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1.
  • Fullman, N., et al. (författare)
  • Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016
  • 2017
  • Ingår i: Lancet. - 0140-6736 .- 1474-547X. ; 390:10100, s. 1423-1459
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The UN's Sustainable Development Goals (SDGs) are grounded in the global ambition of "leaving no one behind". Understanding today's gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990-2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030. Methods We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0-100, with 0 as the 2.5th percentile estimated between 1990 and 2030, and 100 as the 97.5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country-specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment. Findings Globally, the median health-related SDG index was 56.7 (IQR 31.9-66.8) in 2016 and country-level performance markedly varied, with Singapore (86.8, 95% uncertainty interval 84.6-88.9), Iceland (86.0, 84.1-87.6), and Sweden (85.6, 81.8-87.8) having the highest levels in 2016 and Afghanistan (10.9, 9.6-11.9), the Central African Republic (11.0, 8.8-13.8), and Somalia (11.3, 9.5-13.1) recording the lowest. Between 2000 and 2016, notable improvements in the UHC index were achieved by several countries, including Cambodia, Rwanda, Equatorial Guinea, Laos, Turkey, and China; however, a number of countries, such as Lesotho and the Central African Republic, but also high-income countries, such as the USA, showed minimal gains. Based on projections of past trends, the median number of SDG targets attained in 2030 was five (IQR 2-8) of the 24 defined targets currently measured. Globally, projected target attainment considerably varied by SDG indicator, ranging from more than 60% of countries projected to reach targets for under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria, to less than 5% of countries projected to achieve targets linked to 11 indicator targets, including those for childhood overweight, tuberculosis, and road injury mortality. For several of the health-related SDGs, meeting defined targets hinges upon substantially faster progress than what most countries have achieved in the past. Interpretation GBD 2016 provides an updated and expanded evidence base on where the world currently stands in terms of the health-related SDGs. Our improved measure of UHC offers a basis to monitor the expansion of health services necessary to meet the SDGs. Based on past rates of progress, many places are facing challenges in meeting defined health-related SDG targets, particularly among countries that are the worst off. In view of the early stages of SDG implementation, however, opportunity remains to take actions to accelerate progress, as shown by the catalytic effects of adopting the Millennium Development Goals after 2000. With the SDGs' broader, bolder development agenda, multisectoral commitments and investments are vital to make the health-related SDGs within reach of all populations. Copyright The Authors. Published by Elsevier Ltd. This is an Open Access article published under the CC BY 4.0 license.
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  • Calon, T. G. A., et al. (författare)
  • Minimally Invasive Ponto Surgery Versus the Linear Incision Technique With Soft Tissue Preservation for Bone Conduction Hearing Implants: A Multicenter Randomized Controlled Trial
  • 2018
  • Ingår i: Otology & Neurotology. - : Ovid Technologies (Wolters Kluwer Health). - 1531-7129 .- 1537-4505. ; 39:7, s. 882-893
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective:To compare the surgical outcomes of the Minimally Invasive Ponto Surgery (MIPS) technique with those of the linear incision technique with soft-tissue preservation for bone-anchored hearing systems (BAHS).Design:Sponsor-initiated multicenter, open, randomized, controlled clinical trial.Setting:Maastricht University Medical Centre, Ziekenhuisgroep Twente and Medisch Centrum Leeuwarden, all situated in The Netherlands.Participants:Sixty-four adult patients eligible for unilateral BAHS surgery.Interventions Single-stage BAHS surgery with 1:1 randomization to the linear incision technique with soft-tissue preservation (control) or the MIPS (test) group.Primary and Secondary Outcome Measurements:Primary objective: compare the incidence of inflammation (Holgers Index 2) during 12 weeks' follow-up after surgery. Secondary objectives: skin dehiscence, pain scores, loss of sensibility around the implant, soft-tissue overgrowth, skin sagging, implant extrusion, cosmetic results, surgical time, wound healing and Implant Stability Quotient measurements.Results:Sixty-three subjects were analyzed in the intention-to-treat population. No significant difference was found for the incidence of inflammation between groups. Loss of skin sensibility, cosmetic outcomes, skin sagging, and surgical time were significantly better in the test group. No statistically significant differences were found for dehiscence, pain, and soft-tissue overgrowth. A nonsignificant difference in extrusion was found for the test group. The Implant Stability Quotient was statistically influenced by the surgical technique, abutment length, and time.Conclusion:No significant differences between the MIPS and the linear incision techniques were observed regarding skin inflammation. MIPS results in a statistically significant reduction in the loss of skin sensibility, less skin sagging, improved cosmetic results, and reduced surgical time. Although nonsignificant, the implant extrusion rate warrants further research.
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  • Edberg, Niklas J. T., et al. (författare)
  • Effects of Saturn's magnetospheric dynamics on Titan's ionosphere
  • 2015
  • Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 120:10, s. 8884-8898
  • Tidskriftsartikel (refereegranskat)abstract
    • We use the Cassini Radio and Plasma Wave Science/Langmuir probe measurements of the electron density from the first 110 flybys of Titan to study how Saturn's magnetosphere influences Titan's ionosphere. The data is first corrected for biased sampling due to varying solar zenith angle and solar energy flux (solar cycle effects). We then present results showing that the electron density in Titan's ionosphere, in the altitude range 1600-2400km, is increased by about a factor of 2.5 when Titan is located on the nightside of Saturn (Saturn local time (SLT) 21-03h) compared to when on the dayside (SLT 09-15 h). For lower altitudes (1100-1600km) the main dividing factor for the ionospheric density is the ambient magnetospheric conditions. When Titan is located in the magnetospheric current sheet, the electron density in Titan's ionosphere is about a factor of 1.4 higher compared to when Titan is located in the magnetospheric lobes. The factor of 1.4 increase in between sheet and lobe flybys is interpreted as an effect of increased particle impact ionization from approximate to 200eV sheet electrons. The factor of 2.5 increase in electron density between flybys on Saturn's nightside and dayside is suggested to be an effect of the pressure balance between thermal plus magnetic pressure in Titan's ionosphere against the dynamic pressure and energetic particle pressure in Saturn's magnetosphere.
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  • Calbet, J. A. L., et al. (författare)
  • A time-efficient reduction of fat mass in 4 days with exercise and caloric restriction
  • 2015
  • Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 25:2, s. 223-233
  • Tidskriftsartikel (refereegranskat)abstract
    • To determine whether a fast reduction in fat mass can be achieved in 4 days by combining caloric restriction (CR: 3.2kcal/kg body weight per day) with exercise (8-h walking+45-min arm cranking per day) to induce an energy deficit of approximate to 5000kcal/day, 15 overweight men underwent five experimental phases: pretest, exercise+CR for 4 days (WCR), control diet+reduced exercise for 3 days (DIET), and follow-up 4 weeks (POST1) and 1 year later (POST2). During WCR, the diet consisted solely of whey protein (n=8) or sucrose (n=7) (0.8g/kg body weight per day). After WCR, DIET, POST1, and POST2, fat mass was reduced by a mean of 2.1, 2.8, 3.8, and 1.9kg (P<0.05), with two thirds of this loss from the trunk; and lean mass by 2.8, 1.0, 0.5, and 0.4kg, respectively. After WCR, serum glucose, insulin, homeostatic model assessment, total and low-density lipoprotein cholesterol and triglycerides were reduced, and free fatty acid and cortisol increased. Serum leptin was reduced by 64%, 50%, and 33% following WCR, DIET, and POST1, respectively (P<0.05). The effects were similar in both groups. In conclusion, a clinically relevant reduction in fat mass can be achieved in overweight men in just 4 days by combining prolonged exercise with CR.
