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Sökning: WFRF:(Sundin Peter)

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  • Ferrua, Francesca, et al. (författare)
  • Hematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT/ESID-IEWP-SCETIDE-PIDTC Study.
  • 2019
  • Ingår i: The Journal of allergy and clinical immunology. - 1097-6825. ; 143:6, s. 2238-2253
  • Tidskriftsartikel (refereegranskat)abstract
    • CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables relevance with respect to survival and cure.Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 78.2%, 58.1% and 72.3% 5 years post-HSCT. Results were better in transplants performed ≥2000 and in children <10 years old at HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT ≤2 years from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC) and bone marrow-derived stem cells. Most rejections occurred after reduced intensity or non-myeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was ≥50% donor in 85.2%.HSCT is curative in CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS and DFS. Prospective studies are required to compare risks of HSCT with those of life-long supportive therapy.
  • Jadidi, M., et al. (författare)
  • Evaluation of a new system for chest tomosynthesis: Aspects of image quality of different protocols determined using an anthropomorphic phantom
  • 2015
  • Ingår i: British Journal of Radiology. - 0007-1285 .- 1748-880X. ; 88:1053
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To compare the image quality obtained with the different protocols in a new chest digital tomosynthesis (DTS) system. Methods: A chest phantom was imaged with chest X-ray equipment with DTS. 10 protocols were used, and for each protocol, nine acquisitions were performed. Four observers visually rated the quality of the reconstructed section images according to pre-defined quality criteria in four different classes. The data were analysed with visual grading characteristics (VGC) analysis, using the vendorrecommended protocol [12-s acquisition time, source-toimage distance (SID) 180 cm] as reference, and the area under the VGC curve (AUCVGC) was determined for each protocol and class of criteria. Results: Protocols with a smaller swing angle resulted in a lower image quality for the classes of criteria "disturbance" and "homogeneity in nodule" but a higher image quality for the class "structure". The class "demarcation" showed little dependency on the swing angle. All protocols but one (6.3 s, SID 130 cm) obtained an AUCVGC significantly ,0.5 (indicating lower quality than reference) for at least one class of criteria. Conclusion: The study indicates that the DTS protocol with 6.3 s yields image quality similar to that obtained with the vendor-recommended protocol (12 s) but with the clinically important advantage for patients with respiratory impairment of a shorter acquisition time. Advances in knowledge: The study demonstrates that the image quality may be strongly affected by the choice of protocol and that the vendor-recommended protocol may not be optimal. © 2015 The Authors.
  • Sackey, Peter, et al. (författare)
  • Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam : A pilot study
  • 2008
  • Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 36:3, s. 801-806
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To compare memories from the intensive care unit (ICU) and short- and long-term psychological morbidity in patients after sedation with intravenous midazolam or inhaled isoflurane. DESIGN: Prospective long-term follow-up after randomized controlled trial. SETTING: General ICU at Karolinska University Hospital, Solna, Stockholm. PATIENTS: Forty patients in need of sedation during ventilator treatment. INTERVENTIONS: Patients were randomized to receive isoflurane or midazolam for goal-directed sedation until extubation or for a maximum of 96 hrs. MEASUREMENTS AND MAIN RESULTS: For short-term follow-up, doctors', nurses', and physiotherapists' notes from the 4 days following exposure to the study drugs were reviewed for words indicating adequate or pathologic cognitive and psychological recovery. For long-term follow-up, all 6-month survivors received questionnaires including the ICU Memory Tool (ICU-MT), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), and Well-Being Index. Additionally, several screening questions for previous posttraumatic stress symptoms were included. In the short term follow-up, no significant differences were found between groups. In the long-term follow-up, a trend toward fewer hallucinations/delusions after isoflurane sedation than after midazolam (two of ten isoflurane patients vs. five of seven midazolam patients) was found (p = .06). None of the five solely isoflurane-sedated patients reported hallucinations/delusions from the ICU. There was no difference in groups in long-term psychological morbidity as measured with HADS and IES. Memories of negative feelings in the ICU (ICU-MT) were associated with high HADS and IES scores (Fisher's exact test, p = .02 and p = .01, respectively). CONCLUSIONS: Sedation of ICU patients with isoflurane may result in fewer delusional memories or hallucinations from the ICU compared with more commonly used intravenous sedation. Memories of negative feelings from the ICU were associated with symptoms of depression or anxiety or symptoms indicating posttraumatic stress disorder. Further study of memory and cognitive/psychological recovery after prolonged isoflurane sedation beyond 96 hrs is warranted.
