A Nonlinear Relation between Body Mass Index and Long-Term Poststroke Functional Outcome-The Importance of Insulin Resistance, Inflammation, and Insulin-like Growth Factor-Binding Protein-1.

Both high serum insulin-like growth factor-binding protein-1 (s-IGFBP-1) and insulin resistance (IR) are associated with poor functional outcome poststroke, whereas overweight body mass index (BMI; 25-30) is related to fewer deaths and favorable functional outcome in a phenomenon labeled "the obesity paradox". Furthermore, IGFBP-1 is inversely related to BMI, in contrast to the linear relation between IR and BMI. Here, we investigated s-IGFBP-1 and IR concerning BMI and 7-year poststroke functional outcome. We included 451 stroke patients from the Sahlgrenska Study on Ischemic Stroke (SAHLSIS) with baseline measurements of s-IGFBP1, homeostasis model assessment of IR (HOMA-IR), BMI (categories: normal-weight (8.5-25), overweight (25-30), and obesity (>30)), and high-sensitivity C-reactive protein (hs-CRP) as a measure of general inflammation. Associations with poor functional outcome (modified Rankin scale [mRS] score: 3-6) after 7 years were evaluated using multivariable binary logistic regression, with overweight as reference due to the nonlinear relationship. Both normal-weight (odds-ratio [OR] 2.32, 95% confidence interval [CI] 1.30-4.14) and obese (OR 2.25, 95% CI 1.08-4.71) patients had an increased risk of poor functional outcome, driven by deaths only in the normal-weight. In normal-weight, s-IGFBP-1 modestly attenuated (8.3%) this association. In the obese, the association was instead attenuated by HOMA-IR (22.4%) and hs-CRP (10.4%). Thus, a nonlinear relation between BMI and poor 7-year functional outcome was differently attenuated in the normal-weight and the obese.

Effects of exercise on symptoms of anxiety in primary care patients: A randomized controlled trial.

BACKGROUND: There is a need for high-quality research regarding exercise interventions for persons with anxiety disorders. We investigate whether a 12-week exercise intervention, with different intensities, could reduce anxiety symptoms in patients with anxiety disorders. METHODS: 286 patients were recruited from primary care in Sweden. Severity of symptoms was self-assessed using the Beck Anxiety Inventory (BAI) and the Montgomery Åsberg Depression Rating Scale (MADRS-S). Participants were randomly assigned to one of two group exercise programs with cardiorespiratory and resistance training and one control/standard treatment non-exercise group, with 1:1:1 allocation. RESULTS: Patients in both exercise groups showed larger improvements in both anxiety and depressive symptoms compared to the control group. No differences in effect sizes were found between the two groups. To study a clinically relevant improvement, BAI and MADRS-S were dichotomized with the mean change in the control group as reference. In adjusted models the odds ratio for improved symptoms of anxiety after low-intensity training was 3.62 (CI 1.34-9.76) and after moderate/high intensity 4.88 (CI 1.66-14.39), for depressive symptoms 4.96 (CI 1.81-13.6) and 4.36 (CI 1.57-12.08) respectively. There was a significant intensity trend for improvement in anxiety symptoms. LIMITATIONS: The use of self-rating measures which bears the risk of an under- or overestimation of symptoms. CONCLUSIONS: A 12-week group exercise program proved effective for patients with anxiety syndromes in primary care. These findings strengthen the view of physical exercise as an effective treatment and could be more frequently made available in clinical practice for persons with anxiety issues.

Anxiety severity and cognitive function in primary care patients with anxiety disorder: a cross-sectional study.

