Publications by authors named "Lars Karlsson"

98 Publications

Growth Hormone and Neuronal Hemoglobin in the Brain-Roles in Neuroprotection and Neurodegenerative Diseases.

Front Endocrinol (Lausanne) 2020 8;11:606089. Epub 2021 Jan 8.

Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

In recent years, evidence for hemoglobin (Hb) synthesis in both animal and human brains has been accumulating. While circulating Hb originating from cerebral hemorrhage or other conditions is toxic, there is also substantial production of neuronal Hb, which is influenced by conditions such as ischemia and regulated by growth hormone (GH), insulin-like growth factor-I (IGF-I), and other growth factors. In this review, we discuss the possible functions of circulating and brain Hb, mainly the neuronal form, with respect to the neuroprotective activities of GH and IGF-I against ischemia and neurodegenerative diseases. The molecular pathways that link Hb to the GH/IGF-I system are also reviewed, although the limited number of reports on this topic suggests a need for further studies. In summary, GH and/or IGF-I appear to be significant determinants of systemic and local brain Hb concentrations through mediating responses to oxygen and metabolic demand, as part of the neuroprotective effects exerted by GH and IGF-I. The nature and quantity of the latter deserve further exploration in specific experiments.
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http://dx.doi.org/10.3389/fendo.2020.606089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821093PMC
May 2021

Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.

N Engl J Med 2020 12 9;383(26):2538-2546. Epub 2020 Dec 9.

From the Department of Molecular and Clinical Medicine, Institute of Medicine (J.N., P.S.) and the Department of Radiology, Institute of Clinical Sciences (K.L., M.F.), Sahlgrenska Academy, Gothenburg University, Gothenburg, the Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University (S.J., H.R.), and the Department of Surgical Sciences, Vascular Surgery, Uppsala University (B.K., B.S., G.T.), Uppsala, the Department of Clinical and Experimental Medicine, Linköping University, Linköping (Manne Andersson), Sweden and County Hospital Ryhov, Region Jönköping County, Department of Surgery, Jönköping (Manne Andersson), the Department of Vascular Surgery, Sunderby Hospital, Luleå (Mattias Andersson), the Department of Vascular Surgery, Halland Hospital, Halmstad (P.D.), the Department of Clinical Science and Education, Karolinska Institute (P.G.), the Departments of Surgery (P.G.) and Radiology (N.N.), Södersjukhuset, the Department of Radiology, Unit of Peripheral Interventional Radiology, Karolinska University Hospital (M.D., J.E.), and the Department. of Vascular Surgery, Karolinska University Hospital and the Karolinska Institute, (C.-M.W.), Stockholm, the Vascular Center, Department of Thoracic and Vascular Surgery, Skåne University Hospital, Malmö (T.F.), the Department of Vascular Surgery, Skaraborgs Hospital, Skövde (M.H.), the Department of Surgery, Kristianstad Hospital, Kristianstad (A.H.), the Department of Vascular Surgery, Växjö Hospital, Växjö (P.J.), the Department of Surgery, Gävle Hospital, Gävle (L.K.), the Department of Clinical Sciences, Faculty of Medicine (H.L.), Lund University (H.L., J.S.), Lund, the Vascular Unit, Department of Surgery, Helsingborg Hospital, Helsingborg (H.L.), the Section of Vascular Surgery, Surgical and Ear Clinic, Södra Älvsborg Hospital, Borås (K.L.), the Vascular Unit, the Department of Surgery, NU-Hospital Group, Trollhättan/Uddevalla (S.M.), the Department of Vascular Surgery, Karlstad Central Hospital, Karlstad (B.S.), the Department of Surgery, Västervik Hospital, Västervik (J.S.), the Department of Cardiothoracic and Vascular Surgery, Örebro University Hospital, Örebro (A.T.), the Department of Radiation Sciences, Radiology, Umeå University, Umeå (M.T.), the Department of Surgery, Sundsvall District Hospital, Sundsvall (J.W.), and the Department of Vascular Surgery, Kalmar Hospital, Kalmar (A.Ö.) - all in Sweden.

Background: The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.

Methods: We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.

Results: No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).

Conclusions: In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).
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http://dx.doi.org/10.1056/NEJMoa2005206DOI Listing
December 2020

Comparing efficacy and safety in catheter ablation strategies for atrial fibrillation: protocol of a network meta-analysis of randomised controlled trials.

BMJ Open 2020 11 23;10(11):e041819. Epub 2020 Nov 23.

Research Center of Epidemiology and Statistics (CRESS-U1153), Univeristé de Paris, Paris, Île-de-France, France.

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia. Catheter ablation (CA) of AF is an increasingly offered therapeutic approach, primary to relieve AF-related symptoms. Despite the development of new ablation approaches, there is no consensus regarding the most efficient ablation strategy. The objective of this network meta-analysis (NMA) is to compare the efficacy and safety of all different CA approaches for the treatment of patients with paroxysmal (PAF) and non-PAF (non-PAF).

