euthanized day 12 for mechanical, histological and flow cytometric evaluation. Dexamethasone treatment days 0-4 reduced the cross-sectional area, peak force and stiffness by day 7 to less than half (p amp;lt; 0.001 for all), while material properties (peak stress and elastic modulus) were not significantly affected. In contrast, dexamethasone treatment days 5-9 increased peak force by 39% (p = 0.002) and stiffness by 58% (p amp;lt; 0.001). The cross-sectional area was reduced by 42% (p amp;lt; 0.001). Peak stress and elastic modulus were more than doubled (p amp;lt; 0.001 for both). Semi-quantitative histology at day 12 showed that late dexamethasone treatment improved collagen alignment, and flow cytometry revealed reduced numbers of CD8a(+) cytotoxic T cells in the tendon callus. These results suggest that downregulation of lingering inflammation during the early remodeling phase can improve healing.

  • 44.
    Bogl, H. P.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Schilcher, J.
    Gavle Central Hospital, Sweden.
    Undisturbed local bone formation capacity in patients with atypical femoral fractures: a case series2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, no 8, p. 2439-2444Article in journal (Refereed)
    Abstract [en]

    We excised the fracture site in 8 patients with incomplete atypical femoral fractures by drilling an 11-mmdiameter hole. New bone formation could be seen in the hole within a normal time frame. Delayed healing of these fractures might be unrelated to an impaired capacity to form bone. Introduction Incomplete atypical femoral fractures (undisplaced cracks) heal slowly or not at all, and often progress to a complete fracture with minimal trauma. The impaired healing has been attributed to an impaired biologic healing capacity related to bisphosphonate use, or, alternatively, to the mechanical environment within the fracture crack. This study aimed to investigate the capacity for bone formation after resection of the fracture site. Methods Between 2008 and 2014, we recruited eight patients with incomplete atypical femoral fractures. All used oral bisphosphonates before the fracture for on average 8 years (range 4 to 15) and complained of thigh pain. The fractures were stabilized with reamed cephalomedullary nails. During surgery, the fracture site in the lateral cortex was resected with a cylindrical drill (diameter 11.5 mm). The cylindrical cortical defect allowed radiographic evaluation of new bone formation, and the patients were followed clinically and radiologically for 24 months (range 15 to 92). Results After 3 months, newly formed bone could be seen in the cortical defects in all patients. After 13-26 months, the previous defects showed continuous cortical bone. At final follow-up, all patients reported full recovery of pre-surgical complaints. No complications occurred and no reoperations were performed. Conclusions New bone formation occurred within a time frame that appears normal for healing of cortical bone defects. This suggests that the capacity to form new bone is intact.

  • 45.
    Bondi, J.
    et al.
    Akershus University Hospital, Norway; Drammen Hospital, Norway.
    Avdagic, J.
    Akershus University Hospital, Norway; Innlandet Hospital, Norway.
    Karlbom, U.
    Uppsala University Hospital, Sweden.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Kalman, Thordis Disa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Saltyte Benth, J.
    Akershus University Hospital, Norway; University of Oslo, Norway.
    Naimy, N.
    Akershus University Hospital, Norway.
    Oresland, T.
    Akershus University Hospital, Norway; University of Oslo, Norway.
    Randomized clinical trial comparing collagen plug and advancement flap for trans-sphincteric anal fistula2017In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 9, p. 1160-1166Article in journal (Refereed)
    Abstract [en]

    Background: The role of a collagen plug for treating anal fistula is not well established. A randomized prospective multicentre non-inferiority study of surgical treatment of trans-sphincteric cryptogenic fistulas was undertaken, comparing the anal fistula plug with the mucosal advancement flap with regard to fistula recurrence rate and functional outcome. Methods: Patients with an anal fistula were evaluated for eligibility in three centres, and randomized to either mucosal advancement flap surgery or collagen plug, with clinical follow-up at 3 and 12 months. The primary outcome was the fistula recurrence rate. Anal pain (visual analogue scale), anal incontinence (St Marks score) and quality of life (Short Form 36 questionnaire) were also reported. Results: Ninety-four patients were included; 48 were allocated to the plug procedure and 46 to advancement flap surgery. The median follow-up was 12 (range 9-24) months. The recurrence rate at 12 months was 66 per cent (27 of 41 patients) in the plug group and 38 per cent (15 of 40) in the flap group (P = 0.006). Anal pain was reduced after operation in both groups. Anal incontinence did not change in the follow-up period. Patients reported an increased quality of life after 3 months. There were no differences between the groups with regard to pain, incontinence or quality of life. Conclusion: There was a considerably higher recurrence rate after the anal fistula plug procedure than following advancement flap repair.