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  • Calon, Tim G A, et al. (författare)
  • Minimally Invasive Ponto Surgery compared to the linear incision technique without soft tissue reduction for bone conduction hearing implants: study protocol for a randomized controlled trial.
  • 2016
  • Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Over the last years, less invasive surgical techniques with soft tissue preservation for bone conduction hearing implants (BCHI) have been introduced such as the linear incision technique combined with a punch. Results using this technique seem favorable in terms of rate of peri-abutment dermatitis (PAD), esthetics, and preservation of skin sensibility. Recently, a new standardized surgical technique for BCHI placement, the Minimally Invasive Ponto Surgery (MIPS) technique has been developed by Oticon Medical AB (Askim, Sweden). This technique aims to standardize surgery by using a novel surgical instrumentation kit and minimize soft tissue trauma.A multicenter randomized controlled trial is designed to compare the MIPS technique to the linear incision technique with soft tissue preservation. The primary investigation center is Maastricht University Medical Center. Sixty-two participants will be included with a 2-year follow-up period. Parameters are introduced to quantify factors such as loss of skin sensibility, dehiscence of the skin next to the abutment, skin overgrowth, and cosmetic results. A new type of sampling method is incorporated to aid in the estimation of complications. To gain further understanding of PAD, swabs and skin biopsies are collected during follow-up visits for evaluation of the bacterial profile and inflammatory cytokine expression. The primary objective of the study is to compare the incidence of PAD during the first 3 months after BCHI placement. Secondary objectives include the assessment of parameters related to surgery, wound healing, pain, loss of sensibility of the skin around the implant, implant extrusion rate, implant stability measurements, dehiscence of the skin next to the abutment, and esthetic appeal. Tertiary objectives include assessment of other factors related to PAD and a health economic evaluation.This is the first trial to compare the recently developed MIPS technique to the linear incision technique with soft tissue preservation for BCHI surgery. Newly introduced parameters and sampling method will aid in the prediction of results and complications after BCHI placement.Registered at the CCMO register in the Netherlands on 24 November 2014: NL50072.068.14 . Retrospectively registered on 21 April 2015 at ClinicalTrials.gov: NCT02438618 . This trial is sponsored by Oticon Medical AB.
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  • Lindman, Henrik, et al. (författare)
  • A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1)
  • 2018
  • Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 94, s. 79-86
  • Tidskriftsartikel (refereegranskat)abstract
    • Study aim: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). Methods: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0–2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75–90 mg/m2, C 900–1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3–4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). Results: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3–4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67–1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57–1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. Conclusions: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.
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  • Simpkin, Andrew J., et al. (författare)
  • Prostate-specific antigen patterns in US and European populations : comparison of six diverse cohorts
  • 2016
  • Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 118:6, s. 911-918
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa).SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations.RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations.CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.
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  • Born, D. -P, et al. (författare)
  • Circadian variation of salivary immunoglobin A, alpha-amylase activity and mood in response to repeated double-poling sprints in hypoxia
  • 2016
  • Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 116:1, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To assess the circadian variations in salivary immunoglobin A (sIgA) and alpha-amylase activity (sAA), biomarkers of mucosal immune function, together with mood during 2 weeks of repeated sprint training in hypoxia (RSH) and normoxia (RSN). Methods: Over a 2-week period, 17 competitive cross-country skiers performed six training sessions, each consisting of four sets of five 10-s bouts of all-out double-poling under either normobaric hypoxia (FiO2: 13.8 %, 3000 m) or normoxia. The levels of sIgA and sAA activity and mood were determined five times during each of the first (T1) and sixth (T6) days of training, as well as during days preceding (baseline) and after the training intervention (follow-up). Results: With RSH, sIgA was higher on T6 than T1 (P = 0.049), and sAA was increased on days T1, T6, and during the follow-up (P < 0.01). With RSN, sIgA remained unchanged and sAA was elevated on day T1 only (P = 0.04). Similarly, the RSH group demonstrated reduced mood on days T1, T6, and during the follow-up, while mood was lowered only on T1 with RSN (P < 0.01). Conclusions: The circadian variation of sIgA and sAA activity, biomarkers of mucosal immune function, as well as mood were similar on the first day of training when repeated double-poling sprints were performed with or without hypoxia. Only with RSH did the levels of sIgA and sAA activity rise with time, becoming maximal after six training sessions, when mood was still lowered. Therefore, six sessions of RSH reduced mood, but did not impair mucosal immune function. © 2015, Springer-Verlag Berlin Heidelberg.
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  • Cheng, Arthur J., et al. (författare)
  • Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle
  • 2017
  • Ingår i: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 595:24, s. 7413-7426
  • Tidskriftsartikel (refereegranskat)abstract
    • Key points: We investigated whether intramuscular temperature affects the acute recovery of exercise performance following fatigue-induced by endurance exercise. Mean power output was better preserved during an all-out arm-cycling exercise following a 2 h recovery period in which the upper arms were warmed to an intramuscular temperature of ˜ 38°C than when they were cooled to as low as 15°C, which suggested that recovery of exercise performance in humans is dependent on muscle temperature. Mechanisms underlying the temperature-dependent effect on recovery were studied in intact single mouse muscle fibres where we found that recovery of submaximal force and restoration of fatigue resistance was worsened by cooling (16-26°C) and improved by heating (36°C). Isolated whole mouse muscle experiments confirmed that cooling impaired muscle glycogen resynthesis. We conclude that skeletal muscle recovery from fatigue-induced by endurance exercise is impaired by cooling and improved by heating, due to changes in glycogen resynthesis rate.Manipulation of muscle temperature is believed to improve post-exercise recovery, with cooling being especially popular among athletes. However, it is unclear whether such temperature manipulations actually have positive effects. Accordingly, we studied the effect of muscle temperature on the acute recovery of force and fatigue resistance after endurance exercise. One hour of moderate-intensity arm cycling exercise in humans was followed by 2 h recovery in which the upper arms were either heated to 38°C, not treated (33°C), or cooled to ∼15°C. Fatigue resistance after the recovery period was assessed by performing 3 × 5 min sessions of all-out arm cycling at physiological temperature for all conditions (i.e. not heated or cooled). Power output during the all-out exercise was better maintained when muscles were heated during recovery, whereas cooling had the opposite effect. Mechanisms underlying the temperature-dependent effect on recovery were tested in mouse intact single muscle fibres, which were exposed to ∼12 min of glycogen-depleting fatiguing stimulation (350 ms tetani given at 10 s interval until force decreased to 30% of the starting force). Fibres were subsequently exposed to the same fatiguing stimulation protocol after 1-2 h of recovery at 16-36°C. Recovery of submaximal force (30 Hz), the tetanic myoplasmic free [Ca2+] (measured with the fluorescent indicator indo-1), and fatigue resistance were all impaired by cooling (16-26°C) and improved by heating (36°C). In addition, glycogen resynthesis was faster at 36°C than 26°C in whole flexor digitorum brevis muscles. We conclude that recovery from exhaustive endurance exercise is accelerated by raising and slowed by lowering muscle temperature.