BACKGROUND: Deficits in cognitive performance are reported in patients with anxiety disorders, but research is limited and inconsistent. We aimed to investigate cross-sectional associations between cognitive function, with focus on executive function, and anxiety severity in primary care patients diagnosed with anxiety disorders. METHODS: 189 Swedish patients aged 18-65 years (31% men) with anxiety disorders diagnosed according to Mini International Neuropsychiatric Interview were included. Severity of anxiety was assessed using Beck Anxiety Inventory self-assessment scale. Digit span, block design and matrix reasoning tests from the Wechsler Adult Intelligence Scale IV, and the design fluency test from the Delis-Kaplan Executive Function System were used. Multivariable linear regression models were applied to investigate the relationship of anxiety severity and cognitive functioning. Comparisons were also performed to a normed non-clinical population, using the Wilcoxon signed rank test. RESULTS: More severe anxiety was associated with lower digit span test scores (R2 = 0.109, B = -0.040, p = 0.018), but not with block design, matrix reasoning or design fluency tests scores, after adjustment for comorbid major depression in a multivariable model. When compared to a normed population, patients with anxiety performed significantly lower on the block design, digit span forward, digit span sequencing and matrix reasoning tests. CONCLUSIONS: Severity of anxiety among patients with anxiety disorder was associated with executive functions related to working memory, independently of comorbid major depression, but not with lower fluid intelligence. A further understanding of the executive behavioral control in patients with anxiety could allow for more tailored treatment strategies including medication, therapy and interventions targeted to improve specific cognitive domains.

Circulating granulocyte colony-stimulating factor and functional outcome after ischemic stroke: an observational study.

Objectives: While granulocyte colony-stimulating factor (G-CSF) has shown beneficial effects in experimental ischemic stroke (IS), these effects have not been reproduced clinically. Small-to-medium-sized observational studies have reported varying associations for G-CSF with stroke severity and post-stroke functional outcome, prompting their investigation in a larger study.Methods: Endogenous serum G-CSF (S-GCSF) was measured in the acute phase and after 3 months in patients with IS (N = 435; 36% females; mean age, 57 years) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Stroke severity was scored according to the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) assessed functional outcomes at 3-month and 2-year post-stroke. Correlation and logistic regression analyses with confounder adjustments assessed the relationships.Results: The acute S-GCSF level was 23% higher than at 3-month post-stroke (p < 0.001). Acute G-CSF correlated weakly with stroke severity quintiles (r = 0.12, p = 0.013) and with high-sensitivity C-reactive protein (r = 0.29, p < 0.001). The association between S-GCSF (as quintiles, q) and poor functional outcome at 3 months (mRS 3-6; S-GCSF-q5 vs. S-GCSF-q1, age- and sex-adjusted odds ratio: 4.27, 95% confidence interval: 1.82-9.99; p = 0.001) withstood adjustment for cardiovascular risk factors and stroke subtype, but not additional correction for stroke severity. Post-stroke changes in S-GSCF and absolute 3-month S-GCSF were not associated with 3-month or 2-year functional outcomes.Discussion: Early post-stroke S-GCSF is increased in severe IS and associated with 3-month poor functional outcomes. The change in S-GCSF and the 3-month S-GCSF appear to be less-important, and S-GCSF likely reflects inflammation in large infarctions.

Assessing Sunscreen Protection Using UV Photography: Descriptive Study.

BACKGROUND: Photography using a UV transmitting filter allows UV light to pass and can be used to illuminate UV blocking lotions such as sunscreens. OBJECTIVE: The aim of this study is to compare currently available UV photography cameras and assess whether these devices can be used as visualization tools for adequate coverage of sun protection lotions. METHODS: This study was conducted in 3 parts: in phase 1, 3 different UV cameras were tested; in phase 2, we explored whether UV photography could work on a range of sun protection products; and in phase 3, a UV webcam was developed and was field-tested in a beach setting. In phase 1, volunteers were recruited, and researchers applied 3 sun protection products (ranging from sun protection factor [SPF] 15 to 50+) to the participants' faces and arms. UV photography was performed using 3 UV cameras, and the subsequent images were compared. In phase 2, volunteers were recruited and asked to apply their own SPF products to their faces in their usual manner. UV photographs were collected in the morning and afternoon to assess whether the coverage remained over time. Qualitative interviews were conducted to assess the participants' level of satisfaction with the UV image. In phase 3, a small portable UV webcam was designed using a plug-and-play approach to enable the viewing of UV images on a larger screen. The developed webcam was deployed at a public beach setting for use by the public for 7 days. RESULTS: The 3 UV camera systems tested during phase 1 identified the application of a range of sun protection lotions of SPF 15 to 50+. The sensitivity of the UV camera devices was shown to be adequate, with SPF-containing products applied at concentrations of 2 and 1 mg/cm2 clearly visible and SPF-containing products applied at a concentration of 0.4 mg/cm2 having lower levels of coverage. Participants in phase 2 reported high satisfaction with the UV photography images, with 83% (29/35) of participants likely to use UV photography in the future. During phase 2, it was noted that many participants used tinted SPF-containing cosmetics, and several tinted products were further tested. However, it was observed that UV photography could not identify the areas missed for all tinted products. During phase 3, the electrical components of the UV webcam remained operational, and the camera was used 233 times by the public during field-testing. CONCLUSIONS: In this study, we found that UV photography could identify the areas missed by sun protection lotions with chemical filters, and participants were engaged with personalized feedback. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000975190; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377089 ; Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000145101; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376672.