Methods And Analysis: We will perform a systematic search to identify randomised controlled trials of different CA approaches for the treatment of PAF and non-PAF, through the final search date of 1 March 2020. Information sources will include major bibliographic databases (MEDLINE, Web of Science and CENTRAL) and clinical trial registries. Our primary outcomes will be the efficacy (recurrence-free survival) and safety of different CA approaches for the treatment of AF. Secondary outcomes will be all-cause mortality and procedural time. An NMA will be performed to determine the relative effects of different catheter ablation approaches (such as pulmonary vein isolation alone or in combination with ablation lines, ablation of complex fractionated atrial electrograms, etc). In PAF, a separate analysis will be performed including different energy sources (such as radiofrequency, cryogenic and laser energy). Risk of bias assessment and sensitivity analyses will be conducted to assess the robustness of the findings to potential bias.

Ethics And Dissemination: No ethical approval will be needed because data are collected from previous studies. The results will be presented through peer-review journals and conference presentation.

Prospero Registration Number: CRD42020169494.
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http://dx.doi.org/10.1136/bmjopen-2020-041819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684831PMC
November 2020

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis.

Mol Neurobiol 2021 Apr 16;58(4):1465-1481. Epub 2020 Nov 16.

Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.
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http://dx.doi.org/10.1007/s12035-020-02189-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932943PMC
April 2021

Update to the European Bioanalysis Forum recommendation on biomarkers assays; bringing context of use into practice.

Bioanalysis 2020 Oct 7;12(20):1427-1437. Epub 2020 Oct 7.

European Bioanalysis Forum vzw (EBF), Havenlaan 86c b204, Brussels 1000, Belgium.

In 2012, the European Bioanalysis Forum published a recommendation on biomarker method development and the bioanalysis of biomarkers in support of drug development. Since then, there has been significant discussion on how to bring the topic of context of use of biomarker assays to the forefront so that the purpose of the assay, the use of the data and the decisions being made with the data are well defined and clearly understood, not just by the bioanalytical scientist, but across all stakeholders. Therefore, it is imperative that discussions between the bioanalytical laboratory and the end users of the data happen early (and regularly) in the drug development process to enable the right assays to be developed and appropriately validated to generate the correct data and allow suitable decisions to be made. This updated refinement to the previous European Bioanalysis Forum recommendation will highlight the items to consider when discussing context of use for biomarker assay development and validation, thus enabling the correct conversations to occur and the move away from the misapplication of PK assay validation criteria to biomarker assays.
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http://dx.doi.org/10.4155/bio-2020-0243DOI Listing
October 2020

Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse.

Eur J Pharmacol 2020 Aug 11;880:173171. Epub 2020 May 11.

Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA.

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
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http://dx.doi.org/10.1016/j.ejphar.2020.173171DOI Listing
August 2020

Echocardiographic and Biochemical Factors Predicting Arrhythmia Recurrence After Catheter Ablation of Atrial Fibrillation-An Observational Study.

Front Physiol 2019 2;10:1215. Epub 2019 Oct 2.

Division of Cardiovascular Medicine and CMIV, Linköping University, Linköping, Sweden.

RFA is a well-established treatment for symptomatic patients with AF. However, the success rate of a single procedure is low. We aimed to investigate the association between the risk of recurrence of atrial fibrillation (AF) after a single radiofrequency ablation (RFA) procedure and cardiac neurohormonal function, left atrial (LA) mechanical function as well as proteins related to inflammation, fibrosis, and apoptosis. We studied 189 patients undergoing RFA between January 2012 and April 2014, with a follow-up period of 12 months. A logistic regression analysis was performed to investigate the association between pre-ablation LA emptying fraction (LAEF), MR-proANP, Caspase-8 (CASP8), Neurotrophin-3 (NT3), and the risk for recurrence of AF after a single RFA procedure. 119 (63.0%) patients had a recurrence during a mean follow-up of 402 ± 73 days. An increased risk of recurrence was associated with: Elevated MR-proANP (fourth quartile vs. first quartile: HR, 2.80 (95% CI, 1.14-6.90]; = 0.025); Low LAEF (fourth quartile vs. first quartile: hazard ratio [HR], 2.41 [95% CI, 1.01-5.79]; = 0.045); Elevated CASP8 (fourth quartile vs. first quartile: HR 12.198 95% CI 2.216-67.129; = 0.004); Elevated NT-3 (fourth quartile vs. first quartile: HR 7.485 95% CI 1.353-41.402; = 0.021). In a receiver operating characteristic curve analysis, the combination of MR-proANP, CASP8, and NT3 produced an area under the curve of 0.819; CI 95% (0.710-0.928). Patients with better LA mechanical function and lower levels of atrial neurohormones as well as of proteins related to fibrosis and apoptosis, have a better outcome after an RFA procedure. No. NCT01553045 (https://clinicaltrials.gov/ct2/show/NCT01553045?term=NCT01553045&rank=1).
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http://dx.doi.org/10.3389/fphys.2019.01215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783634PMC
October 2019

Gender and age differences in symptoms and health-related quality of life in patients with atrial fibrillation referred for catheter ablation.

Pacing Clin Electrophysiol 2019 11 24;42(11):1431-1439. Epub 2019 Sep 24.

Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Background: Primary indication for catheter ablation of atrial fibrillation (AF) is to reduce symptoms and improve health-related quality of life (HRQoL). There are data showing differences between the genders and between younger and older patients. To evaluate this, we studied a large Scandinavian cohort of patients referred for catheter ablation of AF.

Methods: Consecutive patients filled out the ASTA questionnaire, assessing symptoms, HRQoL, and perception of arrhythmia, prior to ablation. Patients were recruited from four Swedish and one Danish tertiary center.

