Publications by authors named "Dorthe Skovgaard"

31 Publications

Chronic hyperglycemia, hypercholesterolemia, and metabolic syndrome are associated with risk of tendon injury.

Scand J Med Sci Sports 2021 May 8. Epub 2021 May 8.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Copenhagen University Hospital - Bispebjerg and Frederiksberg and Center for Healthy Aging, Institute of Sports Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark.

Tendon injury is a considerable problem affecting both physically active and sedentary people. The aim of this study was to examine the relationship between markers for metabolic disorders (hyperglycemia, hypercholesterolemia, and metabolic syndrome) and the risk of developing tendon injuries requiring referral to a hospital. The Copenhagen City Heart Study is a prospective study of diabetic and non-diabetic individuals from the Danish general population with different physical activity levels. The cohort was followed for 3 years via national registers with respect to tendon injuries. Data from 5856 individuals (median age 62 years) were included. The overall incidence of tendon injury in both upper and lower extremities that required an out-patient or in-house visit to a hospital was ~5.7/1000 person years. Individuals with elevated HbA1c (glycated hemoglobin) even in the prediabetic range (HbA1c>5.7%) had a ~3 times higher risk of tendon injury in the lower extremities only, as compared to individuals with normal HbA1C levels. Hypercholesterolemia (total cholesterol>5 mmol/L) increased risk of tendon injury in the upper extremities by ~1.5 times, and individuals with metabolic syndrome had ~2.5 times higher risk of tendon injury in both upper and lower extremities. In conclusion, these data demonstrate for the first time in a large cohort with different physical activity levels that the indicators for metabolic syndrome are a powerful systemic determinant of tendon injury, and two of its components, hyperglycemia and hypercholesterolemia, each independently make tendons susceptible for damage and injury.
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http://dx.doi.org/10.1111/sms.13984DOI Listing
May 2021

Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial.

JAMA 2021 04;325(14):1403-1413

Department of Nutrition Sciences, University of Alabama at Birmingham.

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.

Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.

Design, Setting, And Participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).

Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.

Main Outcomes And Measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.

Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.

Conclusions And Relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

Trial Registration: ClinicalTrials.gov Identifier: NCT03611582.
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http://dx.doi.org/10.1001/jama.2021.1831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905697PMC
April 2021

Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data.

Int J Obes (Lond) 2021 May 18;45(5):923-933. Epub 2021 Jan 18.

Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

In the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.
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http://dx.doi.org/10.1038/s41366-020-00733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081661PMC
May 2021

The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity.

Diabetes Obes Metab 2021 03 3;23(3):754-762. Epub 2021 Jan 3.

Novo Nordisk A/S, Søborg, Denmark.

Aim: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity.

Materials And Methods: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch.

Results: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration. Ad libitum energy intake was 35% lower with semaglutide versus placebo (1736 versus 2676 kJ; estimated treatment difference -940 kJ; P <0.0001). Semaglutide reduced hunger and prospective food consumption, and increased fullness and satiety when compared with placebo (all P <0.02). The CoEQ indicated better control of eating and fewer/weaker food cravings with semaglutide versus placebo (P <0.05). Body weight was reduced by 9.9% with semaglutide and 0.4% with placebo. Safety was consistent with the known profile of semaglutide.

Conclusions: In adults with obesity, once-weekly s.c. semaglutide 2.4 mg suppressed appetite, improved control of eating, and reduced food cravings, ad libitum energy intake and body weight versus placebo. There was no evidence of delayed gastric emptying at week 20, assessed indirectly via paracetamol absorption.
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http://dx.doi.org/10.1111/dom.14280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898914PMC
March 2021

Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial.

Diabetes Care 2020 05 5;43(5):1085-1093. Epub 2020 Mar 5.

Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Objective: Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.

Research Design And Methods: Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs.

Results: Individuals were randomized to liraglutide 3.0 mg ( = 198) or placebo ( = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed.

Conclusions: In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.
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http://dx.doi.org/10.2337/dc19-1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171937PMC
May 2020

Regional differences in turnover, composition, and mechanics of the porcine flexor tendon.

Connect Tissue Res 2020 09 28;61(5):475-484. Epub 2019 May 28.

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, and Center for Healthy Aging, University of Copenhagen , Copenhagen, Denmark.