Deployment of a Smart Handwashing Station in a School Setting During the COVID-19 Pandemic: Field Study.

BACKGROUND: Hand hygiene is one of the most effective ways to remove germs, prevent the spread of infectious pathogens, and avoid getting sick. Since the COVID-19 pandemic began, health authorities have been advocating good hand hygiene practices. OBJECTIVE: The primary aim of this study is to field test a prototype smart handwashing station deployed in a school setting during the COVID-19 pandemic. METHODS: We deployed a smart handwashing station and examined key technological considerations including connectivity, security, and data management systems, as well as the health and safety of users. RESULTS: The smart handwashing station was deployed for 10 days in a school setting in Australia during the COVID-19 pandemic. The smart handwashing station's electrical components remained operational during field testing and underwent robust cleaning protocols each day. The handwashing station was used 1138 times during the field test and there was no COVID-19 transmission at the school during the testing. CONCLUSIONS: This study demonstrates that a personalized feedback approach using technology can successfully be implemented at a school and can provide a platform to improve hand hygiene among school-aged children.

Internet of Things Smart Sunscreen Station: Descriptive Proof-of-Concept Study.

BACKGROUND: Skin cancer is the most prevalent but also most preventable cancer in Australia. Outdoor workers are at increased risk of developing skin cancer, and improvements in sun protection are needed. Sunscreen, when applied at the recommended concentration (2 mg/cm2), has been shown to block the harmful molecular effects of ultraviolet radiation in vivo. However, sunscreen is often not applied, reapplied sufficiently, or stored adequately to yield protection and reduce sunburns. OBJECTIVE: The primary aim of this study was to test an Internet of Things approach by deploying a smart sunscreen station to an outdoor regional mining site. METHODS: We deployed a smart sunscreen station and examined the key technological considerations including connectivity, security, and data management systems. RESULTS: The smart sunscreen station was deployed for 12 days at a mining workplace (Dalby, Australia). The smart sunscreen station's electrical components remained operational during field testing, and data were received by the message queuing telemetry transport server automatically at the end of each day of field testing (12/12 days, 100% connectivity). CONCLUSIONS: This study highlights that an Internet of Things technology approach can successfully measure sunscreen usage and temperature storage conditions.

Circulating levels of vascular endothelial growth factor and post-stroke long-term functional outcome.