Results: A total of 2493 patients (72% men) filled out the ASTA questionnaire. Women experienced eight of the nine ASTA scale symptoms more often than men. Patients <65 years reported four symptoms more often, only tiredness was more frequent in those ≥65 years (P = .007). Women and patients <65 years experienced more often palpitations and regarding close to fainting and this was more common among women, no age differences were seen. Women and men scored differently in 10 of the 13 HRQoL items. Only negative impact on sexual life was more common in men (P < .001). Older patients reported more negative influence in four of the HRQoL items and the younger in one; ability to concentrate.

Conclusions: Women experienced a more pronounced symptom burden and were more negatively affected in all HRQoL concerns, except for the negative impact on sexual life, where men reported more influence of AF. Differences between age groups were less pronounced. Disease-specific patient-reported outcomes measures (PROMs) add important information where gender differences should be considered in the care.
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http://dx.doi.org/10.1111/pace.13795DOI Listing
November 2019

Constitutive PGC-1α overexpression in skeletal muscle does not protect from age-dependent decline in neurogenesis.

Sci Rep 2019 08 23;9(1):12320. Epub 2019 Aug 23.

Institute for Neuroscience and Physiology, Center for Brain Repair and Rehabilitation, University of Gothenburg, Box 436, 405 30, Gothenburg, Sweden.

Aerobic exercise prevents age-dependent decline in cognition and hippocampal neurogenesis. The transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) mediates many of the exercise-induced benefits in skeletal muscle, including the release of factors into the circulation with neurotrophic effects. We use a transgenic mouse model with muscle-specific overexpression of PGC-1α to study the contribution of chronic muscle activation on exercise-induced effects on hippocampal neurogenesis in aging. Young and old transgenic and wild type animals of both sexes displayed a robust age-related reduction in newborn BrdU-cells, immature neurons (DCX-cells) and new mature BrdU/NeuN-neurons in the dentate gyrus. No differences were detected between genotypes or sexes. Analysis of serum proteins showed a tendency towards increased levels of myokines and reduced levels of pro-inflammatory cytokines for transgenic animals, but only musclin was found to be significantly up-regulated in transgenic animals. We conclude that constitutive muscular overexpression of PGC-1α, despite potent systemic changes, is insufficient for mimicking exercise-induced effects on hippocampal neurogenesis in aging. Continued studies are required to investigate the complex molecular mechanisms by which circulating signals could mediate exercise-induced effects on the central nervous system in disease and aging, with the aim of discovering new therapeutic possibilities for patients.
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http://dx.doi.org/10.1038/s41598-019-48795-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707251PMC
August 2019

Post-cardioversion Improvement in LV Function Defined by 4D Flow Patterns and Energetics in Patients With Atrial Fibrillation.

Front Physiol 2019 29;10:659. Epub 2019 May 29.

Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Background: Atrial fibrillation (AF) is a prevalent cause of cardiovascular morbidity, including thromboembolism and heart failure. Left ventricular dysfunction (LVD) detected in AF patients may be either precursor or consequence of the arrythmia. Successful cardioversion of chronic AF is often followed by a transient period of left atrial (LA) stunning, where depressed mechanical atrial contraction persists despite reinstitution of sinus rhythm. To determine if AF-associated LVD would improve with resolution of LA dysfunction, AF patients were examined immediately and 4 weeks after cardioversion to sinus rhythm. 4D flow cardiovascular magnetic resonance (CMR) assesses ventricular function according to the volumes and energetics of functional components of the LV volume. Previously, described 4D CMR markers of LVD include decreased volume and end-diastolic kinetic energy (KE) of the , which is the portion of LV volume that passes directly from inflow to outflow in a single cycle. We hypothesize that impaired LV flow patterns and energetics will be found immediately after cardioversion during atrial stunning, and that those parameters will improve as atrial function returns.

Methods: Ten patients with a history of AF underwent CMR 2-3 h (Time-1) and 4 weeks (Time-2), following electrical cardioversion to sinus rhythm. 4D phase-contrast velocity data and morphological images were acquired at a 3T CMR system. Using a previously evaluated method, pathlines were emitted from the LV end diastolic volume (LVEDV) and traced forward and backward in time until end-systole. The LVEDV was automatically separated into four functional flow components whose volume and KE were calculated.

Results: Left atrial fractional area change increased over the follow-up period ( = 0.001), indicating recovery of LA mechanical function. LVEF increased between Time-1 and Time-2 ( = 0.003); LVEDVI did not change ( = 0.319). Over that interval, the ratios of /LVEDV volume and KE increased ( = 0.001 and = 0.003, respectively), while the ratios of /LVEDV volume and KE decreased ( = 0.001 and = 0.005, respectively).

Conclusion: Post-cardioversion recovery of LA function was associated with improvements in conventional and 4D CMR markers of LV function. Flow-specific measures demonstrate the negative but potentially reversible impact of LA dysfunction on volume and energetic aspects of LV function.
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http://dx.doi.org/10.3389/fphys.2019.00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549517PMC
May 2019

The effect of ticagrelor on growth of small abdominal aortic aneurysms-a randomized controlled trial.

Cardiovasc Res 2020 02;116(2):450-456

Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala SE-751 85, Sweden.