Purpose: Recent data suggest that there is a lack of turnover in the core of human tendon, but it remains unknown whether there are regional differences between core and periphery of the cross section. The purpose of this project was to investigate regional differences in turnover as estimated by the accumulation of fluorescent Advanced Glycation End-products (AGEs) and regional differences in mechanical properties.

Materials And Methods: Tendons were obtained from lean control ( = 4) and diabetic Göttingen minipigs (streptozotocin-induced, = 6). The deep digital flexor tendon of one hind limb was separated into a proximal, central and distal part. Autofluorescence was measured in the core and periphery of the proximal and distal parts of the tendon, and mechanical properties were tested on fascicles taken from the core and periphery of the central tendon (only diabetic animals).

Results: Autofluorescence was greater in the proximal than the distal part. In the distal part of the lean control animals, autofluorescent AGE accumulation was also greater in the core than the periphery. Peak modulus in the core region (704 ± 79 MPa) was higher than the periphery (466 ± 53 MPa, < 0.05) in diabetic tendons.

Conclusion: Taken together, autofluorescence varied both along the length and across the tendon cross section, indicating higher turnover in the distal and peripheral regions. In addition, mechanical properties differed across the tendon cross-section.
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http://dx.doi.org/10.1080/03008207.2019.1620222DOI Listing
September 2020

Urokinase Plasminogen Activator Receptor-PET with Ga-NOTA-AE105: First Clinical Experience with a Novel PET Ligand.

PET Clin 2017 Jul 8;12(3):311-319. Epub 2017 Apr 8.

Department of Clinical Physiology, Nuclear Medicine & PET, Cluster for Molecular Imaging Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 4011, Copenhagen DK-2100, Denmark. Electronic address:

Urokinase plasminogen activator receptor (uPAR) is a key component in proteolysis and extracellular matrix degradation during cancer invasion and metastasis. uPAR overexpression is an important biomarker for aggressiveness in several solid tumors and provides independent clinical information. A recent major breakthrough was obtained with human translation of uPAR PET using Ga-NOTA-AE105. Clinical results are encouraging and several large-scale clinical trials are now ongoing. This review focuses on uPAR PET with Ga-NOTA-AE105 as a new broadly applicable diagnostic and prognostic imaging biomarker in cancer.
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http://dx.doi.org/10.1016/j.cpet.2017.02.003DOI Listing
July 2017

An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon.

Physiol Rep 2017 Mar;5(6)

Department of Orthopedic Surgery M, Institute of Sports Medicine and IOC Research Centre Copenhagen, Bispebjerg Hospital and Center for Healthy Aging Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark

Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the relationship between AGE content in the diet and accumulation of AGEs in weight-bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high-fat diet low in AGEs high-fat diet (HFD) ( = 14) or normal diet high in AGEs (ND) ( = 11). AGE content in ND was six to 50-fold higher than HFD The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight-bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal-derived hydroimidazolone (MG-H1) and carboxyethyllysine (CEL) in Achilles and tail tendon was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pentosidine with high-pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML ( < 0.0001), CEL ( < 0.0001), MG-H1 and pentosidine (for both ND and HFD) ( < 0.0001). The AGE-rich diet (ND) resulted in an increase in CML ( < 0.0001), MG-H1 ( < 0.001) and pentosidine ( < 0.0001) but not CEL, in Achilles and tail tendon. This is the first study to provide evidence for AGE accumulation in injury-prone, weight-bearing Achilles tendon associated with intake of an AGE-rich diet. This indicates that food-derived AGEs may alter tendon properties and the development of tendon injuries.
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http://dx.doi.org/10.14814/phy2.13215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371572PMC
March 2017

Imaging of Prostate Cancer Using Urokinase-Type Plasminogen Activator Receptor PET.

PET Clin 2017 Apr 31;12(2):243-255. Epub 2017 Jan 31.

Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 4011, Copenhagen, DK-2100, Denmark. Electronic address:

Urokinase-type plasminogen activator receptor (uPAR) overexpression is an important biomarker for aggressiveness in cancer including prostate cancer (PC) and provides independent clinical information in addition to prostate-specific antigen and Gleason score. This article focuses on uPAR PET as a new diagnostic and prognostic imaging biomarker in PC. Many preclinical uPAR-targeted PET imaging studies using AE105 in cancer models have been undertaken with promising results. A major breakthrough was obtained with the recent human translation of uPAR PET in using Cu- and Ga-labelled versions of AE105, respectively. Clinical results from patients with PC included in these studies are encouraging and support continuation with large-scale clinical trials.
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http://dx.doi.org/10.1016/j.cpet.2016.12.005DOI Listing
April 2017

PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives.