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  • Fell, SM, et al. (författare)
  • Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA
  • 2017
  • Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 31:10, s. 1036-1053
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently identified pathogenic KIF1Bβ mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bβ in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bβ mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bβ-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bβ loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bβ mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
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  • Gejl, K. D., et al. (författare)
  • Repeated high-intensity exercise modulates Ca2+ sensitivity of human skeletal muscle fibers
  • 2016
  • Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 26:5, s. 488-497
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of short-term high-intensity exercise on single fiber contractile function in humans are unknown. Therefore, the purposes of this study were: (a) to access the acute effects of repeated high-intensity exercise on human single muscle fiber contractile function; and (b) to examine whether contractile function was affected by alterations in the redox balance. Eleven elite cross-country skiers performed four maximal bouts of 1300m treadmill skiing with 45min recovery. Contractile function of chemically skinned single fibers from triceps brachii was examined before the first and following the fourth sprint with respect to Ca2+ sensitivity and maximal Ca2+-activated force. To investigate the oxidative effects of exercise on single fiber contractile function, a subset of fibers was incubated with dithiothreitol (DTT) before analysis. Ca2+ sensitivity was enhanced by exercise in both MHC I (17%, P<0.05) and MHC II (15%, P<0.05) fibers. This potentiation was not present after incubation of fibers with DTT. Specific force of both MHC I and MHC II fibers was unaffected by exercise. In conclusion, repeated high-intensity exercise increased Ca2+ sensitivity in both MHC I and MHC II fibers. This effect was not observed in a reducing environment indicative of an exercise-induced oxidation of the human contractile apparatus.
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  • Gillman, Anna, et al. (författare)
  • Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards
  • 2015
  • Ingår i: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 81:7, s. 2378-2383
  • Tidskriftsartikel (refereegranskat)abstract
    • Influenza A virus (IAV) has its natural reservoir in wild waterfowl and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate (OC)), stockpiled as Tamiflu® for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may there exert evolutionary pressure on avian IAV in waterfowl, resulting in development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo Mallard (Anas platyrhynchos) study we tested if an OC-resistant avian IAV strain (A(H1N1)/NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected Mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission in 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV, induced by OC exposure of the natural host, can persist in absence of the drug. Thus, there is a risk that human pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir resistant pandemic IAV would be a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment and resistance surveillance of IAV in wild birds.
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  • Jimenez-Pascual, Ana, et al. (författare)
  • ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells
  • 2019
  • Ingår i: Cancer Discovery. - 2159-8274 .- 2159-8290. ; 9:11, s. 1574-1589
  • Tidskriftsartikel (refereegranskat)abstract
    • Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM.Significance: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.
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19.
  • Killander, F., et al. (författare)
  • No breast cancer subgroup can be spared postoperative radiotherapy after breast-conserving surgery. Fifteen-year results from the Swedish Breast Cancer Group randomised trial, SweBCG 91 RT
  • 2016
  • Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 67, s. 57-65
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients. Patients and methods A total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 years and thereafter referred to the Swedish mammography screening program. Results After 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P < 0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P = 0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P = 0.68, nor was breast cancer–specific mortality significantly higher. Conclusions RT after BCS significantly reduced the incidence of IBTR at 15 years of follow-up. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systemic therapy are needed to omit RT after BCS.
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  • Larsen, Filip J, et al. (författare)
  • High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation
  • 2016
  • Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 30:1, s. 417-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Intense exercise training is a powerful stimulus that activates mitochondrial biogenesis pathways and thus increases mitochondrial density and oxidative capacity. Moderate levels of reactive oxygen species (ROS) during exercise are considered vital in the adaptive response, but high ROS production is a serious threat to cellular homeostasis. Although biochemical markers of the transition from adaptive to maladaptive ROS stress are lacking, it is likely mediated by redox sensitive enzymes involved in oxidative metabolism. One potential enzyme mediating such redox sensitivity is the citric acid cycle enzyme aconitase. In this study, we examined biopsy specimens of vastus lateralis and triceps brachii in healthy volunteers, together with primary human myotubes. An intense exercise regimen inactivated aconitase by 55-72%, resulting in inhibition of mitochondrial respiration by 50-65%. In the vastus, the mitochondrial dysfunction was compensated for by a 15-72% increase in mitochondrial proteins, whereas H2O2 emission was unchanged. In parallel with the inactivation of aconitase, the intermediary metabolite citrate accumulated and played an integral part in cellular protection against oxidative stress. In contrast, the triceps failed to increase mitochondrial density, and citrate did not accumulate. Instead, mitochondrial H2O2 emission was decreased to 40% of the pretraining levels, together with a 6-fold increase in protein abundance of catalase. In this study, a novel mitochondrial stress response was highlighted where accumulation of citrate acted to preserve the redox status of the cell during periods of intense exercise.
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21.
  • Martin-Rincon, M., et al. (författare)
  • Exercise mitigates the loss of muscle mass by attenuating the activation of autophagy during severe energy deficit
  • 2019
  • Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 11:11
  • Tidskriftsartikel (refereegranskat)abstract
    • The loss of skeletal muscle mass with energy deficit is thought to be due to protein breakdown by the autophagy-lysosome and the ubiquitin-proteasome systems. We studied the main signaling pathways through which exercise can attenuate the loss of muscle mass during severe energy deficit (5500 kcal/day). Overweight men followed four days of caloric restriction (3.2 kcal/kg body weight day) and prolonged exercise (45 min of one-arm cranking and 8 h walking/day), and three days of control diet and restricted exercise, with an intra-subject design including biopsies from muscles submitted to distinct exercise volumes. Gene expression and signaling data indicate that the main catabolic pathway activated during severe energy deficit in skeletal muscle is the autophagy-lysosome pathway, without apparent activation of the ubiquitin-proteasome pathway. Markers of autophagy induction and flux were reduced by exercise primarily in the muscle submitted to an exceptional exercise volume. Changes in signaling are associated with those in circulating cortisol, testosterone, cortisol/testosterone ratio, insulin, BCAA, and leucine. We conclude that exercise mitigates the loss of muscle mass by attenuating autophagy activation, blunting the phosphorylation of AMPK/ULK1/Beclin1, and leading to p62/SQSTM1 accumulation. This includes the possibility of inhibiting autophagy as a mechanism to counteract muscle loss in humans under severe energy deficit. 
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22.
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23.