OBJECTIVES: Vascular endothelial growth factor (VEGF) acts in angiogenesis and neuroprotection, although the beneficial effects on experimental ischemic stroke (IS) have not been replicated in clinical studies. We investigated serum VEGF (s-VEGF) in the acute stage (baseline) and 3 months post-stroke in relation to stroke severity and functional outcome. METHODS: The s-VEGF and serum high-sensitivity C-reactive protein (hs-CRP) concentrations were measured in patients enrolled in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) at the acute time-point (median 4 days, N = 492, 36% female; mean age, 57 years) and at 3 months post-stroke (N = 469). Baseline stroke severity was classified according to the National Institutes of Health Stroke Scale (NIHSS), and functional outcomes (3 months and 2 years) were evaluated using the modified Rankin Scale (mRS), dichotomized into good (mRS 0-2), and poor (mRS 3-6) outcomes. Multivariable logistic regression analyses were adjusted for covariates. RESULTS: The baseline s-VEGF did not correlate with stroke severity but correlated moderately with hs-CRP (r = .17, P < .001). The baseline s-VEGF was 39.8% higher in total anterior cerebral infarctions than in lacunar cerebral infarctions. In binary logistic regression analysis, associations with 3-month functional outcome were non-significant. However, an association between the 3-month s-VEGF and poor 2-year outcome withstood adjustments for age, sex, cardiovascular covariates, and stroke severity (per 10-fold increase in s-VEGF, odds ratio [OR], 2.56, 95% confidence interval [CI] 1.12-5.82) or hs-CRP (OR 2.53, CI 1.15-5.55). CONCLUSIONS: High 3-month s-VEGF is independently associated with poor 2-year functional outcome but not with 3-month outcome.

Hypoxia but not shy-bold phenotype mediates thermal preferences in a threatened freshwater fish, Notropis percobromus.

For ectothermic animals, ambient temperature strongly influences developmental growth rate and individual fitness. While many ectotherms live in environments that are spatially hetero-thermal, the coupling between behavioural phenotypes (e.g., shy or bold behaviour) and thermal preferences remains uncertain. Relative to shy counterparts, bolder phenotypes may exert higher preference for ambient temperatures that are closer to their thermal optimum, thereby accelerating development. In addition, ectotherms should select colder temperatures in low oxygen conditions (hypoxia) according to the oxygen- and capacity-limited thermal tolerance (OCLTT) hypothesis. Using wild caught carmine shiner (Notropis percobromus), this study examined thermoregulatory behaviour in individuals exhibiting consistent behavioural phenotypes along the shy-bold continuum and between ecologically relevant normal oxygen concentration (normoxic) and hypoxic treatments. Furthermore, the behaviour observed in the laboratory was compared to environmental data from the natal stream. Results demonstrated that individual shy-bold behavioural phenotype was consistent before and after a simulated aerial predator attack, indicating consistency of behaviour across situations. Individual preferred and avoidance temperatures varied substantially, but were unrelated to shy-bold behavioural phenotypes. In contrast, individual preferred and maximum avoidance temperatures were significantly reduced in hypoxia, consistent with the OCLTT hypothesis. These findings might indicate suppressed development rates in hypoxia, not only by the limited oxygen for aerobic metabolism, but also by the preference for colder water in hypoxia. Furthermore, the tolerated thermal ranges were reduced in hypoxia. Using test conditions confirmed by field data, our study demonstrates the strong influence of oxygen availability on thermoregulatory behaviours and preferences in aquatic environments.

Effects of exercise on symptoms of anxiety, cognitive ability and sick leave in patients with anxiety disorders in primary care: study protocol for PHYSBI, a randomized controlled trial.

BACKGROUND: Anxiety disorders are common and associated with reduced quality of life, impaired physical and mental health and an increased economic burden for society. While evidence exists for the effectiveness of exercise treatment for depression, there is a need for high-quality randomized clinical trials (RCT) with a focus on anxiety disorders. Further research is also warranted regarding outcomes of cognitive function, other health-related variables, dose-response effects, work ability and potential mechanisms. METHOD/DESIGN: Using a parallel, RCT design with three assessment points (baseline, post-intervention and one-year follow-up), we aim to assess the effect of a 12-week exercise intervention in primary care patients with anxiety disorders (n = 180), diagnosed using the Mini International Neuropsychiatric Interview (M.I.N.I; Swedish version 6.0.0d DSM-IV). Participants are randomly assigned to three physical exercise groups: one low-intensity training group, one moderate- to high intensity training group and one control non-exercise group. Assessments include measures of anxiety symptoms, cognitive function, physical health variables such as cardiovascular fitness, sick-leave and levels of hormones/cytokines in blood samples. DISCUSSION: Findings from this study will provide novel insights regarding the effects of exercise treatment on not only anxiety symptoms but also other outcomes including mental and physical health, cognitive function, dose-response effects, work ability/sick leave and on biomarkers that may help explain underlying mechanisms. TRIAL REGISTRATION: The trial was registered at ClinicalTrial.gov NCT03247270 August 8, 2017.