Clin Transl Imaging 2016 4;4(6):457-465. Epub 2016 Jul 4.

Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, National University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)-provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer Cu-DOTA-AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome.
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http://dx.doi.org/10.1007/s40336-016-0197-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118403PMC
July 2016

Safety, Dosimetry, and Tumor Detection Ability of Ga-NOTA-AE105: First-in-Human Study of a Novel Radioligand for uPAR PET Imaging.

J Nucl Med 2017 03 8;58(3):379-386. Epub 2016 Sep 8.

Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark

The overexpression of urokinase-type plasminogen activator receptors (uPARs) represents an established biomarker for aggressiveness in most common malignant diseases, including breast cancer (BC), prostate cancer (PC), and urinary bladder cancer (UBC), and is therefore an important target for new cancer therapeutic and diagnostic strategies. In this study, uPAR PET imaging using a Ga-labeled version of the uPAR-targeting peptide (AE105) was investigated in a group of patients with BC, PC, and UBC. The aim of this first-in-human, phase I clinical trial was to investigate the safety and biodistribution in normal tissues and uptake in tumor lesions. Ten patients (6 PC, 2 BC, and 2 UBC) received a single intravenous dose of Ga-NOTA-AE105 (154 ± 59 MBq; range, 48-208 MBq). The biodistribution and radiation dosimetry were assessed by serial whole-body PET/CT scans (10 min, 1 h, and 2 h after injection). Safety assessment included measurements of vital signs with regular intervals during the imaging sessions and laboratory blood screening tests performed before and after injection. In a subgroup of patients, the in vivo stability of Ga-NOTA-AE105 was determined in collected blood and urine. PET images were visually analyzed for visible tumor uptake of Ga-NOTA-AE105, and SUVs were obtained from tumor lesions by manually drawing volumes of interest in the malignant tissue. No adverse events or clinically detectable pharmacologic effects were found. The radioligand exhibited good in vivo stability and fast clearance from tissue compartments primarily by renal excretion. The effective dose was 0.015 mSv/MBq, leading to a radiation burden of 3 mSv when the clinical target dose of 200 MBq was used. In addition, radioligand accumulation was seen in primary tumor lesions as well as in metastases. This first-in-human, phase I clinical trial demonstrates the safe use and clinical potential of Ga-NOTA-AE105 as a new radioligand for uPAR PET imaging in cancer patients.
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http://dx.doi.org/10.2967/jnumed.116.178970DOI Listing
March 2017

(123)I-MIBG Scintigraphy in the Subacute State of Takotsubo Cardiomyopathy.

JACC Cardiovasc Imaging 2016 08 22;9(8):982-90. Epub 2016 Jun 22.

Department of Clinical Physiology, Nuclear Medicine, and PET, Centre of Diagnostic Investigation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: The study sought to investigate adrenergic activity in patients with takotsubo cardiomyopathy (TTC).

Background: TTC is a specific type of reversible heart failure possibly caused by excessive catecholamine stimulation of the myocardium. Scintigraphic iodine-123-meta-iodobenzylguanidine (mIBG) imaging of the heart and measurement of plasma catecholamines can be used to assess adrenergic activity in vivo. The authors hypothesized that sympathetic nerve activity is increased in the subacute state of TTC, and this study used cardiac mIBG imaging and plasma levels of norepinephrine and epinephrine as markers to assess this hypothesis.

Methods: In this study, 32 patients with TTC and 20 controls were examined at admission and again on follow-up with echocardiography, mIBG scintigraphy, and plasma catecholamine measurements.

