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PURPOSE: To assess the feasibility of a newly developed algorithm, called deep learning synthetic strain (DLSS), to infer myocardial velocity from cine steady-state free precession (SSFP) images and detect wall motion abnormalities in patients with ischemic heart disease. MATERIALS AND METHODS: In this retrospective study, DLSS was developed by using a data set of 223 cardiac MRI examinations including cine SSFP images and four-dimensional flow velocity data (November 2017 to May 2021). To establish normal ranges, segmental strain was measured in 40 individuals (mean age, 41 years ± 17 [SD]; 30 men) without cardiac disease. Then, DLSS performance in the detection of wall motion abnormalities was assessed in a separate group of patients with coronary artery disease, and these findings were compared with consensus results of four independent cardiothoracic radiologists (ground truth). Algorithm performance was evaluated by using receiver operating characteristic curve analysis. RESULTS: Median peak segmental radial strain in individuals with normal cardiac MRI findings was 38% (IQR: 30%-48%). Among patients with ischemic heart disease (846 segments in 53 patients; mean age, 61 years ± 12; 41 men), the Cohen κ among four cardiothoracic readers for detecting wall motion abnormalities was 0.60-0.78. DLSS achieved an area under the receiver operating characteristic curve of 0.90. Using a fixed 30% threshold for abnormal peak radial strain, the algorithm achieved a sensitivity, specificity, and accuracy of 86%, 85%, and 86%, respectively. CONCLUSION: The deep learning algorithm had comparable performance with subspecialty radiologists in inferring myocardial velocity from cine SSFP images and identifying myocardial wall motion abnormalities at rest in patients with ischemic heart disease.Keywords: Neural Networks, Cardiac, MR Imaging, Ischemia/Infarction Supplemental material is available for this article. © RSNA, 2023.

BACKGROUND Computed tomography (CT) has an established role in detecting perforation of implanted pacemaker and defibrillator leads. The clinical significance of incidental finding of delayed lead perforation remains unclear. The aim of this study was to assess the prevalence of lead perforation as detected by CT in a cohort of patients undergoing transvenous laser lead extraction and characterize the association between finding of incidental lead perforation with periprocedural outcomes. METHODS Consecutive patients that underwent chest CT and lead extraction were retrospectively assessed for presence of lead perforation. A total of 143 patients and 348 leads were assessed. The finding of lead perforation was correlated with findings from peri-procedural transesophageal echocardiography (TEE) and outcomes of the lead extraction procedure. RESULTS Lead perforations (including perforations

This article studies the influence of product lifetime labelling on purchase decisions. Based on consumer theory of Lancaster, experimental survey data are collected from a population representative sample of 499 German consumers, using choice-based conjoint analysis. Hierarchical Bayes utility modelling suggests a substantial positive effect of product lifetime labelling on purchase decisions. However, the effect is not linear but decreasing with higher levels of product lifetime. The relative importance of the product lifetime label is found to be higher than that of the product's energy consumption or brand. Additionally, we show that the introduction of product lifetime labelling renders the positive influence of existing brands on purchase decisions less impactful. Therefore, strategic implications for companies differ substantially, depending on companies' current brand-building. Besides implications for business strategy, the study informs marketers and policymakers about the potential of product lifetime labelling to stimulate the supply of, and demand for, more durable products.

Quantitative imaging measurements can be facilitated by artificial intelligence (AI) algorithms, but how they might impact decision-making and be perceived by radiologists remains uncertain. After creation of a dedicated inspiratory-expiratory CT examination and concurrent deployment of a quantitative AI algorithm for assessing air trapping, five cardiothoracic radiologists retrospectively evaluated severity of air trapping on 17 examination studies. Air trapping severity of each lobe was evaluated in three stages: qualitatively (visually); semiquantitatively, allowing manual region-of-interest measurements; and quantitatively, using results from an AI algorithm. Readers were surveyed on each case for their perceptions of the AI algorithm. The algorithm improved interreader agreement (intraclass correlation coefficients: visual, 0.28; semiquantitative, 0.40; quantitative, 0.84; P < .001) and improved correlation with pulmonary function testing (forced expiratory volume in 1 second–to–forced vital capacity ratio) (visual r = −0.26, semiquantitative r = −0.32, quantitative r = −0.44). Readers perceived moderate agreement with the AI algorithm (Likert scale average, 3.7 of 5), a mild impact on their final assessment (average, 2.6), and a neutral perception of overall utility (average, 3.5). Though the AI algorithm objectively improved interreader consistency and correlation with pulmonary function testing, individual readers did not immediately perceive this benefit, revealing a potential barrier to clinical adoption. Keywords: Technology Assessment, Quantification © RSNA, 2021

Purpose To assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation. Materials and methods We obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score. Results Pneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19. Conclusions Radiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms.