Aims: To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs).

Methods And Results: In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naïve patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P = 0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P = 0.372). MRI diameter change was 2.5 mm vs. 1.8 mm (P = 0.113), US diameter change 2.3 mm vs. 2.2 mm (P = 0.778), and ILT volume change 12.9% vs. 10.4% (P = 0.590).

Conclusion: In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor.

Trial Registration: The TicAAA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02070653.
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http://dx.doi.org/10.1093/cvr/cvz133DOI Listing
February 2020

Characterization of acoustic emission analysis in applications for inhalation device performance assessment.

Int J Pharm 2019 May 5;563:304-313. Epub 2019 Apr 5.

AstraZeneca R&D, Pharmaceutical Technology & Development,Pepparedsleden 1, 431 83 Mölndal, Sweden. Electronic address:

Acoustic Emission (AE) measurement technology has gained wide appreciation in material sciences and process monitoring. In inhalation research, AE has been used for adherence indicating applications in clinical studies. Promising results from feasibility studies using AE combined with multivariate data analysis (AE-MVDA) in the analysis of devices for inhalation have prompted a broader study reported in this paper. This work presents the novel application of AE-MVDA for assessment of the combined inhalation device and formulation performance. The purpose is to evaluate the benefits that this technology can provide to inhalation product development programs. The work was carried out using two different dry powder inhaler device model systems while investigating different performance features. The devices were filled with dry powder formulations with both placebo and with active pharmaceutical ingredient (API). The acquired AE data was analyzed using multivariate data analysis tools such as Principal component analysis (PCA) and orthogonal projections to latent structures (OPLS). The AE profiles were indicative for device and formulation performance. Normal and deviating performances were readily picked up in the AE data. Moreover, performance trends between doses withdrawn from the inhalers were also observable. Lastly, differences in the AE profile between the formulations could be detected. The overall conclusion from the AE-MVDA measurement approach evaluation is that it has the potential to add value as a cost-effective, non-invasive quality and performance monitoring technology both in development and in production of inhaled medicines.
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http://dx.doi.org/10.1016/j.ijpharm.2019.04.011DOI Listing
May 2019

A decade of catheter ablation of cardiac arrhythmias in Sweden: ablation practices and outcomes.

Eur Heart J 2019 03;40(10):820-830

Department of Cardiology, Karolinska University Hospital, SE-171 76, Solna, Sweden.

Aims: Catheter ablation is considered the treatment of choice for many tachyarrhythmias, but convincing 'real-world' data on efficacy and safety are lacking. Using Swedish national registry data, the ablation spectrum, procedural characteristics, as well as ablation efficacy and reported adverse events are reported.

Methods And Results: Consecutive patients (≥18 years of age) undergoing catheter ablation in Sweden between 01 January 2006 and 31 December 2015 were included in the study. Follow-up (repeat ablation and vital status) was collected through 31 December 2016. A total of 26 642 patients (57 ± 15 years, 62% men), undergoing a total of 34 428 ablation procedures were included in the study. In total, 4034 accessory pathway/Wolff-Parkinson-White syndrome (12%), 7358 AV-nodal re-entrant tachycardia (21%), 1813 atrial tachycardia (5.2%), 5481 typical atrial flutter (16%), 11 916 atrial fibrillation (AF, 35%), 2415 AV-nodal (7.0%), 581 premature ventricular contraction (PVC, 1.7%), and 964 ventricular tachycardia (VT) ablations (2.8%) were performed. Median follow-up time was 4.7 years (interquartile range 2.7-7.0). The spectrum of treated arrhythmias changed over time, with a gradual increase in AF, VT, and PVC ablation (P < 0.001). Decreasing procedural times and utilization of fluoroscopy with time, were seen for all arrhythmia types. The rates of repeat ablation differed between ablation types, with the highest repeat ablation seen in AF (41% within 3 years). The rate of reported adverse events was low (n = 595, 1.7%). Death in the immediate period following ablation was rare (n = 116, 0.34%).

Conclusion: Catheter ablations have shifted towards more complex procedures over the past decade. Fluoroscopy time has markedly decreased and the efficacy of catheter ablation seems to improve for AF.
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http://dx.doi.org/10.1093/eurheartj/ehy709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403459PMC
March 2019

The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive-like rats.

Acta Physiol (Oxf) 2019 04 25;225(4):e13211. Epub 2018 Nov 25.

Department of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

Aim: Major depressive disorder is a common and debilitating condition with substantial economic impact. Treatment options, although effective, are aimed at relieving the symptoms with limited disease modification. Ketamine, a commonly used anaesthetic, has received substantial attention as it shows rapid antidepressant effects clinically. We studied the effects of ketamine on hippocampal function and dentate gyrus proliferation in rats showing a depressive-like phenotype.

Methods: Adolescent and adult animals were pre-natally exposed to the glucocorticoid analog dexamethasone, and we verified a depressive-like phenotype using behavioural tests, such as the sucrose preference. We subsequently studied the effects of ketamine on hippocampal synaptic transmission, plasticity and dentate gyrus proliferation. In addition, we measured hippocampal glutamate receptor expression. We also tested the ketamine metabolite hydroxynorketamine for NMDA-receptor independent effects.