  • Simpkin, Andrew J, et al. (författare)
  • Development, validation and evaluation of an instrument for active monitoring of men with clinically localised prostate cancer : systematic review, cohort studies and qualitative study
  • 2015
  • Ingår i: Health Services and Delivery Research. - : National Institute for Health Research. - 2050-4349 .- 2050-4357. ; 3:30
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Active surveillance [(AS), sometimes called active monitoring (AM)],is a National Institute for Health and Care Excellence-recommended management option for men with clinically localised prostate cancer (PCa). It aims to target radical treatment only to those who would benefit most. Little consensus exists nationally or internationally about safe and effective protocols for AM/AS or triggers that indicate if or when men should move to radical treatment.Objective:The aims of this project were to review how prostate-specific antigen (PSA) has been used in AM/AS programmes; to develop and test the validity of a new model for predicting future PSA levels; to develop an instrument, based on PSA, that would be acceptable and effective for men and clinicians to use in clinical practice; and to design a robust study to evaluate the cost-effectiveness of the instrument.Methods:A systematic review was conducted to investigate how PSA is currently used to monitor men in worldwide AM/AS studies. A model for PSA change with age was developed using Prostate testing for cancer and Treatment (ProtecT) data and validated using data from two PSA-era cohorts and two pre-PSA-era cohorts. The model was used to derive 95% PSA reference ranges (PSARRs) across ages. These reference ranges were used to predict the onset of metastases or death from PCa in one of the pre-PSA-era cohorts. PSARRs were incorporated into an active monitoring system (AMS) and demonstrated to 18 clinicians and 20 men with PCa from four NHS trusts. Qualitative interviews investigated patients’ and clinicians’ views about current AM/AS protocols and the acceptability of the AMS within current practice.Results:The systematic review found that the most commonly used triggers for clinical review of PCa were PSA doubling time (PSADT) < 3 years or PSA velocity (PSAv) > 1 ng/ml/year. The model for PSA change (developed using ProtecT study data) predicted PSA values in AM/AS cohorts within 2 ng/ml of observed PSA in up to 79% of men. Comparing the three PSA markers, there was no clear optimal approach to alerting men to worsening cancer. The PSARR and PSADT markers improved the model c-statistic for predicting death from PCa by 0.11 (21%) and 0.13 (25%), respectively, compared with using diagnostic information alone [PSA, age, tumour stage (T-stage)]. Interviews revealed variation in clinical practice regarding eligibility and follow-up protocols. Patients and clinicians perceive current AM/AS practice to be framed by uncertainty, ranging from uncertainty about selection of eligible AM/AS candidates to uncertainty about optimum follow-up protocols and thresholds for clinical review/radical treatment. Patients and clinicians generally responded positively to the AMS. The impact of the AMS on clinicians’ decision-making was limited by a lack of data linking AMS values to long-term outcomes and by current clinical practice, which viewed PSA measures as one of several tools guiding clinical decisions in AM/AS. Patients reported that they would look to clinicians, rather than to a tool, to direct decision-making.Limitations:The quantitative findings were severely hampered by a lack of clinical outcomes or events (such as metastases). The qualitative findings were limited through reliance on participants’ reports of practices and recollections of events rather than observations of actual interactions.Conclusions:Patients and clinicians found that the instrument provided additional, potentially helpful, information but were uncertain about the current usefulness of the risk model we developed for routine management. Comparison of the model with other monitoring strategies will require clinical outcomes from ongoing AM/AS studies.Funding:The National Institute for Health Research Health Services and Delivery Research programme.
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24.
  • Simpkin, Andrew J, et al. (författare)
  • Systematic Review and Meta-analysis of Factors Determining Change to Radical Treatment in Active Surveillance for Localized Prostate Cancer.
  • 2015
  • Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 67:6
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Many men with clinically localized prostate cancer are being monitored as part of active surveillance (AS) programs, but little is known about reasons for receiving radical treatment.OBJECTIVES: A systematic review of the evidence about AS was undertaken, with a meta-analysis to identify predictors of radical treatment.EVIDENCE ACQUISITION: A comprehensive search of the Embase, MEDLINE and Web of Knowledge databases to March 2014 was performed. Studies reporting on men with localized prostate cancer followed by AS or monitoring were included. AS was defined where objective eligibility criteria, management strategies, and triggers for clinical review or radical treatment were reported.EVIDENCE SYNTHESIS: The 26 AS cohorts included 7627 men, with a median follow-up of 3.5 yr (range of medians 1.5-7.5 yr). The cohorts had a wide range of inclusion criteria, monitoring protocols, and triggers for radical treatment. There were eight prostate cancer deaths and five cases of metastases in 24,981 person-years of follow-up. Each year, 8.8% of men (95% confidence interval 6.7-11.0%) received radical treatment, most commonly because of biopsy findings, prostate-specific antigen triggers, or patient choice driven by anxiety. Studies in which most men changed treatment were those including only low-risk Gleason score 6 disease and scheduled rebiopsies.CONCLUSIONS: The wide variety of AS protocols and lack of robust evidence make firm conclusions difficult. Currently, patients and clinicians have to make judgments about the balance of risks and benefits in AS protocols. The publication of robust evidence from randomized trials and longer-term follow-up of cohorts is urgently required.PATIENT SUMMARY: We reviewed 26 studies of men on active surveillance for prostate cancer. There was evidence that studies including men with the lowest risk disease and scheduled rebiopsy had higher rates of radical treatment.
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25.
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26.
  • Stalberg, K., et al. (författare)
  • Lymphovascular space invasion as a predictive factor for lymph node metastases and survival in endometrioid endometrial cancer - a Swedish Gynecologic Cancer Group (SweGCG) study
  • 2019
  • Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 58:11, s. 1628-1633
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The aim of this study is to evaluate the impact of lymphovascular space invasion (LVSI) on the risk of lymph node metastases and survival in endometrioid endometrial adenocarcinoma. Material and methods: As regard the study design, this is a cohort study based on prospectively recorded data. Patients with endometrioid endometrial adenocarcinoma registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2017 with FIGO stages I-III and verified nodal status were identified (n = 1587). LVSI together with established risk factors, namely DNA ploidy, FIGO grade, myometrial invasion and age, were included in multivariable regression analyses with lymph node metastases as the dependent variable. Associations between the risk factors and overall and relative survival were included in multivariable models. Estimates of risk ratios (RR), hazard ratios (HR), excess mortality rate ratios (EMR), and 95% confidence intervals (95% CI) were calculated. Results: The presence of LVSI presented the strongest association with lymph node metastases (RR = 5.46, CI 3.69-8.07, p < .001) followed by deep myometrial invasion (RR = 1.64, CI 1.13-2.37). In the multivariable survival analyses, LVSI (EMR = 7.69, CI 2.03-29.10,) and non-diploidy (EMR = 3.23, CI 1.25-8.41) were associated with decreased relative survival. In sub-analyses including only patients with complete para-aortic and pelvic lymphadenectomy and negative lymph nodes (n = 404), only LVSI (HR = 2.50, CI 1.05-5.98) was associated with a worsened overall survival. Conclusion: This large nationwide study identified LVSI as the strongest independent risk factor for lymph node metastases and decreased survival in patients with endometrioid adenocarcinomas. Moreover, decreased overall survival was also seen in patients with LVSI-positive tumors and negative lymph nodes, indicating that hematogenous dissemination might also be important.
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27.
  • Stray-Pedersen, Asbjorg, et al. (författare)
  • Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
  • 2017
  • Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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28.
  • Thorn, L. M., et al. (författare)
  • Clinical and MRI Features of Cerebral Small-Vessel Disease in Type 1 Diabetes
  • 2019
  • Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:2, s. 327-330
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVETo assess the prevalence of cerebral small-vessel disease (SVD) in subjects with type 1 diabetes compared with healthy control subjects and to characterize the diabetes-related factors associated with SVD.RESEARCH DESIGN AND METHODSThis substudy was cross-sectional in design and included 191 participants with type 1 diabetes and median age 40.0 years (interquartile range 33.0-45.1) and 30 healthy age- and sex-matched control subjects. All participants underwent clinical investigation and brain MRIs, assessed for cerebral SVD.RESULTSCerebral SVD was more common in participants with type 1 diabetes than in healthy control subjects: any marker 35% vs. 10% (P = 0.005), cerebral microbleeds (CMBs) 24% vs. 3.3% (P = 0.008), white matter hyperintensities 17% vs. 6.7% (P = 0.182), and lacunes 2.1% vs. 0% (P = 1.000). Presence of CMBs was independently associated with systolic blood pressure (odds ratio 1.03 [95% CI 1.00-1.05], P = 0.035).CONCLUSIONSCerebral SVD, CMBs in particular, is more common in young people with type 1 diabetes compared with healthy control subjects.
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29.