  • Bailey, Leslie, et al. (författare)
  • Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
  • 2007
  • Ingår i: FEBS Letters. - : Elsevier. - 0014-5793 .- 1873-3468. ; 581:4, s. 587-595
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.
  • Block, Keith I., et al. (författare)
  • Designing a broad-spectrum integrative approach for cancer prevention and treatment
  • 2015
  • Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
  • Forskningsöversikt (refereegranskat)abstract
    • Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
  • Byström, Per, et al. (författare)
  • Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer
  • 2009
  • Ingår i: Annals of Oncology. - 0923-7534 .- 1569-8041. ; 20:6, s. 1057-1061
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.
  • Eriksson, Olof, et al. (författare)
  • In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
  • 2010
  • Ingår i: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 37:3, s. 357-363
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass. METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls. RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone. CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.
  • Hessman, Ola, et al. (författare)
  • High success rate of parathyroid reoperation may be achieved with improved localization diagnosis
  • 2008
  • Ingår i: World Journal of Surgery. - 0364-2313 .- 1432-2323. ; 32:5, s. 774-81; discussion 782
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Because of the difficulty of reoperative parathyroid surgery, preoperative imaging studies have been increasingly adopted. We report the use of consistently applied localization diagnosis to yield high success rates in parathyroid reoperations. METHODS: Parathyroid reoperation was performed after previous parathyroid surgery in 144 patients with nonmalignant hyperparathyroidism (HPT) between 1962 and 2007. From the year 2000, 46 patients who underwent parathyroid reoperation and 14 patients who were subjected to thyroid surgery before primary parathyroid operation were investigated with sestamibi scintigraphy (MIBI), 11C-methionine PET/CT (met-PET), surgeon-performed ultrasound (US), US-guided fine-needle aspiration biopsy (US-FNA), and selective venous sampling (SVS) with rapid PTH (Q-PTH) analyses. When imaging was considered adequate, additional studies were generally not obtained. RESULTS: Reversal of hypercalcemia was achieved by reoperation in 134 of 144 (93%) of all patients with previous parathyroid surgery. In patients operated from year 2000, MIBI had 90% sensitivity and 88% predictive value, met-PET 79% sensitivity and 87% predictive value, and US 72% sensitivity and 93% predictive value. SVS with Q-PTH analyses provided accurate localization or regionalization in 11 of 11 recently selected patients. Q-PTH analyses in fine-needle aspirations verified parathyroid origin of excised specimens, and intraoperative Q-PTH helped decide when operations could be terminated. In patients subjected to the algorithm of imaging procedures, reversal of hypercalcemia and apparent cure was obtained after the reoperation in 45 of 46 patients with previous parathyroid surgery, implying a success rate of 98%, and in all patients with previous thyroid surgery. CONCLUSIONS: Reoperative parathyroid surgery is challenging. Results can be improved by consistently applied sensitive methods of preoperative imaging, and reoperative procedures may then achieve nearly the same success rates as primary operations.
  • Jahan, Mahabuba, et al. (författare)
  • Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
  • 2011
  • Ingår i: EJNMMI research. - 2191-219X. ; 1:1, s. 33-
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundFluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ.Methods[18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling.Results[18F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 ± 0.002 min-1), resulting in a six fold increase in half-life stability.Conclusions[18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.
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