Results: Surprisingly, our extensive experimental survey revealed limited effects of ketamine or its metabolite on hippocampal function in control as well as depressive-like animals. We found no effects on synaptic efficacy or induction of long-term potentiation in adolescent and adult animals. Also there was no difference when comparing the dorsal and ventral hippocampus. Importantly, however, ketamine 24 hours prior to experimentation significantly increased the dentate gyrus proliferation, as revealed by Ki-67 immunostaining, in the depressive-like phenotype.

Conclusion: We find limited effects of ketamine on hippocampal glutamatergic transmission. Instead, alterations in dentate gyrus proliferation could explain the antidepressant effects of ketamine.
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http://dx.doi.org/10.1111/apha.13211DOI Listing
April 2019

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke.

Neuroscience 2018 08 31;384:314-328. Epub 2018 May 31.

Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30 Gothenburg, Sweden.

Physical exercise can improve morphological outcomes after ischemic stroke and ameliorate irradiation-induced reduction of hippocampal neurogenesis in rodents, but the mechanisms underlying these effects remain largely unknown. The transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is considered to be one of the central factors responsible for exercise-induced benefits in skeletal muscle, including the release of neurotrophic factors into the circulation. In order to test if PGC-1α overexpression in skeletal muscle could simulate the exercise-induced effects on recovery after cranial irradiation and stroke, we used male adult transgenic mice overexpressing murine PGC-1α under the control of muscle creatinine kinase promoter and subjected them to either whole brain irradiation at a dose of 4 Gy or photothrombotic stroke to the sensory motor cortex. Muscular PGC-1α overexpression did not ameliorate irradiation-induced reduction of newborn BrdU-labeled cells in the dentate gyrus, immature neurons, or newborn mature neurons. In the stroke model, muscular overexpression of PGC-1α resulted in an increased infarct size without any changes in microglia activation or reactive astrocytosis. No difference could be detected in the number of migrating neural progenitor cells from the subventricular zone to the lesioned neocortex or in vascular density of the contralateral neocortex in comparison to wildtype animals. We conclude that forced muscular overexpression of PGC-1α does not have a beneficial effect on hippocampal neurogenesis after irradiation, but rather a detrimental effect on the infarct volume after stroke in mice. This suggests that artificial muscle activation through the PGC-1α pathway is not sufficient to mimic exercise-induced recovery after cranial irradiation and stroke.
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http://dx.doi.org/10.1016/j.neuroscience.2018.05.036DOI Listing
August 2018

Association between IL-6 production in synovial explants from rheumatoid arthritis patients and clinical and imaging response to biologic treatment: A pilot study.

PLoS One 2018 22;13(5):e0197001. Epub 2018 May 22.

The Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Introduction: The need for biomarkers which can predict disease course and treatment response in rheumatoid arthritis (RA) is evident. We explored whether clinical and imaging responses to biologic disease modifying anti-rheumatic drug treatment (bDMARD) were associated with the individual's mediator production in explants obtained at baseline.

Methods: RA Patients were evaluated by disease activity score 28 joint C-reactive protein (DAS 28-)), colour Doppler ultrasound (CDUS) and 3 Tesla RA magnetic resonance imaging scores (RAMRIS). Explants were established from synovectomies from a needle arthroscopic procedure prior to initiation of bDMARD. Explants were incubated with the bDMARD in question, and the productions of interleukin-6 (IL-6), monocyte chemo-attractive protein-1 (MCP-1) and macrophage inflammatory protein-1-beta (MIP-1b) were measured by multiplex immunoassays. The changes in clinical and imaging variables following a minimum of 3 months bDMARD treatment were compared to the baseline explant results. Mixed models and Spearman's rank correlations were performed. P-values below 0.05 were considered statistically significant.

Results: 16 patients were included. IL-6 production in bDMARD-treated explants was significantly higher among clinical non-responders compared to responders (P = 0.04), and a lack of suppression of IL-6 by the bDMARDS correlated to a high DAS-28 (ρ = 0.57, P = 0.03), CDUS (ρ = 0.53, P = 0.04) and bone marrow oedema (ρ = 0.56, P = 0.03) at follow-up. No clinical association was found with explant MCP-1 production. MIP-1b could not be assessed due to a large number of samples below the detection limit.

Conclusions: Synovial explants appear to deliver a disease-relevant output testing which when carried out in advance of bDMARD treatment can potentially pave the road for a more patient tailored treatment approach with better treatment effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963776PMC
July 2018

Formation of Blood Foam in the Air Trap During Hemodialysis Due to Insufficient Automatic Priming of Dialyzers.

Artif Organs 2018 May 15;42(5):533-539. Epub 2018 Mar 15.

Department of Public Health and Clinical Medicine, University of Umeå, Umeå, Sweden.