  • Wedenoja, S, et al. (författare)
  • A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR
  • 2017
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 14208-
  • Tidskriftsartikel (refereegranskat)abstract
    • Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital chloride diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish (P < 0.05) and over 120,000 global alleles (P < 0.0001) (ExAC database). Functional studies showed that while SLC26A3 is a strong activator of CFTR-dependent anion transport, SLC26A3-p.Asp688His mutant retains normal Cl−/HCO3− exchange activity but suppresses CFTR, despite unaffected domain binding and expression. These results suggest a novel mechanism for human male infertility─impaired anion transport by the coupled SLC26A3 and CFTR.
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30.
  • Zinner, Christoph, et al. (författare)
  • The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans
  • 2016
  • Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 7:SEP
  • Tidskriftsartikel (refereegranskat)abstract
    • To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 x 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO(2)peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO(2)peak and Wmax increased 3-11% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8%, P < 0.05), but not the legs (-0.6%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, V-E, and V-t were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O-2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.
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31.
  • Aksel Jacobsen, Freja, et al. (författare)
  • A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation
  • 2018
  • Ingår i: Journal of Neuroimmune Pharmacology. - New York, NY : Springer-Verlag New York. - 1557-1890 .- 1557-1904. ; 13:2, s. 265-276
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis. © 2018 The Author(s)
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32.
  • Andersson, Erik, 1984- (författare)
  • PHYSIOLOGICAL AND BIOMECHANICAL FACTORS DETERMINING CROSS-COUNTRY SKIING PERFORMANCE
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Cross-country (c.c.) skiing is a complex sport discipline from both physiological and biomechanical perspectives, with varying course topographies that require different proportions of the involved sub-techniques to be utilised. A relatively new event in c.c. skiing is the sprint race, involving four separate heats, each lasting 2-4 min, with diverse demands from distance races associated with longer durations. Therefore, the overall aim of the current thesis has been to examine the biomechanical and physiological factors associated with sprint c.c. skiing performance through novel measurements conducted both in the field (Studies I-III) and the laboratory (Studies IV and V).In Study I sprint skiing velocities and sub-techniques were analysed with a differential global navigation satellite system in combination with video recording. In Studies II and III the effects of an increasing velocity (moderate, high and maximal) on the biomechanics of uphill classical skiing with the diagonal stride (DS) (Study II) and herringbone (HB) (Study III) sub-techniques were examined.In Study I the skiers completed the 1,425 m (2 x 712 m) sprint time trial (STT) in 207 s, at an average velocity of 24.8 km/h, with multiple technique transitions (range: 21-34) between skiing techniques (i.e., the different gears [G2-7]). A pacing strategy involving a fast start followed by a gradual slowing down (i.e., positive pacing) was employed as indicated by the 2.9% faster first than second lap. The slower second lap was primarily related to a slower (12.9%) uphill velocity with a shift from G3 towards a greater use of G2. The maximal oxygen uptake ( O2max) was related to the ability to maintain uphill skiing velocity and the fastest skiers used G3 to a greater extent than G2. In addition, maximal speed over short distances (50 and 20 m) with the G3 and double poling (DP) sub-techniques exerted an important impact on STT performance.Study II demonstrated that during uphill skiing (7.5°) with DS, skiers increased cycle rate and cycle length from moderate to high velocity, while cycle rate increased and cycle length decreased at maximal velocity. Absolute poling, gliding and kick times became gradually shorter with an elevated velocity. The rate of pole and leg force development increased with elevated velocity and the development of leg force in the normal direction was substantially faster during skiing on snow than previous findings for roller skiing, although the peak force was similar in both cases. The fastest skiers applied greater peak leg forces over shorter durations.Study III revealed that when employing the HB technique on a steep uphill slope (15°), the skiers positioned their skis laterally (“V” between 25 to 30°) and planted their poles at a slight lateral angle (8 to 12°), with most of the propulsive force being exerted on the inside forefoot. Of the total propulsive force, 77% was generated by the legs. The cycle rate increased across all three velocities (from 1.20 to 1.60 Hz), while cycle length only increased from moderate to high velocity (from 2.0 to 2.3 m). Finally, the magnitude and rate of leg force generation are important determinants of both DS and HB skiing performance, although the rate is more important in connection with DS, since this sub-technique involves gliding.In Studies IV and V skiers performed pre-tests for determination of gross efficiency (GE), O2max, and Vmax on a treadmill. The main performance test involved four self-paced STTs on a treadmill over a 1,300-m simulated course including three flat (1°) DP sections interspersed with two uphill (7°) DS sections.The modified GE method for estimating anaerobic energy production during skiing on varying terrain employed in Study IV revealed that the relative aerobic and anaerobic energy contributions were 82% and 18%, respectively, during the 232 s of skiing, with an accumulated oxygen (O2) deficit of 45 mL/kg. The STT performance time was largely explained by the GE (53%), followed by O2 (30%) and O2 deficit (15%). Therefore, training strategies designed to reduce energetic cost and improve GE should be examined in greater detail.In Study V metabolic responses and pacing strategies during the four successive STTs were investigated. The first and the last trials were the fastest (both 228 s) and were associated with both a substantially larger and a more rapid anaerobic energy supply, while the average O2 during all four STTs was similar. The individual variation in STT performance was explained primarily (69%) by the variation in O2 deficit. Furthermore, positive pacing was employed throughout all the STTs, but the pacing strategy became more even after the first trial. In addition, considerably higher (~ 30%) metabolic rates were generated on the uphill than on the flat sections of the course, reflecting an irregular production of anaerobic energy. Altogether, a fast start appears important for STT performance and high work rates during uphill skiing may exert a more pronounced impact on skiing performance outdoors, due to the reduction in velocity fluctuations and thereby overall air-drag.
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34.