Postoperative Thromboprophylaxis With New Oral Anticoagulants is Superior to LMWH in Hip Arthroplasty Surgery: Findings from the Swedish Registry.

BACKGROUND: Although the use of thromboprophylaxis is well established, there is no consensus on the preferred thromboprophylaxis regimen after THA; large, population-based studies offer an opportunity to examine this problem in a robust way that can complement results from randomized trials. QUESTIONS/PURPOSES: Using data from a large national registry, we asked: (1) Is there any difference between low-molecular weight heparin (LMWH) and new oral anticoagulants in preventing symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), after THA? (2) Are there any differences in safety parameters, such as bleeding, reoperations and mortality, between LMWH and new oral anticoagulants? METHODS: Between 2008 and 2012, 78,066 THAs were performed in Sweden. This study evaluated 32,663 (42%) of them, selected through the merger of several national registries. These patients underwent unilateral THA due to primary osteoarthritis. They had not experienced any venous thromboembolic events 5 years before the index operation and were not prescribed potent antithrombotic agents, of any type, in the 6 months before the index operation. Additionally, their postoperative thromboprophylaxis was confirmed in a national registry by purchase of prescribed medications. We divided the cohort into two groups: those patients who received new oral anticoagulants (5752, 18%) and those who received LMWH (26,881, 82%) as postoperative thromboprophylaxis. Our primary endpoints were the frequencies of symptomatic DVT and symptomatic PE within 3 months of surgery. Our secondary comparison was a between-group comparison of bleeding (by way of diagnostic coding), reoperation, and mortality within 3 months of surgery. Odds ratios (OR) are presented with 95% confidence intervals (CIs) as pooled results for the two groups after adjustment for duration of thromboprophylaxis (short or extended for at least 28 days), year of the index operation, Elixhauser comorbidity index, sex, age and previous treatment with platelet aggregation inhibitors. RESULTS: The risk of symptomatic DVT was lower in the group that received new oral anticoagulants than the group that received LMWH (0.3% versus 0.6%, OR, 0.47; 95% CI, 0.27-0.76; p = 0.026). The risk of symptomatic PE was lower in the group that received new oral anticoagulants than the group that received LMWH (0.1% versus 0.4%, OR, 0.36; 95% CI, 0.16-0.69; p = 0.005). There was no difference in the risk of bleeding (by way of diagnostic coding) (OR, 1.03; 95% CI, 0.82-1.28; p = 0.688), reoperation (OR, 1.02; 95% CI, 0.71-1.44; p = 0.860) or mortality (OR, 0.83; 95% CI, 0.31-1.88; p = 0.883) between groups. CONCLUSIONS: New oral anticoagulants were associated with a lower risk of symptomatic DVT and symptomatic PE in this large, registry study, and we observed no differences in the risk of bleeding, reoperation, or death between the groups. Although we were able to control for a number of potential confounding variables, we cannot ascertain the indications that drove the prescription decisions in this setting, and there were important between-group differences in terms of duration of thromboprophylaxis (new oral anticoagulants generally were used for a longer period of time after surgery). Future studies, preferably large randomized trials with pragmatic inclusion criteria, to analyze symptomatic DVT, symptomatic PE and death are needed to confirm or refute our findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Bifunctional Molecular Probes for Activity-Based Visualization of Quinone-Dependent Amine Oxidases.