Objectives The aim of this study was to assess if pre-procedural computed tomography (CT) could identify high-risk operative features and predict increased procedural complexity. Background Unpredictable lead adhesions can make lead extraction complicated. Adhesions are known to affect leads with longer indwelling time but can unpredictably affect newer leads. Methods Consecutive patients who had CTs performed ≤90 days before their planned lead extraction (LE) were included. CTs were reviewed blinded to outcome according to a preset checklist. The outcome was a combined endpoint of procedural complexity and major complications. Results Between January 1, 2015 and July 1, 2018, 143 patients underwent CT and LE. Median age was 68 years (interquartile range [IQR]: 54.4 to 76.5), and 35% were female. Median age of extracted leads was 111 months, and 126 (43%) were >10 years. CT detected lead perforation ≥5 mm (n = 13), 1 cm (n = 102), lead fracture (n = 8), and severe ipsilateral venous stenosis/occlusion (n = 36). The procedure was complex in 63 cases. There were 2 deaths, and 6 major complications. Patients with severe lead adhesions had more complex procedures (n = 36 vs 29; p = 0.04), whereas none of the other findings on CT were significantly associated with worse outcome. In patients with leads that had an indwelling time Conclusions Pre-procedural CT can be used to locate severe lead adhesions in patients planned for lead extraction. In patients with indwelling leads

Increasing consumers’ willingness to pay (WTP) for environmentally friendly products is a key challenge for sustainable development in market economies. Still, how consumers react to favorable and unfavorable environmental information of different quantitative extents is largely unknown. This research therefore uses prospect theory and competing theoretical foundations to derive pertinent hypotheses and test them by using a multi-level structural equation model. The analysis draws on a survey-based experiment conducted among a representative sample of the German population. Results confirm key assertions of prospect theory. The negative effect caused by unfavorable product carbon footprint information on WTP is stronger than the positive effect caused by respective favorable information. Besides this negativity bias, consumers tend to generally reward or punish deviations of a product's environmental performance from industry average instead of consistently accounting for the size of these deviations. From a sustainable development perspective, the observed patterns highlight a problematic contrast between the need for substantial environmental improvements and limited market incentives for companies. Consequently, political intervention is needed to introduce negative labeling, raise consumers’ reference points, set minimum industry standards, and subsidize companies for radical improvements.

MRI is an essential diagnostic tool in the anatomic and functional evaluation of cardiovascular disease. In many practices, 2D phase-contrast (2D-PC) MRI has been used for blood flow quantification. Four-dimensional flow MRI is a time-resolved volumetric acquisition that captures the vector field of blood flow along with anatomic images. It also provides a simpler acquisition compared with 2D-PC and facilitates a more accurate and comprehensive hemodynamic assessment. Advancements in accelerated imaging have significantly shortened scanning times for 4D flow MRI while preserving image quality, enabling this technology to transition from the research arena to routine clinical practice. In this article, we review technical optimization based on our more than 10 years of clinical experience with 4D flow MRI. We also present pearls and pitfalls in the practical application of 4D flow MRI, including how to quantify cardiovascular shunts, valvular or vascular stenosis, and valvular regurgitation. As experience increases, and as 4D flow sequences and postprocessing software become more broadly available, 4D flow MRI will likely become an essential component of cardiac imaging in practices involved in the management of congenital and acquired structural heart disease.

Immune-mediated lung diseases are a complex group of diseases characterized by inflammatory cellular infiltration of the lungs which can result in progressive airway remodeling and parenchymal injury. Diseases have variable presentation depending on antigen exposure, patient predisposition, and type of immune response. Early recognition, removal of the inciting antigen, and steroid intervention are important to prevent disease progression. This article will review key clinical, radiologic, and pathologic features of immune-mediated lung diseases.

BACKGROUND: Mucous exudates occluding the lumen of small airways are associated with reduced lung function and mortality in subjects with COPD; however, luminal plugs in large airways have not been widely studied. We aimed to examine the associations of chest CT scan-identified luminal plugging with lung function, health-related quality of life, and COPD phenotypes. METHODS: We randomly selected 100 smokers without COPD and 400 smokers with COPD from the COPDGene Study. Luminal plugging was visually identified on inspiratory CT scans at baseline and 5-year follow-up. The relationships of luminal plugging to FEV(1), St. George’s Respiratory Questionnaire (SGRQ) score, emphysema on CT scan (defined as the percentage of low attenuation area < 950 Hounsfield units [%LAA-950]), and chronic bronchitis were assessed using linear and logistic multivariable analyses. RESULTS: Overall, 111 subjects (22%) had luminal plugging. The prevalence of luminal plugging was higher in subjects with COPD than those without COPD (25% vs 10%, respectively; P = .001). In subjects with COPD, luminal plugging was significantly associated with FEV(1) % predicted (estimate, −6.1; SE, 2.1; P = .004) and SGRQ score (estimate, 4.9; SE, 2.4; P = .04) in adjusted models. Although luminal plugging was associated with log %LAA-950 (estimate, 0.43; SE, 0.16; P = .007), its relationship with chronic bronchitis did not reach statistical significance (P = .07). Seventy-three percent of subjects with COPD with luminal plugging at baseline had it 5 years later. CONCLUSIONS: In subjects with COPD, CT-identified luminal plugging is associated with airflow obstruction, worse health-related quality of life, and emphysema phenotype. This imaging feature may supplement the current clinical assessment of chronic mucus hypersecretion in COPD.