Results: Ejection fraction (EF) was initially 36 ± 9% but increased to >60% (p = 0.0004) in all patients with TTC. In the control subjects EF was initially higher (51 ± 11%; p = 0.0004) than in the patients with TTC. However, EF of the patients with TTC exceeded that of the control subjects on follow-up (56 ± 8%; p = 0.0007). The mIBG imaging showed a lower late (4-h) heart-to-mediastinum ratio (H/Mlate) (2.00 ± 0.38) and a higher washout rate (WR) (45 ± 12%) in the subacute state of TTC, both when compared with follow-up (H/Mlate: 2.42 ± 0.45; p = 0.0004; WR: 33 ± 14%; p = 0.0004) and when compared with the control group in the subacute state (H/Mlate: 2.34 ± 0.60, p = 0.035; WR: 33 ± 19%, p = 0.026). On follow-up, no differences in mIBG parameters were observed between the TTC and control groups (H/Mlate: 2.41 ± 0.51, p = 0.93; WR: 30 ± 13%, p = 0.48) group. In the TTC group, plasma epinephrine levels were elevated in the subacute state (Log2[epinephrine]: 6.13 ± 1.04 pg/ml), both when compared with follow-up (5.25 ± 0.62 pg/ml; p = 0.0004) and when compared with the control group in the subacute state (5.46 ± 0.69 pg/ml; p = 0.044), and these levels remained elevated in the TTC group on follow-up compared with the control group (4.56 ± 0.95 pg/ml; p = 0.014). No significant differences in plasma norepinephrine levels were observed.

Conclusions: The present study supports a possible role of adrenergic hyperactivity in TTC.
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http://dx.doi.org/10.1016/j.jcmg.2016.01.028DOI Listing
August 2016

First-in-human uPAR PET: Imaging of Cancer Aggressiveness.

Theranostics 2015 13;5(12):1303-16. Epub 2015 Sep 13.

1. Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark.

A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with (64)Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of (64)Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of (64)Cu-DOTA-AE105 for uPAR PET imaging in cancer patients.
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http://dx.doi.org/10.7150/thno.12956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615734PMC
August 2016

Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma.

J Nucl Med 2016 Feb 1;57(2):272-8. Epub 2015 Oct 1.

Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark

Unlabelled: Glioblastoma is one of the most malignant types of human cancer, and the prognosis is poor. The development and validation of novel molecular imaging biomarkers has the potential to improve tumor detection, grading, risk stratification, and treatment monitoring of gliomas. The aim of this study was to explore the potential of PET imaging of the urokinase-type plasminogen activator receptor (uPAR) in glioblastoma.

Methods: The uPAR messenger RNA expression of tumors from 19 glioblastoma patients was analyzed, and a cell culture derived from one of these patients was used to establish an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and, for comparison, O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of (64)Cu-NOTA-AE105 was confirmed by alignment of hematoxylin- and eosin-stained and uPAR immunohistochemistry-stained slides of the brain with the activity distribution as determined using autoradiography.

Results: uPAR expression was found in all 19 glioblastoma patient tumors, and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with (64)Cu and (68)Ga was straightforward, resulting in a specific activity of approximately 20 GBq/μmol and a radiochemical purity of more than 98% for (64)Cu-NOTA-AE105 and more than 97% for (68)Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both (68)Ga-NOTA-AE105 and (64)Cu-NOTA-AE105. Absolute uptake in tumor was higher for (18)F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for (64)Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or (68)Ga-NOTA-AE105 (0.4 ± 0.1 %ID/g). A similar pattern was observed in background brain tissue, where uptake was 1.9 ± 0.1 %ID/g for (18)F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for (68)Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for (64)Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both (68)Ga-NOTA-AE105 (7.6 ± 2.1, P < 0.05) and (64)Cu-NOTA-AE105 (10.6 ± 2.3, P < 0.01) than for (18)F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of (64)Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells.

Conclusion: On the basis of our translational study, uPAR PET may be a highly promising imaging biomarker for glioblastoma. Further clinical exploration of uPAR PET in glioblastoma is therefore justified.
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http://dx.doi.org/10.2967/jnumed.115.161703DOI Listing
February 2016

Rubidium-82 uptake in metastases from neuroendocrine tumors: No flow response to adenosine.

J Nucl Cardiol 2016 08 10;23(4):840-2. Epub 2015 Sep 10.

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet & Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1007/s12350-015-0251-zDOI Listing
August 2016

Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue.

Age (Dordr) 2014 5;36(4):9665. Epub 2014 Jul 5.