  • 46.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Alayev, Anya
    Yeshiva Univ, NY 10033 USA.
    Berman, Adi Y.
    Yeshiva Univ, NY 10033 USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Holz, Marina K.
    Yeshiva Univ, NY 10033 USA; Albert Einstein Coll Med, NY 10467 USA; Albert Einstein Coll Med, NY 10467 USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 1, p. 17-27Article in journal (Refereed)
    Abstract [en]

    Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ER alpha-positive cell lines was compared with that in ER alpha-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ER alpha signaling, here shown by a coupled increase of ER alpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ER alpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ER alpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ER alpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

  • 47.
    Brink, Rob C.
    et al.
    University of Medical Centre Utrecht, Netherlands.
    Schlosser, Tom P. C.
    University of Medical Centre Utrecht, Netherlands.
    Colo, Dino
    University of Medical Centre Utrecht, Netherlands.
    Vavruch, Ludek
    Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Medicine and Health Sciences.
    van Stralen, Marijn
    University of Medical Centre Utrecht, Netherlands.
    Vincken, Koen L.
    University of Medical Centre Utrecht, Netherlands.
    Malmqvist, Marcus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kruyt, Moyo C.
    University of Medical Centre Utrecht, Netherlands.
    Tropp, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Spinal Surgery.
    Castelein, Rene M.
    University of Medical Centre Utrecht, Netherlands.
    Anterior Spinal Overgrowth Is the Result of the Scoliotic Mechanism and Is Located in the Disc2017In: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 42, no 11, p. 818-822Article in journal (Refereed)
    Abstract [en]

    Study Design. Cross-sectional study. Objective. To investigate the presence and magnitude of anterior spinal overgrowth in neuromuscular scoliosis and compare this with the same measurements in idiopathic scoliosis and healthy spines. Summary of Background Data. Anterior spinal overgrowth has been described as a potential driver for the onset and progression of adolescent idiopathic scoliosis (AIS). Whether this anterior overgrowth is specific for AIS or also present in nonidiopathic scoliosis has not been reported. Methods. Supine computed tomography (CT) scans of thirty AIS patients (thoracic Cobb 21-81 degrees), thirty neuromuscular (NM) scoliotic patients (thoracic Cobb 19-101 degrees) and 30 nonscoliotic controls were used. The difference in length in per cents between the anterior and posterior side {[(Delta A-P)/P] * 100%, abbreviated to A-P%} of each vertebral body and intervertebral disc, and between the anterior side of the spine and the spinal canal (A-C%) were determined. Results. The A-P% of the thoracic curves did not differ between the AIS (+1.2 perpendicular to 2.2%) and NM patients (+0.9 +/- 4.1%, P = 0.663), both did differ, however, from the same measurements in controls (-3.0 +/- 1.6%; Pamp;lt; 0.001) and correlated linearly with the Cobb angle (AIS r = 0.678, NM r = 0.687). Additional anterior length was caused by anterior elongation of the discs (AIS: A-P% disc +17.5 +/- 12.7% vs. A-P% body - 2.5 +/- 2.6%; Pamp;lt; 0.001, NM: A-P% disc + 19.1 +/- 18.0% vs. A-P% body -3.5 +/- 5.1%; Pamp;lt; 0.001). The A-C% T1-S1 in AIS and NM patients were similar (+ 7.9 +/- 1.8% and + 8.7 +/- 4.0%, P = 0.273), but differed from the controls (+4.2 +/- 3.3%; Pamp;lt; 0.001). Conclusion. So called anterior overgrowth has been postulated as a possible cause for idiopathic scoliosis, but apparently it occurs in scoliosis with a known origin as well. This suggests that it is part of a more generalized scoliotic mechanism, rather than its cause. The fact that the intervertebral discs contribute more to this increased anterior length than the vertebral bodies suggests an adaptation to altered loading, rather than a primary growth disturbance.

  • 48.
    Bäckström, Denise
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Norrköping.
    Injury mortality in Sweden; changes over time and the effect of age and injury mechanism2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Injuries are one of the most common causes of death in the world. Varying types of injuries dominate in different parts of the world, which also have separate influences mortality. In Scandinavia blunt injuries dominates and the majority of those who die do so pre hospital. Over time different injury pattern may vary and by analyzing this we can assess when, where and how preventive work can be reinforced. The aim of this thesis was to study injury epidemiology in Sweden and assess the contribution of different injury patters on mortality.

    Method: We used the Swedish cause of death and the national patient registries which have a complete national coverage. ICISS was calculated (based on ICD-10) in the in hospital population. We have chosen to do this investigation with a broad perspective using the term injury, which includes trauma but also other diagnoses like suffocation and drowning.