We were encouraged to investigate the reasons for large amounts of foam observed in bloodlines during hemodialysis (HD). Foam was visible in the venous air trap within the Artis Gambro dialysis device. Estimates of the extent of foam were graded (0-no foam, 10-extensive foam) by two persons that were blind to the type of dialyzer used. Thirty-seven patients were involved in the dialysis procedures. Consecutive dialyses were graded using dialyzers from Fresenius Medical Care (CorDiax dialyzers that were used for high flux HD-FX80 and FX100, and for hemodiafiltration-FX1000). The extracorporeal circuit was primed automatically by dialysate using Gambro Artis software 8.15 006 (Gambro, Dasco, Medolla Italy, Baxter, Chicago, IL, USA). The priming volume recommended by the manufacturer was 1100 mL, whereas our center uses 1500 mL. Extensive amounts of blood foam were visual in the air traps. Although the manufacturer recommended extension of priming volume up to 3000 mL, this did not eliminate the foam. Microbubble measurement during HD revealed the air to derive from the dialyzers. When changing to PF210H dialyzers (Baxter) and using a priming volume of 1500 mL, the foam was significantly less (P < 0.01). The extent of foam correlated with the size of the FX-dialyzer surface (P = 0.002). The auto-priming program was updated to version 8.21 by the manufacturer and the extent of foam in the air trap using FX dialyzers was now reduced and there was no longer a difference between FX and PF dialyzers, although less foam was still visible in the venous air trap during several dialyses. In conclusion, this study urgently calls attention to blood foam development in the venous air trap when using Artis devices and priming software 8.15 in combination with Fresenius dialyzers. Updated auto-priming software (version 8.21) of Artis should be requested to reduce the extent of foam for the Fresenius dialyzers. Other interactions may also be present. We recommend further studies to clarify these problems. Meanwhile caution is warranted for the combined use of dialysis devices and dialyzers with incompatible automatic priming.
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http://dx.doi.org/10.1111/aor.13070DOI Listing
May 2018

A clinical decision support tool for improving adherence to guidelines on anticoagulant therapy in patients with atrial fibrillation at risk of stroke: A cluster-randomized trial in a Swedish primary care setting (the CDS-AF study).

PLoS Med 2018 03 13;15(3):e1002528. Epub 2018 Mar 13.

Department of Cardiology, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Background: Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains significant undertreatment. The main aim of the current study was to investigate whether a clinical decision support tool (CDS) for stroke prevention integrated in the electronic health record could improve adherence to guidelines for stroke prevention in patients with AF.

Methods And Findings: We conducted a cluster-randomized trial where all 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), were randomized to be part of the CDS intervention or to serve as controls. The CDS produced an alert for physicians responsible for patients with AF and at increased risk for thromboembolism (according to the CHA2DS2-VASc algorithm) without anticoagulant therapy. The primary endpoint was adherence to guidelines after 1 year. After randomization, there were 22 and 21 primary care clinics in the CDS and control groups, respectively. There were no significant differences in baseline adherence to guidelines regarding anticoagulant therapy between the 2 groups (CDS group 70.3% [5,186/7,370; 95% CI 62.9%-77.7%], control group 70.0% [4,187/6,009; 95% CI 60.4%-79.6%], p = 0.83). After 12 months, analysis with linear regression with adjustment for primary care clinic size and adherence to guidelines at baseline revealed a significant increase in guideline adherence in the CDS (73.0%, 95% CI 64.6%-81.4%) versus the control group (71.2%, 95% CI 60.8%-81.6%, p = 0.013, with a treatment effect estimate of 0.016 [95% CI 0.003-0.028]; number of patients with AF included in the final analysis 8,292 and 6,508 in the CDS and control group, respectively). Over the study period, there was no difference in the incidence of stroke, transient ischemic attack, or systemic thromboembolism in the CDS group versus the control group (49 [95% CI 43-55] per 1,000 patients with AF in the CDS group compared to 47 [95% CI 39-55] per 1,000 patients with AF in the control group, p = 0.64). Regarding safety, the CDS group had a lower incidence of significant bleeding, with events in 12 (95% CI 9-15) per 1,000 patients with AF compared to 16 (95% CI 12-20) per 1,000 patients with AF in the control group (p = 0.04). Limitations of the study design include that the analysis was carried out in a catchment area with a high baseline adherence rate, and issues regarding reproducibility to other regions.

Conclusions: The present study demonstrates that a CDS can increase guideline adherence for anticoagulant therapy in patients with AF. Even though the observed difference was small, this is the first randomized study to our knowledge indicating beneficial effects with a CDS in patients with AF.

Trial Registration: ClinicalTrials.gov NCT02635685.
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http://dx.doi.org/10.1371/journal.pmed.1002528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849292PMC
March 2018

Left Atrial 4D Blood Flow Dynamics and Hemostasis following Electrical Cardioversion of Atrial Fibrillation.

Front Physiol 2017 12;8:1052. Epub 2017 Dec 12.

Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored. 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2-3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed. From Time-1 to Time-2: Heart rate decreased (61 ± 7 vs. 56 ± 8 bpm, = 0.01); Maximum change in left atrial volume increased (8 ± 4 vs. 22 ± 15%, = 0.009); The duration of stasis (68 ± 11 vs. 57 ± 8%, = 0.002) and the volume of stasis (14 ± 9 vs. 9 ± 7%, = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 ± 3.3 vs. 3.3 ± 2.2 μg/L, = 0.008). A significant correlation was found between TAT and the volume of stasis ( = 0.69, < 0.001) at Time-1 and between TAT and the duration of stasis ( = 0.34, = 0.04) at Time-2. In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.
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http://dx.doi.org/10.3389/fphys.2017.01052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732934PMC
December 2017

Catheter ablation of ventricular tachycardia in a patient with a left endoventricular patch: a case report.

Eur Heart J Case Rep 2017 Dec 20;1(2):ytx016. Epub 2017 Dec 20.