Institute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Bldg. 8, Bispebjerg Bakke 23, DK-2400, Copenhagen, NV, Denmark,

Life-long regular endurance exercise is known to counteract the deterioration of cardiovascular and metabolic function and overall mortality. Yet it remains unknown if life-long regular endurance exercise can influence the connective tissue accumulation of advanced glycation endproducts (AGEs) that is associated with aging and lifestyle-related diseases. We therefore examined two groups of healthy elderly men: 15 master athletes (64 ± 4 years) who had been engaged in life-long endurance running and 12 old untrained (66 ± 4 years) together with two groups of healthy young men; ten young athletes matched for running distance (26 ± 4 years), and 12 young untrained (24 ± 3 years). AGE cross-links (pentosidine) of the patellar tendon were measured biochemically, and in the skin, it was assessed by a fluorometric method. In addition, we determined mechanical properties and microstructure of the patellar tendon. Life-long regular endurance runners (master athletes) had a 21 % lower AGE cross-link density compared to old untrained. Furthermore, both master athletes and young athletes displayed a thicker patellar tendon. These cross-sectional data suggest that life-long regular endurance running can partly counteract the aging process in connective tissue by reducing age-related accumulation of AGEs. This may not only benefit skin and tendon but also other long-lived protein tissues in the body. Furthermore, it appears that endurance running yields tendon tissue hypertrophy that may serve to lower the stress on the tendon and thereby reduce the risk of injury.
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http://dx.doi.org/10.1007/s11357-014-9665-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150896PMC
March 2015

BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography.

PLoS One 2014 6;9(5):e96736. Epub 2014 May 6.

Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet and University Hospital of Copenhagen, Copenhagen, Denmark.

Unlabelled: Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients.

Methods: We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry.

Results: During follow-up (mean 1,360 days), 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml (HR 5.5; CI 1.8-17.2; p = 0.003) and LVEF <50% (HR 7.9; CI 3.0-21.4; p<0.001) both significantly predicted CHF. Using the same cut-off points only BNP (HR 1.9; CI 1.3-2.9; p = 0.002) and not LVEF (HR 1.1; CI 0.7-1.8; p = 0.58) was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death.

Conclusion: In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096736PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011788PMC
June 2015

Impact of oral contraceptive use and menstrual phases on patellar tendon morphology, biochemical composition, and biomechanical properties in female athletes.

J Appl Physiol (1985) 2013 Apr 21;114(8):998-1008. Epub 2013 Feb 21.

Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital, and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Sex differences exist with regards to ligament and tendon injuries. Lower collagen synthesis has been observed in exercising women vs. men, and in users of oral contraceptives (OC) vs. nonusers, but it is unknown if OC will influence tendon biomechanics of women undergoing regular training. Thirty female athletes (handball players, 18-30 yr) were recruited: 15 long-term users of OC (7.0 ± 0.6 yr) and 15 nonusers (>5 yr). Synchronized values of patellar tendon elongation (obtained by ultrasonography) and tendon force were sampled during ramped isometric knee extensor maximum voluntary contraction to estimate mechanical tendon properties. Furthermore, tendon cross-sectional area and length were measured from MRI images, and tendon biopsies were obtained for analysis of tendon fibril characteristics and collagen cross-linking. Overall, no difference in tendon biomechanical properties, tendon fibril characteristics, or collagen cross-linking was observed between the OC users and nonusers, or between the different phases of the menstrual cycle. In athletes, tendon cross-sectional area in the preferred jumping leg tended to be larger than that in the contralateral leg (P = 0.09), and a greater absolute (P = 0.01) and normalized tendon stiffness (P = 0.02), as well as a lower strain (P = 0.04), were observed in the jumping leg compared with the contralateral leg. The results indicate that long-term OC use or menstrual phases does not influence structure or mechanical properties of the patellar tendon in female team handball athletes.
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http://dx.doi.org/10.1152/japplphysiol.01255.2012DOI Listing
April 2013

(18)F-FDG PET imaging of murine atherosclerosis: association with gene expression of key molecular markers.

PLoS One 2012 30;7(11):e50908. Epub 2012 Nov 30.

Cluster for Molecular Imaging, Faculty of Health and Medical Sciences and Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: To study whether (18)F-FDG can be used for in vivo imaging of atherogenesis by examining the correlation between (18)F-FDG uptake and gene expression of key molecular markers of atherosclerosis in apoE(-/-) mice.