  • Azzinnari, M, et al. (författare)
  • Efectos del ejercicio en la señalización de NF-kB durante la restricción calórica severa
  • 2017
  • Konferensbidrag (refereegranskat)abstract
    • El sobrepeso y la obesidad, en crecimiento en todo el mundo, se asocian con una alta tasa de mortalidad e morbilidad[1,2]. La causa principal que conduce a éstas condiciones patológicas es un balance energético positivo sostenido a largo plazo, debido a la inactividad física y la ingesta calórica excesiva[3]. Por lo tanto, ejercicio físico y restricción calórica podrían ser dos estratégias eficaces para prevenir y contrastar el excesivo acumulo de grasa corporal que caracteriza estas patologías. Sin embargo, durante dietas muy bajas en calorías (<800 Kcal/día) se pierde no solo masa grasa sino también masa muscular, reportando efectos negativos para la salud[4]. En dichas condiciones,  el ejercicio físico permite preservar masa muscular de manera local y dosis-dependiente, mientras la ingestión de proteínas no ejerce particulares efectos protectivos sobre el tejido contráctil[5]. Los mecanismos moleculares implicados en la preservación de la masa muscular inducida por el ejercicio durante este tipo de dietas no han sido definidos claramente. NF-kB es un factor de transcripción cuya activación provoca atrofia muscular, y su bloqueo puede parcialmente limitar este fenomeno[6]. NF-kB se ha mostrado activado de manera aguda por el ejercicio y la restricción calorica, sin embargo no ha sido definida su respuesta a la restricción calórica en conjunción con el ejercicio prolongado de baja intensidad. Además, cuando los niveles basales de NF-kB son altos, el ejercicio no parece aumentar ulteriormente su señalización[7]. Por las razones presentadas, NF-kB podría desempeñar un rol en la preservación de masa magra inducida por el ejercicio durante  la restricción calórica.El objetivo del estudio es establecer la respuesta de NF-kB a la restricción calórica severa en conjunción con el ejercicio prolongado de baja intensidad. Las hipótesis fueron las siguientes: 1) la restricción calórica severa activaría la via de NF-kB y 2) dicha activación será atenuada por el ejercicio de manera local y dosis-dependiente.15 sujetos con sobrepeso y obesidad fueron sometidos a tres fases experimentales: fase 1, en la que la dieta y el nivel de actividad física de los participantes fue monitorizado durante una semana (PRE); fase 2, caracterizada por cuatro días de ejercicio prolongado y de restricción calórica severa (RCE); fase 3, caracterizada por tres días de ejercicio reducido y una dieta isoenergética (DC). Durante la fase 2, los sujetos ingeriron hidratos de carbono o proteínas (0.8 g/kg peso corporal/día; 320 kcal/día) y hicieron 45 minutos de pedaleo con un solo miembro superior (15% Ppeak) seguidos de 8 horas de caminata (4.5 km/h; 35 km/día). Las biopsias musculares fueron recogidas de ambos los deltoides y del vasto lateral en la fase 1 y después de la fase 2 y 3. Mediante Western blot, se determinó la expresión de NF-κB p105, NF-κB p50, la fosforilación de la Serina 32/36 de IκBα e IκBα total. La composición corporal se midió mediante DXA. Estadística: ANOVA para medidas repetidas.Durante los 4 días de restricción calórica severa el deficit energético fue de 5500 Kcal. Después de la fase 2 los sujetos perdieron menos masa magra en los miembros inferiores y en el brazo ejercitado respecto al brazo de control: 57% (P<0.05) y 29% (P=0.05), respectivamente. Tras la fase 2 y 3, el contenido de p105 y de p50 fue menor en los miembros inferiores respecto a los superiores: efecto extremidad P=0.003 y P=0.024 para p105 y p50, respectivamente. Tras la fase 3, la fosforilación de la Serina 32/36 de IkBα aumentó únicamente en las piernas, mientras la expresión total IkBα fue mayor solo en los miembros ejercitados (P<0.05).El ejercicio físico atenuó la activación de la señalización de NF-kB durante 4 días de restricción calórica severa, limitando el incremento de la expresión de p50 y p105, que resultó más baja después de la fase 2 y la fase 3 en los miembros inferiores respecto a los miembros superiores, posiblemente debido a la mayor cantidad de ejercicio a la que fueron sometidos. Además, la expresión total de IkBα fue más alta tras la fase 3 solo en los miembros ejercitados, indicando una posible inhibición de la vía de   NF-kB inducida por el ejercicio. Por lo tanto, dado la menor activación de la señalización de NF-kB en los miembros que perdieron menor masa muscular, los resultados sugieren que los efectos protectores del ejercicio físico sobre el tejido contráctil podrían ser mediados a una menor activación de la señalización de NF-kB.El ejercicio físico desempeña una función preservadora sobre la masa muscular durante la restricción calórica severa. La preservación de masa muscular es dosis-dependiente (a mayor volumen, mayor preservación) y está mediada, al menos parcialmente, por una menor activación de la señalización por NF-kB.1.Hill, J. O., H. R. Wyatt, et al. (2012). Circulation 126(1): 126-132.2.Di Angelantonio, E., N. Bhupathiraju Sh, et al. (2016). Lancet 388(10046): 776-786. 3.Chaston, T. B., J. B. Dixon, et al. (2007). Int J Obes (Lond) 31(5): 743-750. 4.Calbet, J. A., J. G. Ponce-Gonzalez, et al. (2017). Front Physiol (Accepted, In press).5.Cai, D., J. D. Frantz, et al. (2004). Cell 119(2): 285-298.6.Tantiwong, P., K. Shanmugasundaram, et al. (2010). Am J Physiol Endocrinol Metab 299(5): E794-801.7.NCD-RisC (2016). Lancet 387(10026): 1377-1396.
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35.
  • Berclaz, Corinne, et al. (författare)
  • Label-free fast 3D coherent imaging reveals pancreatic islet micro-vascularization and dynamic blood flow
  • 2016
  • Ingår i: Biomedical Optics Express. - 2156-7085. ; 7:11, s. 4569-4580
  • Tidskriftsartikel (refereegranskat)abstract
    • In diabetes, pancreatic ß-cells play a key role. These cells are clustered within structures called islets of Langerhans inside the pancreas and produce insulin, which is directly secreted into the blood stream. The dense vascularization of islets of Langerhans is critical for maintaining a proper regulation of blood glucose homeostasis and is known to be affected from the early stage of diabetes. The deep localization of these islets inside the pancreas in the abdominal cavity renders their in vivo visualization a challenging task. A fast label-free imaging method with high spatial resolution is required to study the vascular network of islets of Langerhans. Based on these requirements, we developed a label-free and three-dimensional imaging method for observing islets of Langerhans using extended-focus Fourier domain Optical Coherence Microscopy (xfOCM). In addition to structural imaging, this system provides threedimensional vascular network imaging and dynamic blood flow information within islets of Langerhans. We propose our method to deepen the understanding of the interconnection between diabetes and the evolution of the islet vascular network.
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36.
  • Berghog, J, et al. (författare)
  • Women and groin hernia repair
  • 2015
  • Ingår i: 1ST World Conference on Abdominal Wall Hernia Surgery, Milan, April, 2015. ; , s. S285-S285
  • Konferensbidrag (refereegranskat)abstract
    • The lifetime risk of having a groin hernia repair is estimated to be 27% for men and 3% for women. Recently published register data showing an increased recurrence rate in women compared to men raises questions concerning method of choice for female groin hernia.
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37.
  • Berndt, Adele, 1966-, et al. (författare)
  • Mobilapplikationer inom dagligvaruhandeln Konsumtionens medialisering genom nya digitala tjänster
  • 2017
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Projektet “Medialiserad shopping” utforskar den växande andelen digitala element inom detaljhandeln, samt hur nya tekniska verktyg förändrar shopping som vardagsrutin och kundupplevelse. Materialet belyser hur kunderna upplever den nya teknikens roll och visar samtidigt på de driv krafter som ligger bakom digital innovation bland detaljhandlare. Rapporten sammanfattar det arbete som utförts inom projektet och tar upp frågor kring utvecklingen och användningen av digitala medier inom omnikanalhandeln. Under 2015–2016 genomförde forskare vid Jönköping University och Göteborgs universitet en serie studier av matvarubutikernas omnikanalmiljö i vilka kunder och andra intressenter deltog. En rad olika metoder för datainsamling användes, till exempel enkäter som besvarades av cirka 500 kunder, djupintervjuer och deltagande observationer av konsumenter, kunddagböcker och fler än 150 videoobservationer. • Kvantitativa data visar på ett växande antal användare av shoppingappar, men att användningsgraden ökar långsammare än förväntat. • Appanvändning och besöksfrekvens går hand i hand, vilket kan tolkas som att appanvändarna är mer butikslojala än genomsnittskunden. • Vidare ser inte kunderna appen som ett sammanhållet teknologiskt servicepaket, utan väljer ut de funktioner som motsvarar deras specifika behov och struntar i resten. • Än så länge har introduktionen av den nya tekniken inte förändrat beteendemönstren i någon större utsträckning. Funktionerna är normalt sett utformade så att de härmar redan existerande verktyg och kundvanor. I den mån kunderna använder mobila enheter i butiken handlar detta enbart om att ersätta gammal teknik, som till exempel papper och penna för att hålla reda på inköpslistan eller handenheten vid självskanning. • Kvalitativa data insamlade genom intervjuer med, observationer av och dagböcker skrivna av konsumenter visar att mobiltelefonen uppfyller en rad emotionella och praktiska funktioner under shoppingen, men att detaljhandlarna inte alls har tagit fasta på de emotionella aspekterna. • När det gäller detaljhandlarna beskriver rapporten tre huvudsakliga drivkrafter som påverkar apputvecklingen: i) handlarnas uppfattning av konkurrensmiljön, ii) utvecklingen av kunders köpbeteenden, samt iii) organisatoriska begränsningar, det vill säga i vilken utsträckning organisationens försörjningskedjor och distributions- strukturer tillåter att handlaren skapar nya tjänster baserat på mobil teknik.