The design, synthesis, and evaluation of two bifunctional molecular probes that can be used to visualize quinone-dependent amine oxidase enzymes in an activity-dependent manner are described. These probes use alkylhydrazines to irreversibly bind the target enzymes, which can then be visualized with either Western blotting or in-gel fluorescence. The results show that the Western blotting readout, which utilizes commercially available anti-nitrophenyl antibodies to detect a simple dinitrophenyl antigen, provides a stronger readout than the fluorescein-based fluorescence readout. This visualization strategy can be used to measure the potency of enzyme inhibitors by selectively visualizing the active enzyme that remains after treatment with an inhibitor. Looking forward, this probe molecule and visualization strategy will enable activity-based protein-profiling experiments, such as determining inhibitor selectivity values within full proteome mixtures, for this family of amine oxidase enzymes.

Use of dual-mobility cup in revision hip arthroplasty reduces the risk for further dislocation: analysis of seven hundred and ninety one first-time revisions performed due to dislocation, reported to the Swedish Hip Arthroplasty Register.

PURPOSE: Dislocation after total hip arthroplasty (THA) is a common reason for revision. The last decade fostered a significant increase in the use of dual-mobility cups (DMCs). Here we report our study on the short-term survival rate of a cemented DMC reported to the Swedish Hip Arthroplasty Register (SHAR) compared with other cemented designs used in first-time revision due to dislocation. METHODS: During 2005-2015, 984 first-time revisions for dislocation were reported to SHAR. In 436 of these cases a cemented dual articular cup was used. During the same time period, 355 revisions performed with a standard cemented cup (femoral head size 28-36 mm) were reported to the SHAR. Patients receiving a DMC were slightly older (75 years, p = 0.005). Re-revision for all reasons was used as primary endpoint. We also anlaysed risk for re-revision of the acetabular component and re-revision due to dislocation. Kaplan-Meier implant survival and a Cox regression analyses adjusted for age and gender were performed. RESULTS: Implant survival at 4 years for all reasons (91% ± 3.7% vs 86% ± 4.1%, p = 0.02), and especially for re-operation because of dislocation, favours the DMC group (96% ± 3.0% vs 92% ± 3.3%, p = 0.001). DISCUSSION: Our findings indicate that use of a cemented DMC reduces the short- to mid-term risk of a second revision in first-time revisions compared with classic cup designs. Longer follow-up is needed to establish any long-term clinical advantages when DMCs are used in revisions performed due to dislocation.

Stability of two angular stable locking plates for open wedge high tibial osteotomy (HTO): TomoFix™ versus LOQTEQ® HTO plate.

INTRODUCTION: The aim of this study was to test the mechanical stability of LOQTEQ® HTO plate in comparison to the TomoFix™ internal plate fixator. MATERIALS AND METHODS: An unstable fracture gap model with two standardized polyoxymethylene (POM) cylinders was used for this study. With this model 5 LOQTEQ® HTO plates and 5 TomoFix™ were cyclically loaded. The start load was 100 N and increased by 50 N after each successful completed cycle. Each load step included 250,000 cycles. All tests were performed in accordance with the American Society for Testing and Materials (ASTM) Standard Specification and Test Method for Metallic Bone Plates F382-99(2003)e1. RESULTS: The mean fatigue strength of the LOQTEQ® HTO Plate was 155 % of the value gained by the TomoFix™ implant. This difference was statistically significant (t test <0.001). There was also a significant difference in the cycles but both implants survived. The LOQTEQ® HTO Plate system survived 1,520,336.8 (±121,687.7) cycles, whereas the TomoFix™ group passed on average 847,802,600 (±134,660.7) cycles. In both groups, the only failure mode was plate breakage in a shaft hole. CONCLUSIONS: The results of the present study showed that fatigue strength of the LOQTEQ® HTO plate was significantly higher in comparison to TomoFix™. These results justify the clinical use of the LOQTEQ® HTO plate.

Tumor blood volume determination by using susceptibility-corrected DeltaR2* multiecho MR.

PURPOSE: To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. MATERIALS AND METHODS: All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. RESULTS: For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. CONCLUSION: Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.

In vivo optical imaging of cellular inflammatory response in granuloma formation using fluorescence-labeled macrophages.