Methods: Nine groups of apoE(-/-) mice were given normal chow or high-fat diet. At different time-points, (18)F-FDG PET/contrast-enhanced CT scans were performed on dedicated animal scanners. After scans, animals were euthanized, aortas removed, gamma counted, RNA extracted from the tissue, and gene expression of chemo (C-X-C motif) ligand 1 (CXCL-1), monocyte chemoattractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, cluster of differentiation molecule (CD)-68, osteopontin (OPN), lectin-like oxidized LDL-receptor (LOX)-1, hypoxia-inducible factor (HIF)-1α, HIF-2α, vascular endothelial growth factor A (VEGF), and tissue factor (TF) was measured by means of qPCR.

Results: The uptake of (18)F-FDG increased over time in the groups of mice receiving high-fat diet measured by PET and ex vivo gamma counting. The gene expression of all examined markers of atherosclerosis correlated significantly with (18)F-FDG uptake. The strongest correlation was seen with TF and CD68 (p<0.001). A multivariate analysis showed CD68, OPN, TF, and VCAM-1 to be the most important contributors to the uptake of (18)F-FDG. Together they could explain 60% of the (18)F-FDG uptake.

Conclusion: We have demonstrated that (18)F-FDG can be used to follow the progression of atherosclerosis in apoE(-/-) mice. The gene expression of ten molecular markers representing different molecular processes important for atherosclerosis was shown to correlate with the uptake of (18)F-FDG. Especially, the gene expressions of CD68, OPN, TF, and VCAM-1 were strong predictors for the uptake.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511408PMC
May 2013

Effects of estrogen replacement and lower androgen status on skeletal muscle collagen and myofibrillar protein synthesis in postmenopausal women.

J Gerontol A Biol Sci Med Sci 2012 Oct 1;67(10):1005-13. Epub 2012 Mar 1.

Institute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Denmark.

Our aim was to determine synthesis rate of myofibrillar and collagen proteins in 20 postmenopausal women, who were either nonusers (Controls) or users of estrogen replacement therapy (ERT) after hysterectomy/oophorectomy. Myofibrillar and muscle collagen protein fractional synthesis rate (FSR) were determined in a nonexercised leg and 24 hours after exercise in the contralateral leg. A significant interaction between treatment and mechanical loading was observed in myofibrillar protein FSR. At rest, myofibrillar protein FSR was found to be lower in ERT users than in Controls. Exercise enhanced myofibrillar protein FSR only in ERT users. Similarly, muscle collagen FSR tended to be lower in ERT users compared with Controls. In ERT participants, the androgen profile was reduced, whereas estradiol and sex hormone-binding globulin were higher. In conclusion, at rest, myofibrillar protein FSR was lower in hysterectomized/oophorectomized women using ERT compared with healthy postmenopausal women. Nevertheless, resistance exercise in combination with ERT seems to have a counteracting effect on myofibrillar FSR in hysterectomized/oophorectomized women.
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http://dx.doi.org/10.1093/gerona/gls007DOI Listing
October 2012

The Combination of In vivo (124)I-PET and CT Small Animal Imaging for Evaluation of Thyroid Physiology and Dosimetry.

Diagnostics (Basel) 2012 Jun 5;2(2):10-22. Epub 2012 Jun 5.

Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.

Objective: A thyroid rat model combining functional and anatomical information would be of great benefit for better modeling of thyroid physiology and for absorbed dose calculations. Our aim was to show that (124)I-PET and CT small animal imaging are useful as a combined model for studying thyroid physiology and dose calculation.

Methods: Seven rats were subjects for multiple thyroid (124)I-imaging and CT-scans. S-values [mGy/MBqs] for different thyroid sizes were simulated. A phantom with spheres was designed for validation of performances of the small animal PET and CT imaging systems.

Results: Small animal image-based measurements of the activity amount and the volumes of the spheres with a priori known volumes showed a good agreement with their corresponding actual volumes. The CT scans of the rats showed thyroid volumes from 34-70 mL.

Conclusions: The wide span in volumes of thyroid glands indicates the importance of using an accurate volume-measuring technique such as the small animal CT. The small animal PET system was on the other hand able to accurately estimate the activity concentration in the thyroid volumes. We conclude that the combination of the PET and CT image information is essential for quantitative thyroid imaging and accurate thyroid absorbed dose calculation.
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http://dx.doi.org/10.3390/diagnostics2020010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665460PMC
June 2012

Preserved myocardial blood flow in the apical region involved in takotsubo cardiomyopathy by quantitative cardiac PET assessment.

J Nucl Cardiol 2012 Feb;19(1):169-71

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.