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38.
  • Bhatt, Deepak L., et al. (författare)
  • Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
  • 2019
  • Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
  • Tidskriftsartikel (refereegranskat)abstract
    • In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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39.
  • Bill-Axelson, Anna, et al. (författare)
  • Radical Prostatectomy or Watchful Waiting in Prostate Cancer-29-Year Follow-up
  • 2018
  • Ingår i: New England Journal of Medicine. - : Massachussetts Medical Society. - 0028-4793 .- 1533-4406. ; 379:24, s. 2319-2329
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term followup is sparse. METHODS We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model. RESULTS By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer). CONCLUSIONS Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.
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40.
  • Bratt, Ola, 1963, et al. (författare)
  • The Value of an Extensive Transrectal Repeat Biopsy with Anterior Sampling in Men on Active Surveillance for Low-risk Prostate Cancer: A Comparison from the Randomised Study of Active Monitoring in Sweden (SAMS)
  • 2019
  • Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 76:4, s. 461-466
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A systematic repeat biopsy is recommended for men starting on active surveillance for prostate cancer, but the optimal number and distribution of cores are unknown. Objective: To evaluate an extensive repeat transrectal biopsy with anterior sampling in men starting on active surveillance. Design, setting, and participants: Randomised multicentre trial. From 2012 to 2016, 340 Swedish men, aged 40-75 yr, with recently diagnosed low-volume Gleason grade group 1 prostate cancer were included. Intervention: Either an extensive transrectal biopsy with anterior sampling (median 19 cores) or a standard transrectal biopsy (median 12 cores). Outcome measurements and statistical analysis: Primary outcome measure: Gleason grade group >= 2 cancer. Secondary outcomes: Cancer in anteriorly directed biopsy cores and postbiopsy infection. Nonparametric statistical tests were applied. Results and limitations: Gleason grade group >= 2 cancer was detected in 16% of 156 men who had an extensive biopsy and in 10% of 164 men who had a standard biopsy, a 5.7% difference (95% confidence interval [CI]-0.2% to 13%, p = 0.09). There was a strong linear association between prostate-specific antigen (PSA) density and cancer in the anteriorly directed biopsy cores. The odds ratios for cancer in the anteriorly directed cores were for any cancer 2.2 (95% CI 1.3-3.9, p = 0.004) and for Gleason grade group >= 2 cancer 2.3 (95% CI 1.2-4.4, p = 0.015) per 0.1-ng/ml/cm(3) increments. Postbiopsy infections were equally common in the two groups. A limitation is that magnetic resonance imaging was not used. Conclusions: The trial did not support general use of the extensive transrectal repeat biopsy template, but cancer in the anteriorly directed cores was common, particularly in men with high PSA density. The higher the PSA density, the stronger the reason to include anterior sampling at a systematic repeat biopsy. Patient summary: This trial compared two different templates for transrectal prostate biopsy in men starting on active surveillance for low-risk prostate cancer. Cancer was often found in the front part of the prostate, which is not sampled on a standard prostate biopsy. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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41.
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42.
  • Bringman, S., et al. (författare)
  • Location of recurrent groin hernias at TEP after Lichtenstein repair : a study based on the Swedish Hernia Register
  • 2016
  • Ingår i: Hernia. - : Springer Science and Business Media LLC. - 1265-4906 .- 1248-9204. ; 20:3, s. 387-391
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate which type of hernia that has the highest risk of a recurrence after a primary Lichtenstein repair. Male patients operated on with a Lichtenstein repair for a primary direct or indirect inguinal hernia and with a TEP for a later recurrence, with both operations recorded in the Swedish Hernia Register (SHR), were included in the study. The study period was 1994-2014. Under the study period, 130,037 male patients with a primary indirect or direct inguinal hernia were operated on with a Lichtenstein repair. A second operation in the SHR was registered in 2236 of these patients (reoperation rate 1.7 %). TEP was the chosen operation in 737 in this latter cohort. The most likely location for a recurrence was the same as the primary location. If the recurrences change location from the primary place, we recognized that direct hernias had a RR of 1.51 to having a recurrent indirect hernia compared to having a direct recurrence after an indirect primary hernia repair. Recurrent hernias after Lichtenstein are more common on the same location as the primary one, compared to changing the location.
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43.
  • Brouwer, PA, et al. (författare)
  • Thrombectomy using the EmboTrap device: core laboratory-assessed results in 201 consecutive patients in a real-world setting
  • 2018
  • Ingår i: Journal of neurointerventional surgery. - : BMJ. - 1759-8486 .- 1759-8478. ; 10:10, s. 964-
  • Tidskriftsartikel (refereegranskat)abstract
    • We studied patients treated with the EmboTrap revascularization device in a prospective registry which is core laboratory evaluated by physicians from external centers. The goal was to determine how the EmboTrap would perform under the everyday conditions of a high-volume stroke center.MethodsWe examined all patients with acute stroke treated with the Embotrap device from October 2013 to March 2017 in our center. Imaging parameters and times were adjudicated by core laboratory personnel blinded to clinical information, treating physician, and clinical outcomes. Clinical evaluation was performed by independent neurologists and entered in a national registry. Evaluated endpoints were: successful revascularization (modified Thrombolysis in Cerebral Infarction (mTICI) 2b–3) and good clinical outcomes at 3 months (modified Rankin Scale (mRS) 0–2).Results201 consecutive patients with a median NIH Stroke Scale (NIHSS) score of 15 (range 2–30) were included. 170 patients (84.6%) achieved mTICI 2b–3 reperfusion. The median number of attempts was 2 (range 1–10) with 52.8% of the population achieving good functional outcomes (mRS 0–2) at 3 months. On univariate analysis, good functional outcome was associated with the number of attempts, puncture-to-reperfusion time, anterior circulation occlusion, and NIHSS score. On multivariate analysis, pre-treatment NIHSS (OR 0.845 per point, 95% CI 0.793 to 0.908, P<0.001) and puncture-to-reperfusion time (OR 0.9952 per min, 95% CI 0.9914 to 0.9975, P=0.023) were associated with good functional outcomes at 3 months.ConclusionThe Embotrap device has a high rate of successful reperfusion. Our core laboratory-audited single-center experience suggests the technical feasibility and safety of the Embotrap for first-line use in a real-world setting.
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44.
  • Brunstein, Claudio G, et al. (författare)
  • Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation
  • 2019
  • Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 25:3, s. 480-487
  • Tidskriftsartikel (refereegranskat)abstract
    • Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥ 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.
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45.
  • Čančer, Matko, et al. (författare)
  • Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
  • 2019
  • Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:6, s. 855-870
  • Tidskriftsartikel (refereegranskat)abstract
    • Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.
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46.