    Results: During the study period (1999-2012) the number of deaths because of injury was 1213, 25 388, and 18 332 among children, working age and elderly, respectively. Mortality declined in the children and in the working age but inclined in the elderly. Mortality increased with each age group except between the ages of 15–25 and 26–35 years. One thousand two hundred sixty four (97%) of those who died because of penetrating trauma (sharp objects and firearms) were killed by intentional trauma (assault and intentional self-harm). One thousand and seventeen (83%) of the children died prehospital. In the working age 22 211 (80%) of 25 388 died pre hospital. Nine thousand six hundred and eighteen (53%) of 18 332 of the elderly died prehospital. During 2001- 2011 the risk adjusted in hospital mortality decreased in traffic and assault but not in fall related injuries.

    Discussion: Largely, the anticipated injury mortality picture was found, with blunt injuries (traffic accidents) dominating in the working age and falls in elderly. Further a significant portion of the deaths occurred pre hospital. The intentional injuries are dominated by intentional selfharm. The decrease in child injury mortality is notable as Sweden already has one of the lowest incidences in child injury mortality in the world. The decrease in injury mortality in the working age also implies that preventive work has had an effect. The incline in injury mortality in elderly on the other hand needs to be further studied. Areas of particular importance for future preventive work is the incline in injury mortality in elderly and intentional injuries among children. 

    List of papers
    1. Change in child mortality patterns after injuries in Sweden: a nationwide 14-year study.
    Open this publication in new window or tab >>Change in child mortality patterns after injuries in Sweden: a nationwide 14-year study.
    2017 (English)In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 43, no 3, p. 343-349Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Sweden has one of the world's lowest child injury mortality rates, but injuries are still the leading cause of death among children. Child injury mortality in the country has been declining, but this decline seems to decrease recently. Our objective was therefore to further examine changes in the mortality of children's death from injury over time and to assess the contribution of various effects on mortality. The underlying hypothesis for this investigation is that the incidence of lethal injuries in children, still is decreasing and that this may be sex specific.

    PATIENTS AND METHODS: We studied all deaths from injury in Sweden under-18-year-olds during the 14 years 1999-2012. We identified those aged under 18 whose underlying cause of death was recorded as International Classification of Diseases, 10th Revision (ICD-10) diagnosis from V01 to X39 in the Swedish cause of death, where all dead citizens are registered.

    RESULTS: From the 1 January 1999 to 31 December 2012, 1213 children under the age of 18 died of injuries in Sweden. The incidence declined during this period (r = -0.606, p = 0.02) to 3.3 deaths/100,000 children-years (95 % CI 2.6-4.2). Death from unintentional injury was more common than that after intentional injury (p < 0.0001). There was a reduction in the incidence of unintentional injuries during the study period (r = -0.757, p = 0.03). The most common causes of death were injury to the brain (n = 337, 41 %), followed by drowning (n = 109, 13 %). The number of deaths after intentional injury increased (r = 0.585, p = 0.03) and at the end of the period was 1.5 deaths/100,000 children-years. The most common causes of death after intentional injuries were asphyxia (n = 177, 45 %), followed by injury to the brain (n = 76, 19 %).

    DISCUSSION: Mortality patterns in injured children in Sweden have changed from being dominated by unintentional injuries to a more equal distribution between unintentional and intentional injuries as well as between sexes and the overall rate has declined further. These findings are important as they might contribute to the preventive work that is being done to further reduce mortality in injured children.

    Place, publisher, year, edition, pages
    Springer, 2017
    Keywords
    Children, Injury, Mortality, Scandinavia, Trauma
    National Category
    Other Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-135548 (URN)10.1007/s00068-016-0660-y (DOI)000402789500010 ()27084542 (PubMedID)
    Note

    Funding agencies: Swedish Carnegie Hero Fund

    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-11-02Bibliographically approved
    2. Deaths caused by injury among people of working age (18-64) are decreasing, while those among older people (64+) are increasing
    Open this publication in new window or tab >>Deaths caused by injury among people of working age (18-64) are decreasing, while those among older people (64+) are increasing
    Show others...
    2018 (English)In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 44, no 4, p. 589-596Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Injury is an important cause of death in all age groups worldwide, and contributes to many losses of human and economic resources. Currently, we know a few data about mortality from injury, particularly among the working population. The aim of the present study was to examine death from injury over a period of 14 years (1999-2012) using the Swedish Cause of Death Registry (CDR) and the National Patient Registry, which have complete national coverage.

    METHOD: CDR was used to identify injury-related deaths among adults (18 years or over) during the years 1999-2012. ICD-10 diagnoses from V01 to X39 were included. The significance of changes over time was analyzed by linear regression.