Department of Cardiology and Department of Medical and Health Sciences, Linköping University, 58183 Linköping, Sweden.

Surgical resection of a left ventricular aneurysm in the setting of ventricular tachycardia (VT) was first described by Couch in 1959. The technique was further developed by Dor with performance of endocardiectomy and complete myocardial revascularization. Despite an attempt to remove the arrhythmogenic substrate, however, recurrences of VT remain an issue. Furthermore, the surgical technique used entails limited access to the potential area of interest with regard to a percutaneous catheter ablation procedure. We present a case report of a 65-year-old man who was referred for catheter ablation due to recurrent episodes of VT. He had undergone a coronary artery bypass surgery 8 years previously. During surgery, resection of an apical thrombus and reconstruction of an apical aneurysm with a Fontan stitch and an endoventricular patch were performed. The mapping and ablation procedure was aided by intracardiac echocardiography. During mapping, the ablation catheter was noticed to enter the apical pouch from the inferoseptal border of the endoventricular patch. During the ablation procedure, one of the VTs was successfully ablated in the inferior aspect of the apical pouch. This report confirms that the arrhythmogenic substrate underneath an endoventricular patch may be accessed in some instances and that these complex catheter ablation procedures may benefit from the use of intracardiac echocardiography.
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http://dx.doi.org/10.1093/ehjcr/ytx016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177025PMC
December 2017

An Ontology-based Context-aware System for Smart Homes: [email protected]

Sensors (Basel) 2017 Jul 6;17(7). Epub 2017 Jul 6.

Center for Applied Autonomous Sensor Systems, Örebro University, 70182 Örebro, Sweden.

Smart home environments have a significant potential to provide for long-term monitoring of users with special needs in order to promote the possibility to age at home. Such environments are typically equipped with a number of heterogeneous sensors that monitor both health and environmental parameters. This paper presents a framework called [email protected], consisting of an IoT infrastructure, which provides information with an unambiguous, shared meaning across IoT devices, end-users, relatives, health and care professionals and organizations. We focus on integrating measurements gathered from heterogeneous sources by using ontologies in order to enable semantic interpretation of events and context awareness. Activities are deduced using an incremental answer set solver for stream reasoning. The paper demonstrates the proposed framework using an instantiation of a smart environment that is able to perform context recognition based on the activities and the events occurring in the home.
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http://dx.doi.org/10.3390/s17071586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539647PMC
July 2017

Clinical decision support for stroke prevention in atrial fibrillation (CDS-AF): Rationale and design of a cluster randomized trial in the primary care setting.

Am Heart J 2017 May 16;187:45-52. Epub 2017 Feb 16.

Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Department of Cardiology, Linköping University Hospital, Linköping, Sweden.

Background: Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains a significant undertreatment. The main aim of the current study is to investigate whether a clinical decision support tool for stroke prevention (CDS) integrated in the electronic health record can improve adherence to guidelines for stroke prevention in patients with AF.

Methods: We will conduct a cluster randomized trial where 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), will be randomized to be part of the CDS intervention or serve as controls. The CDS will alert responsible physicians of patients with AF and increased risk for thromboembolism according to the CHADSVASc (Congestive heart failure, Hypertension, Age ≥ 74 years, Diabetes mellitus, previous Stroke/TIA/thromboembolism, Vascular disease, Age 65-74 years, Sex category (i.e. female sex)) algorithm without anticoagulant therapy. The primary end point will be adherence to guidelines after 1 year.

Conclusion: The present study will investigate whether a clinical decision support system integrated in an electronic health record can increase adherence to guidelines regarding anticoagulant therapy in patients with AF.
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http://dx.doi.org/10.1016/j.ahj.2017.02.009DOI Listing
May 2017

Research interest and activity among medical students in Gothenburg, Sweden, a cross-sectional study.

BMC Med Educ 2016 Aug 26;16(1):226. Epub 2016 Aug 26.

Department of Otorhinolaryngology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: The proportion of physicians undertaking doctoral studies is decreasing. Early recruitment of medical students could counteract this trend. This follow-up survey investigated research interest and activity among medical students at the Sahlgrenska Academy, Gothenburg, Sweden.

Methods: A questionnaire was administered to all medical students at the Sahlgrenska Academy, as a follow-up to a 2006 survey. The Mann-Whitney U test was used for ordinal variables and the Fisher exact test for categorical variables. Data from Statistics Sweden was used to analyse the number of PhDs awarded to individuals who earned a medical degree in 2000-2012.

Results: Of the students, 16 % were already conducting and another 36 % wanted to conduct research during their studies. The interest was at the same level compared to 2006. The main reasons for conducting research consisted of an interest in scientific problems or the research topic, a wish for personal development or intellectual stimulation. Students engaged in research reported lack of time, increased workload and less time to study as hindering factors.

Conclusions: Recruitment could be improved by offering improved and regular information, clarifying career paths, broadly announcing available projects, and creating new and expanding existing research programmes. The potential for recruitment of Gothenburg medical students to research is substantial, but students are hampered by lack of time, lack of supervisors and lack of information.
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http://dx.doi.org/10.1186/s12909-016-0749-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002212PMC
August 2016

Combining a hip arthroplasty stem with trochanteric reattachment bolt and a polyaxial locking plate in the treatment of a periprosthetic fracture below a well-integrated implant.