UNLABELLED: Near-infrared imaging such as fluorescence reflectance imaging (FRI) and fluorescence-mediated tomography (FMT) yields high signal-to-noise ratios (SNRs) and should thus be well suited for cell-tracking studies. Extravasation of monocytes or macrophages (Ms) is one of the earliest events in inflammation. The purpose of this study was to assess whether FRI and FMT allow for the visualization and quantification of early inflammatory processes by tracing the migration of fluorescence-labeled murine Ms in a cutaneous granuloma model. METHODS: Ms were labeled with a membrane-selective carbocyanine dye (1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide [DiR]). Cellular viability and function (nitric oxide production, phagocytosis, adherence) were assessed in vitro. Local inflammation was induced in mice by the subcutaneous injection of polyacrylamide gel pellets including or excluding a strong inflammatory stimulus (lipopolysaccharide). Labeled Ms were injected intravenously, and FRI and FMT were performed up to 7 d. SNRs were calculated for the pellets, and the 3-dimensional distribution of Ms was assessed using FMT. Cells were harvested from gel pellets and analyzed by flow cytometry. RESULTS: DiR labeling did not affect cell viability or cell function. FRI revealed the migration of labeled Ms into gel pellets and the homing of Ms to different body compartments. The lipopolysaccharide-containing pellets exhibited significantly higher SNRs than did pellets without lipopolysaccharide. FMT showed that Ms distributed mainly in the periphery of the pellets. The cellular infiltrates extracted from the harvested pellets revealed the presence of approximately 10%-23% DiR-positive Ms-expressing typical markers, confirming the transendothelial migration of injected Ms. CONCLUSION: The tagging of Ms with DiR allows the noninvasive tracking of inflammatory cells for several days in vivo. FRI and FMT are versatile techniques to monitor and quantify cellular inflammatory responses in vivo.

Comparison of 1.0 M gadobutrol and 0.5 M gadopentetate dimeglumine-enhanced magnetic resonance imaging in five hundred seventy-two patients with known or suspected liver lesions: results of a multicenter, double-blind, interindividual, randomized clinical phase-III trial.

OBJECTIVE: To evaluate the diagnostic efficacy (accuracy, sensitivity, specificity) of 1.0 M gadobutrol versus 0.5 M gadopentetate for the classification of lesions as either benign or malignant in patients with known or suspected liver lesions. METHODS AND MATERIALS: A multicenter, phase-III, randomized, interindividually controlled comparison study with blinded reader evaluation was performed to investigate the diagnostic efficacy of a bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentetate at a dose of 0.1 mmol Gd/kg BW. The imaging protocol included a dynamic 3D-evaluation, static conventional, and fat saturated T1-weighted sequences. MR datasets were evaluated by 3 independent radiologists. The standard of reference was defined by an independent truth panel (radiologist or hepatologist). The safety evaluation included adverse events, vital signs, and physical examination. RESULTS: A total of 497 of 572 patients were eligible for the final efficacy analysis. Noninferiority of gadobutrol-enhanced magnetic resonance imaging (MRI) for the classification of liver lesions was demonstrated on the basis of diagnostic accuracy determined by the on-site investigators (-0.098, 0.021) as well as for the average reader of the blinded evaluation (-0.096, 0.014) (95% confidence interval), compared with the predefined standard of reference. Very similar increases in sensitivity (ranging from approximately 10% to approximately 55%) and specificity (ranging from approximately 1% to approximately 18%) compared with precontrast MRI were also observed for the 2 contrast agent groups, with maximum differences of 4%.Very similar, low rates of adverse events were recorded for each of the 2 groups. No clinically relevant changes in vital signs or the results of the physical examination were observed in any patient. CONCLUSION: This study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol (0.1 mmol/kg body weight) to 0.5 M gadopentetate (0.1 mmol/kg body weight) in the diagnostic assessment of liver lesions with contrast-enhanced MRI. The known excellent safety profile of gadobutrol was confirmed in this clinical trial and is similar to that of gadopentetate.