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http://dx.doi.org/10.1007/s12350-011-9451-3DOI Listing
February 2012

Use of cis-[18F]fluoro-proline for assessment of exercise-related collagen synthesis in musculoskeletal connective tissue.

PLoS One 2011 Feb 11;6(2):e16678. Epub 2011 Feb 11.

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Protein turnover in collagen rich tissue is influenced by exercise, but can only with difficulty be studied in vivo due to use of invasive procedure. The present study was done to investigate the possibility of applying the PET-tracer, cis-[(18)F]fluoro-proline (cis-Fpro), for non-invasive assessment of collagen synthesis in rat musculoskeletal tissues at rest and following short-term (3 days) treadmill running. Musculoskeletal collagen synthesis was studied in rats at rest and 24 h post-exercise. At each session, rats were PET scanned at two time points following injection of cis-FPro: (60 and 240 min p.i). SUV were calculated for Achilles tendon, calf muscle and tibial bone. The PET-derived results were compared to mRNA expression of collagen type I and III. Tibial bone had the highest SUV that increased significantly (p<0.001) from the early (60 min) to the late (240 min) PET scan, while SUV in tendon and muscle decreased (p<0.001). Exercise had no influence on SUV, which was contradicted by an increased gene expression of collagen type I and III in muscle and tendon. The clearly, visible uptake of cis-Fpro in the collagen-rich musculoskeletal tissues is promising for multi-tissue studies in vivo. The tissue-specific differences with the highest basal uptake in bone are in accordance with earlier studies relying on tissue incorporation of isotopic-labelled proline. A possible explanation of the failure to demonstrate enhanced collagen synthesis following exercise, despite augmented collagen type I and III transcription, is that SUV calculations are not sensitive enough to detect minor changes in collagen synthesis. Further studies including kinetic compartment modeling must be performed to establish whether cis-Fpro can be used for non-invasive in-vivo assessment of exercise-induced changes in musculoskeletal collagen synthesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016678PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037959PMC
February 2011

Imaging of takotsubo cardiomyopathy.

Clin Nucl Med 2010 Dec;35(12):967-71

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.

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http://dx.doi.org/10.1097/RLU.0b013e3181f9dfcdDOI Listing
December 2010

Increased cellular proliferation in rat skeletal muscle and tendon in response to exercise: use of FLT and PET/CT.

Mol Imaging Biol 2010 Dec;12(6):626-34

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Purpose: The purpose of this study is to investigate exercise-induced cellular proliferation in rat skeletal muscle/tendon with the use of 3'-[F-18]fluoro-3'deoxythymidine (FLT) and to quantitatively study concomitant changes in the proliferation-associated factor, Ki67.

Procedures: Wistar rats (n = 13) performed 3 days of treadmill running. Cellular proliferation was investigated 3 days before and 48 h after the running exercise with the use of FLT and positron emission tomography/computed tomography (PET/CT). Results were compared to a sedentary control group (n = 10). Image-derived standardized uptake values were calculated for Achilles tendons and calf muscles and compared to gene expression and immunohistochemical evaluations of Ki67.

Results: Treadmill running induced increased uptake of FLT uptake in calf muscles (30%; p < 0.001) and in Achilles tendon (21%, p < 0.001). The image-derived results were supported by a correlation in calf muscle to Ki67 (protein and mRNA level), while this coherence was not found in tendon.

Conclusion: FLT-PET seems to be a promising tool for imaging of exercise-induced cellular proliferation in musculo-tendinous tissue.
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http://dx.doi.org/10.1007/s11307-010-0316-yDOI Listing
December 2010

Radiation exposure for medical staff performing quantitative coronary perfusion PET with 13N-ammonia.

Radiat Prot Dosimetry 2010 Feb 3;138(2):107-10. Epub 2009 Oct 3.

Department of Clinical Physiology, Nuclear Medicine & PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose: To evaluate radiation doses to medical staff performing quantitative (13)N-ammonia myocardial perfusion positron emission tomography (PET).

Methods: Seventeen PET examinations were performed. Nine examinations consisted of two PET scans (one during rest and one after pharmacological stress with dipyridamole) and eight examinations consisted of three PET scans (additionally a scan after cold pressor testing). The two nuclear technologists and the physician attending the examinations were equipped with an electronic dosemeter over the chest and thermoluminescent dosimetry chips on the right index finger and wrist.