  • Cardinale, Daniele A., 1982-, et al. (författare)
  • Superior Intrinsic Mitochondrial Respiration in Women Than in Men.
  • 2018
  • Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Sexual dimorphism is apparent in humans, however, to date no studies have investigated mitochondrial function focusing on intrinsic mitochondrial respiration (i.e., mitochondrial respiration for a given amount of mitochondrial protein) and mitochondrial oxygen affinity (p50mito) in relation to biological sex in human. A skeletal muscle biopsy was donated by nine active women, and ten men matched for maximal oxygen consumption (VO2max) and by nine endurance trained men. Intrinsic mitochondrial respiration, assessed in isolated mitochondria, was higher in women compared to men when activating complex I (CIP) and complex I+II (CI+IIP) (p < 0.05), and was similar to trained men (CIP, p = 0.053; CI+IIP, p = 0.066). Proton leak and p50mito were higher in women compared to men independent of VO2max. In conclusion, significant novel differences in mitochondrial oxidative function, intrinsic mitochondrial respiration and p50mito exist between women and men. These findings may represent an adaptation in the oxygen cascade in women to optimize muscle oxygen uptake to compensate for a lower oxygen delivery during exercise.
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47.
  • Cornell, Robert F, et al. (författare)
  • Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma
  • 2017
  • Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 23:2, s. 269-277
  • Tidskriftsartikel (refereegranskat)abstract
    • Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.
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48.
  • Fabré, Nicolas, et al. (författare)
  • Alterations in aerobic energy expenditure and neuromuscular function during a simulated cross-country skiathlon with the skating technique
  • 2015
  • Ingår i: Human Movement Science. - : Elsevier BV. - 0167-9457 .- 1872-7646. ; 40, s. 326-340
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, we tested the hypothesis that aerobic energy expenditure (AEE) is higher during a simulated 6-km (2 loops of 3-km each) "skiathlon" than during skating only on a treadmill and attempted to link any such increase to biomechanical and neuromuscular responses. Six elite male cross-country skiers performed two pretesting time-trials (TT) to determine their best performances and to choose an appropriate submaximal speed for collection of physiological, biomechanical and neuromuscular data during two experimental sessions ((exp)). Each skier used, in randomized order, either the classical (CL) or skating technique (SK) for the first 3-km loop, followed by transition to the skating technique for the second 3-km loop. Respiratory parameters were recorded continuously. The EMG activity of the triceps brachii (TBr and vastus lateralis (VLa) muscles during isometric contractions performed when the skiers were stationary (i.e., just before the first loop, during the transition, and after the second loop); their corresponding activity during dynamic contractions; and pole and plantar forces during the second loop were recorded. During the second 3-km of the 'IT, skating speed was significantly higher for the SK-SK than CL-SK. During this second loop, AEE was also higher (+1.5%) for CL-SKexp than SK-SKexp, in association with higher VLa EMG activity during both isometric and dynamic contractions, despite no differences in plantar or pole forces, poling times or cycle rates. Although the underlying mechanism remains unclear, during a skiathlon, the transition between the sections of classical skiing and skating alters skating performance (i.e., skiing speed), AEE and neuromuscular function. (C) 2015 Elsevier B.V. All rights reserved.
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49.
  • Faiss, R, et al. (författare)
  • Elevated Temperature Accelerates Recovery of Mouse and Human Skeletal Muscle Following Fatigue
  • 2015
  • Ingår i: Abstract Book for the 20th Annual <em>ECSS</em> Congress.
  • Konferensbidrag (refereegranskat)abstract
    • IntroductionThis study was designed to determine whether elevated muscle temperature allows muscles to recover their force or power more rapidly following fatigueMethodsIntact single fibers from mouse flexor digitorum brevis muscle were fatigued at 31˚C (70-Hz 350-ms tetani once every 10s until initial force decreased to 30%).  During a subsequent 2-hr recovery period, the fibers were perfused in Tyrode solution at either 31°C (physiological temperature) or 36°C and isometric force and cytoplasmic free [Ca2+] ([Ca2+]i) were measured during 30-Hz tetani evoked periodically.  In addition, seven human subjects performed fatiguing arm exercise consisting of 3 x 5min maximal effort arm cycling at 100 rpm followed by 4 x 15 min at an intensity of 50% of VO2peak. Then followed 2hr of recovery during which both arms were either heated or not heated at 5˚C above physiological temperatures using arm cuffs continuously perfused with temperature-regulated water; the order of heating vs. not heating was randomized between two visits. Intramuscular temperature was recorded with probes inserted 1.5 cm into the lateral head of the triceps brachii muscle. During the recovery period, subjects consumed 1.0 g/hr/kg body weight carbohydrates to support glycogen repletion. After recovery, the subjects repeated the 3 x 5 min time trials to evaluate the effect of the recovery intervention.ResultsRecovery from fatigue in mouse single fibers was dependent on muscle glycogen restoration since fibers perfused with glucose-free Tyrode did not recover contractile force (P<0.05). After 30 min of recovery, the tetanic [Ca2+]i was 107±10% and 92 ± 8% and the corresponding forces were 69±15% vs.49±14% of the initial values for the heated and non-heated muscles, respectively.  In seven human subjects, 2h of muscle heating also appeared to improve muscle recovery, leading to higher mean power output in the post-recovery arm cycling time trial than without muscle heating.DiscussionElevating muscle temperature by 5°C above physiological temperature accelerates recovery in mouse muscle in-vitro and in human skeletal muscle in-vivo and this appears to depend on faster muscle glycogen resynthesis following fatigue.
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50.
  • Faiss, R., et al. (författare)
  • Repeated double-poling sprint training in hypoxia by competitive cross-country skiers
  • 2015
  • Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 47:4, s. 809-817
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Repeated-sprint training in hypoxia (RSH) was recently shown to improve repeated-sprint ability (RSA) in cycling. This phenomenon is likely to reflect fiber type-dependent, compensatory vasodilation, and therefore, our hypothesis was that RSH is even more beneficial for activities involving upper body muscles, such as double poling during cross-country skiing. Methods: In a double-blinded fashion, 17 competitive cross-country skiers performed six sessions of repeated sprints (each consisting of four sets of five 10-s sprints, with 20-s intervals of recovery) either in normoxia (RSN, 300 m; FiO2, 20.9%; n = 8) or normobaric hypoxia (RSH, 3000 m; FiO2, 13.8 %; n = 9). Before (pre) and after (post) training, performance was evaluated with an RSA test (10-s all-out sprints-20-s recovery, until peak power output declined by 30%) and a simulated team sprint (team sprint, 3×3-min all-out with 3-min rest) on a double-poling ergometer. Triceps brachii oxygenation was measured by near-infrared spectroscopy. Results: From pretraining to posttraining, peak power output in the RSA was increased (P < 0.01) to the same extent (29% ± 13% vs 26% ± 18%, nonsignificant) in RSH and in RSN whereas the number of sprints performed was enhanced in RSH (10.9 ± 5.2 vs 17.1 ± 6.8, P < 0.01) but not in RSN (11.6 T 5.3 vs 11.7 ± 4.3, nonsignificant). In addition, the amplitude in total hemoglobin variations during sprints throughout RSA rose more in RSH (P < 0.01). Similarly, the average power output during all team sprints improved by 11% T 9% in RSH and 15% T 7% in RSN. Conclusions: Our findings reveal greater improvement in the performance of repeated double-poling sprints, together with larger variations in the perfusion of upper body muscles in RSH compared with those in RSN. © 2014 by the American College of Sports Medicine.
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