Differentiation of angiogenic burden in human cancer xenografts using a perfusion-type optical contrast agent (SIDAG).

INTRODUCTION: Use of fluorescence imaging in oncology is evolving rapidly, and nontargeted fluorochromes are currently being investigated for clinical application. Here, we investigated whether the degree of tumour angiogenesis can be assessed in vivo by planar and tomographic methods using the perfusion-type cyanine dye SIDAG (1,1'-bis- [4-sulfobutyl]indotricarbocyanine-5,5'-dicarboxylic acid diglucamide monosodium). METHOD: Mice were xenografted with moderately (MCF7, DU4475) or highly vascularized (HT1080, MDA-MB435) tumours and scanned up to 24 hours after intravenous SIDAG injection using fluorescence reflectance imaging. Contrast-to-noise ratio was calculated for all tumours, and fluorochrome accumulation was quantified using fluorescence-mediated tomography. The vascular volume fraction of the xenografts, serving as a surrogate marker for angiogenesis, was measured using magnetic resonance imaging, and blood vessel profile (BVP) density and vascular endothelial growth factor expression were determined. RESULTS: SIDAG accumulation correlated well with angiogenic burden, with maximum contrast to noise ratio for MDA-MB435 (P < 0.0001), followed by HT1080, MCF7 and DU4475 tumours. Fluorescence-mediated tomography revealed 4.6-fold higher fluorochrome concentrations in MDA-MB435 than in DU4475 tumours (229 +/- 90 nmol/l versus 49 +/- 22 nmol/l; P < 0.05). The vascular volume fraction was 4.5-fold (3.58 +/- 0.9% versus 0.8 +/- 0.53%; P < 0.01), blood vessel profile density 5-fold (399 +/- 36 BVPs/mm2 versus 78 +/- 16 BVPs/mm2) and vascular endothelial growth factor expression 4-fold higher for MDA-MB435 than for DU4475 tumours. CONCLUSION: Our data suggest that perfusion-type cyanine dyes allow assessment of angiogenesis in vivo using planar or tomographic imaging technology. They may thus facilitate characterization of solid tumours.

Prediction of antiangiogenic treatment efficacy by iron oxide enhanced parametric magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Tools for monitoring modern target-specific antiangiogenic and antivascular therapies are highly desirable because treatment strategies are time consuming, expensive, and yet sometimes ineffective. Therefore, the aim of this experimental study was to evaluate the predictive value of steady-state ultrasmall particles of iron oxide (USPIO; SH U 555 C)-enhanced magnetic resonance imaging (MRI) for early assessment of antivascular tumor-treatment effectiveness. METHODS: Mice were inoculated with an HT-1080 fibrosarcoma xenograft and subjected to target-specific antivascular therapy using a selective thrombogenic vascular-targeting agent (truncated tissue factor fused to RGD peptide) or saline as control. Four to 8 hours after treatment, the USPIO-induced change in the transverse relaxation rate DeltaR2* was measured by MRI, and the vascular volume fraction (VVF) was calculated by calibrating DeltaR2* of the tumor by DeltaR2* of muscle tissue. Treatment response was defined by histologic grading of vascular thrombosis and tumor necrosis. RESULTS: After thrombogenic treatment, half of the HT-1080 xenograft-bearing animals showed only minor (=nonresponder) whereas the other half showed extensive tumor thrombosis (=responders). For responders, a significant decrease of DeltaR2* and VVF was observed compared with the control group (DeltaR2*: controls: 16 +/- 1 s-1 vs. responder: 4 +/- 2 s-1; P < 0.001) whereas DeltaR2* and VVF remained nearly unchanged for nonresponders (DeltaR2*: nonresponder 14 +/- 2 s-1). VVF and DeltaR2* values correlated inversely with the histologic grading of vascular thrombosis and tumor necrosis (VVF: r = -0.8; DeltaR2*: r = -0.71; P < 0.01). CONCLUSION: USPIO-enhanced MRI allows a noninvasive, early assessment of treatment efficacy of thrombogenic vascular-targeting agents.