Results: The highest mean equivalent dose per examination for a staff member was 453 microSv (417-490 microSv) to the right index finger, 138 microSv (127-149 microSv) to the right wrist and 13 +/- 0.8 microSv to the chest.

Conclusions: Myocardial perfusion PET with (13)N-ammonia exposes the staff to radiation doses that are comparable to doses from (18)F-fluoro-deoxy-glucose scans and the annual doses are well within the recommended upper limits for radiation workers.
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http://dx.doi.org/10.1093/rpd/ncp202DOI Listing
February 2010

Noninvasive 64Cu-ATSM and PET/CT assessment of hypoxia in rat skeletal muscles and tendons during muscle contractions.

J Nucl Med 2009 Jun 14;50(6):950-8. Epub 2009 May 14.

Institute of Sports Medicine, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Unlabelled: The purpose of the present study was to investigate exercise-related changes in oxygenation in rat skeletal muscles and tendons noninvasively with PET/CT and the hypoxia-selective tracer (64)Cu-diacetyl bis(N(4)-methylthiosemicarbazone) (ATSM) and to quantitatively study concomitant changes in gene expression of 2 hypoxia-related genes, hypoxia-inducible factor 1alpha (HIF1alpha) and carbonic anhydrase III (CAIII).

Methods: Two groups of Wistar rats performed 1-leg contractions of the calf muscle by electrostimulation of the sciatic nerve. After 10 min of muscle contractions, (64)Cu-ATSM was injected and contractions were continued for 20 min. PET/CT of both hind limbs was performed immediately and 1 h after the contractions. The exercise group (n = 8) performed only muscle contractions as described, whereas the other group, exercise plus cuff (n = 8), in addition underwent cuff-induced hypoxia during the first PET/CT scan. Standardized uptake values (SUVs) were calculated for the Achilles tendons and triceps surae muscles and were correlated to gene expression of HIF1alpha and CAIII using real-time polymerase chain reaction.

Results: Immediately after the contractions, uptake of (64)Cu-ATSM was significantly increased, by approximately 1.5-fold in muscles and 1.3-fold in tendons, compared with resting conditions. The significant increase was maintained in late PET scans in stimulated muscles and tendons independently of cuff application. In muscles, SUV correlated significantly with gene expression of HIF1alpha and CAIII, whereas this coherence was not found in tendons.

Conclusion: We found enhanced uptake of (64)Cu-ATSM in both early and late PET scans, thereby supporting the possibility that (64)Cu-ATSM registers exercise-induced transient hypoxia in both skeletal muscles and force-transmitting tendons. The fact that skeletal muscles but not tendons showed upregulation of HIF1alpha and CAIII could indicate that healthy tendons are less responsive than skeletal muscles to low levels of oxygen.
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http://dx.doi.org/10.2967/jnumed.109.062216DOI Listing
June 2009

18F-fluorodeoxyglucose and PET/CT for noninvasive study of exercise-induced glucose uptake in rat skeletal muscle and tendon.

Eur J Nucl Med Mol Imaging 2009 May 10;36(5):859-68. Epub 2009 Jan 10.

Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Purpose: To investigate exercise-related glucose uptake in rat muscle and tendon using PET/CT and to study possible explanatory changes in gene expression for the glucose transporters (GLUT1 and GLUT4).

Methods: The sciatic nerve in eight Wistar rats was subjected to electrostimulation to cause unilateral isometric contractions of the calf muscle. (18)F-Fluorodeoxyglucose was administered and a PET/CT scan of the hindlimbs was performed. SUVs were calculated in both Achilles tendons and the triceps surae muscles. To exclude a spill-over effect the tendons and muscles from an ex vivo group of eight rats were cut out and scanned separately (distance>or=1 cm).

Results: Muscle contractions increased glucose uptake approximately sevenfold in muscles (p<0.001) and 36% in tendons (p<0.01). The ex vivo group confirmed the increase in glucose uptake in intact animals. GLUT1 and GLUT4 were expressed in both skeletal muscle and tendon, but no changes in mRNA levels could be detected.

Conclusion: PET/CT can be used for studying glucose uptake in rat muscle and tendon in relation to muscle contractions; however, the increased uptake of glucose was not explained by changes in gene expression of GLUT1 and GLUT4.
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http://dx.doi.org/10.1007/s00259-008-1020-xDOI Listing
May 2009
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