Arthroplast Today 2016 Dec 2;2(4):141-145. Epub 2016 Mar 2.

Department of Orthopaedic surgery, Uddevalla Hospital, NU Hospital Group, Uddevalla, Sweden.

Distally anchored uncemented modular tapered porous stems are often the preferred treatment in total hip arthroplasty revisions and failed subtrochanteric fractures. These conditions mainly affect elderly osteoporotic patients, with an increased risk of later fractures below the well-fixated implant. Treatment in secondary fractures with long looking plates is the recommended treatment, where stability is a key to fracture healing. We report a complicated case in which this was achieved by an innovative technique combing the trochanteric attachment bolt of the stem system and a locking plate with polyaxial screws.
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http://dx.doi.org/10.1016/j.artd.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247515PMC
December 2016

Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro.

Immunology 2015 Jul 19;145(3):367-79. Epub 2015 May 19.

Department of Cellular Pharmacology, Autoimmune Disease Research, Novo Nordisk A/S, Måløv, Denmark.

Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone-marrow-derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte-derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co-culture experiments revealed that interleukin-15-activated, but not resting, NK cells trigger osteoclast apoptosis in a dose-dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function-associated antigen-1, DNAX accessory molecule-1 or tumour necrosis factor-related apoptosis-inducing ligand enhance osteoclast survival when co-cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin-15-activated NK cells may directly affect bone erosion under physiological and pathological conditions.
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http://dx.doi.org/10.1111/imm.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479536PMC
July 2015

Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration.

Eur J Pharmacol 2015 Jan 29;747:1-6. Epub 2014 Nov 29.

Department of Acute and Cardiovascular Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-423 45 Gothenburg, Sweden.

Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40 min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5 µg/kg per dose), whereas single (1 μg/kg) or triple boluses (0.5 μg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0 min before the 30 min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20 min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10 min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia.
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http://dx.doi.org/10.1016/j.ejphar.2014.11.018DOI Listing
January 2015

[Improved information in Medical School may increase recruitment of physician-scientists].

Lakartidningen 2014 Nov 18;111(47):2108-10. Epub 2014 Nov 18.

Sahlgrenska Academy - Göteborg, Sweden Sahlgrenska Academy - Göteborg, Sweden.

The proportion of physicians undertaking doctoral studies has decreased progressively over the last years both in Sweden and internationally. To counteract this trend, it is important to investigate and improve the recruitment of medical students to research. In the fall of 2012, a questionnaire study investigating interest and involvement in research was conducted among all medical students at Sahlgrenska Academy, Gothenburg University in Sweden. The proportion of students involved in research (16 %) was unchanged from a previous similar study in 2006, and participating in a research project was considered to contribute positively to medical studies.  A large number of students (36 %) were interested in conducting research during the semesters, and the main disincentives included lack of time, lack of information, and lack of project and research group.  Research stimulating projects such as the 'Amanuensis Program' had a positive impact on research interest in general. For increased and early recruitment of medical students, efforts should be made to offer improved and regular information about conducting research, to publish available research projects and research groups, and to create and expand research programs for motivated medical students. Along with improved conditions and financial resources, we propose that these measures would help to accommodate the growing need for recruitment of medical students and physicians to research.
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November 2014

Effects of an artificial gravity countermeasure on orthostatic tolerance, blood volumes and aerobic power after short-term bed rest (BR-AG1).

J Appl Physiol (1985) 2015 Jan 23;118(1):29-35. Epub 2014 Oct 23.

Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany;

Exposure to artificial gravity (AG) in a short-arm centrifuge has potential benefits for maintaining human performance during long-term space missions. Eleven subjects were investigated during three campaigns of 5 days head-down bed rest: 1) bed rest without countermeasures (control), 2) bed rest and 30 min of AG (AG1) daily, and 3) bed rest and six periods of 5 min AG (AG2) daily. During centrifugation, the supine subjects were exposed to AG in the head-to-feet direction with 1 G at the center of mass. Subjects participated in the three campaigns in random order. The cardiovascular effects of bed rest and countermeasures were determined from changes in tolerance to a head-up tilt test with superimposed lower body negative pressure (HUT), from changes in plasma volume (PV) and from changes in maximum aerobic power (V̇o2 peak) during upright work on a cycle ergometer. Complete data sets were obtained in eight subjects. After bed rest, HUT tolerance times were 36, 64, and 78% of pre-bed rest baseline during control, AG1 and AG2, respectively, with a significant difference between AG2 and control. PV and V̇o2 peak decreased to 85 and 95% of pre-bed rest baseline, respectively, with no differences between the treatments. It was concluded that the AG2 countermeasure should be further investigated during future long-term bed rest studies, especially as it was better tolerated than AG1. The superior effect of AG2 on orthostatic tolerance could not be related to concomitant changes in PV or aerobic power.
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http://dx.doi.org/10.1152/japplphysiol.00061.2014DOI Listing
January 2015

Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study.

Arthritis Res Ther 2014 May 5;16(3):R107. Epub 2014 May 5.

Introduction: Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans.

Methods: RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model.

Results: Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman's ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman's ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman's ρ = 0.50), BME score (P = 0.04, approximate Spearman's ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman's ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman's ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman's ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance.

Conclusions: The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
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http://dx.doi.org/10.1186/ar4557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078218PMC
May 2014