    RESULTS: The incidence of prehospital death decreased significantly (coefficient -0.22, r (2) = 0.30; p = 0.041) during the study period, while that of deaths in hospital increased significantly (coefficient 0.20, r (2) = 0.75; p < 0.001). Mortality/100,000 person-years in the working age group (18-64 years) decreased significantly (coefficient -0.40, r (2) = 0.37; p = 0.020), mainly as a result of decrease in traffic-related deaths (coefficient -0.34, r (2) = 0.85; p < 0.001). The incidence of deaths from injury among elderly (65 years and older) patients increased because of the increase in falls (coefficient 1.71, r (2) = 0.84; p < 0.001) and poisoning (coefficient 0.13, r (2) = 0.69; p < 0.001).

    CONCLUSION: The epidemiology of injury in Sweden has changed during recent years in that mortality from injury has declined in the working age group and increased among those people 64 years old and over.

    Place, publisher, year, edition, pages
    Springer, 2018
    Keywords
    Elderly, Injury, Mortality, Prehospital, Trauma, Working age
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:liu:diva-142763 (URN)10.1007/s00068-017-0827-1 (DOI)000440981100014 ()28825159 (PubMedID)2-s2.0-85027836250 (Scopus ID)
    Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2018-08-22Bibliographically approved
  • 49.
    Bäckström, Denise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Norrköping.
    Larsen, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Steinvall, Ingrid
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gedeborg, Rolf
    Department of Surgical Sciences, Anaesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden..
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Deaths caused by injury among people of working age (18-64) are decreasing, while those among older people (64+) are increasing2018In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 44, no 4, p. 589-596Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Injury is an important cause of death in all age groups worldwide, and contributes to many losses of human and economic resources. Currently, we know a few data about mortality from injury, particularly among the working population. The aim of the present study was to examine death from injury over a period of 14 years (1999-2012) using the Swedish Cause of Death Registry (CDR) and the National Patient Registry, which have complete national coverage.

    METHOD: CDR was used to identify injury-related deaths among adults (18 years or over) during the years 1999-2012. ICD-10 diagnoses from V01 to X39 were included. The significance of changes over time was analyzed by linear regression.

    RESULTS: The incidence of prehospital death decreased significantly (coefficient -0.22, r (2) = 0.30; p = 0.041) during the study period, while that of deaths in hospital increased significantly (coefficient 0.20, r (2) = 0.75; p < 0.001). Mortality/100,000 person-years in the working age group (18-64 years) decreased significantly (coefficient -0.40, r (2) = 0.37; p = 0.020), mainly as a result of decrease in traffic-related deaths (coefficient -0.34, r (2) = 0.85; p < 0.001). The incidence of deaths from injury among elderly (65 years and older) patients increased because of the increase in falls (coefficient 1.71, r (2) = 0.84; p < 0.001) and poisoning (coefficient 0.13, r (2) = 0.69; p < 0.001).

    CONCLUSION: The epidemiology of injury in Sweden has changed during recent years in that mortality from injury has declined in the working age group and increased among those people 64 years old and over.

  • 50.
    Bäckström, Denise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Norrköping.
    Steinvall, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Change in child mortality patterns after injuries in Sweden: a nationwide 14-year study.2017In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 43, no 3, p. 343-349Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Sweden has one of the world's lowest child injury mortality rates, but injuries are still the leading cause of death among children. Child injury mortality in the country has been declining, but this decline seems to decrease recently. Our objective was therefore to further examine changes in the mortality of children's death from injury over time and to assess the contribution of various effects on mortality. The underlying hypothesis for this investigation is that the incidence of lethal injuries in children, still is decreasing and that this may be sex specific.

    PATIENTS AND METHODS: We studied all deaths from injury in Sweden under-18-year-olds during the 14 years 1999-2012. We identified those aged under 18 whose underlying cause of death was recorded as International Classification of Diseases, 10th Revision (ICD-10) diagnosis from V01 to X39 in the Swedish cause of death, where all dead citizens are registered.

    RESULTS: From the 1 January 1999 to 31 December 2012, 1213 children under the age of 18 died of injuries in Sweden. The incidence declined during this period (r = -0.606, p = 0.02) to 3.3 deaths/100,000 children-years (95 % CI 2.6-4.2). Death from unintentional injury was more common than that after intentional injury (p < 0.0001). There was a reduction in the incidence of unintentional injuries during the study period (r = -0.757, p = 0.03). The most common causes of death were injury to the brain (n = 337, 41 %), followed by drowning (n = 109, 13 %). The number of deaths after intentional injury increased (r = 0.585, p = 0.03) and at the end of the period was 1.5 deaths/100,000 children-years. The most common causes of death after intentional injuries were asphyxia (n = 177, 45 %), followed by injury to the brain (n = 76, 19 %).

    DISCUSSION: Mortality patterns in injured children in Sweden have changed from being dominated by unintentional injuries to a more equal distribution between unintentional and intentional injuries as well as between sexes and the overall rate has declined further. These findings are important as they might contribute to the preventive work that is being done to further reduce mortality in injured children.

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