Patients hospitalized in the intensive care unit (ICU) often have multiple support lines and devices that need routine imaging evaluation by radiologists. In patients with cardiogenic shock or depressed cardiac function, mechanical circulation support devices are used in combination with medical therapies to improve patient outcomes and sometimes can stabilize patients for surgical intervention. This article discusses some of the more commonly encountered mechanical circulation devices seen in ICU patients, including intra-aortic balloon pumps, Impella devices, extracorporeal membrane oxygenation cannulas, and ventricular assist devices. Normal appearance and commonly encountered device-related complications that can be diagnosed on imaging are reviewed.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Background: Mucus dysfunction, a key pathophysiologic feature of chronic obstructive pulmonary disease (COPD), is characterized by increased mucus production and plug formation in the airways leading to airflow obstruction. Computed tomography (CT) has been recently used to identify mucus plugs, providing an alternative way to assess mucus dysfunction. We aimed to test whether mucus plugging on CT is associated with mortality in smokers. Methods: We identified and scored mucus plugging in the intra-parenchymal airways on CT scans from 500 smokers with and without COPD from the COPDGene Study. We used a score based on the number of bronchopulmonary segments with mucus plugs. The score ranges from 0 to 18, with higher values indicating greater burden of mucus plugging on CT. We used Cox regression multivariable models to test the association between mortality and mucus plugging. Results: Ninety-eight subjects (20%) had mucus plugging on CT, with a median score of 2 (range, 1-13). During a follow-up of 7.5 years, 140 (28%) subjects died. After adjusting for age, gender, race, body mass index, current smoking status, pack-years, CT measures of emphysema, and COPD status, a higher mucus plugging score was associated with increased risk of all-cause mortality (per 1-point increase, Hazard Ratio 1.18, 95% Confidence Interval 1.07-1.30) (Figure 1). Conclusion: CT-identified mucus plugging has a prognostic value in smokers. Mucus plugging might be a distinct imaging phenotype.

Background: Thyroid nodules are prevalent worldwide. Detection rates are increasing because of the use of ultrasonography. Ultrasound has become the first-choice imaging modality in evaluating nodules. The decision to perform an US-guided fine-needle aspiration (FNA) is based on a nodule’s sonographic features. Thus, it is essential to accurately risk stratify thyroid nodules so that they are appropriately referred for FNA. Objectives: The aim of this study was to correlate the ultrasound imaging features of thyroid nodules with FNA cytology and surgical histopathology results, and to risk stratify patients using the American Thyroid Association (ATA) classification for each imaging characteristic with the likelihood of the nodule being malignant. Method: Retrospective analysis of a thyroid ultrasound database at Chris Hani Baragwanath Academic Hospital, over the period 2015–2017. Frequencies and percentages were used to summarise the data. Univariate logistic regression analyses were used to assess the accuracy of sonographic features in predicting the histologically determined diagnosis for thyroid tumours. Results: A total of 113 nodules underwent FNA, of which 104 were diagnostic. The best three ultrasound features that pose a higher risk for malignancy are absent halo, presence of microcalcifications and hypoechoic appearance. No single nodule feature is an absolute indicator for malignancy. There is a high agreement between ATA classification and cytopathology or histology when nodule features are grouped into clusters. Agreement between the ATA classification and cytopathology/histology was 86.7% with a kappa of 0.714. The agreement between the cytopathology FNA results and lobectomy histopathology was 98.8% with a kappa of 0.973. Conclusion: This study contributes to the paucity of data available for sub-Saharan Africa and provides reassurance that our results are consistent with international studies. The study confirms that the usage of a thyroid nodule classification system improves characterisation and increases accuracy in detecting thyroid malignancies, thus sparing many patients the morbidity of unnecessary thyroid surgery.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Rationale Glyoxal (GO) and Methylglyoxal (MGO) are two dicarbonyls involved in the formation of advanced glycation end products (AGEs). Endothelial cells in the vessels are in constant contact with circulating AGEs and dicarbonyls. With this project, we aimed to elucidate the effect of GO and MGO on primary human vascular endothelial cells (HVECs). Methods Graft material from patients with coronary heart disease was used as HVECs source. HVECs were treated with different concentrations of GO and MGO. β-Galactosidase related senescence activity and cell morphology were analyzed. AGEs as well as p21 protein expression, glyoxalase-I expression and oxidative stress were detected. Results We here provide evidences that GO and MGO induce senescence in primary HVECs. Mechanistically GO and MGO induce senescence by increasing the ROS production, the expression of p21, the accumulation of AGEs and the arrest of HVECs in the G2 cell cycle phase. Aminoguanidine - a dicarbonyl scavenger - abrogated the effect of GO and MGO. Conclusion Our data are relevant as they suggest that in diseases with elevated dicarbonyl concentrations, deleterious effects on the endothelium and the development of vascular dysfunction have to be expected. On the other hand, treatment of patients with dicarbonyl scavenger could prevent this.

Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is related closely to risk factors for coronary artery disease, but it is unclear whether NAFLD independently contributes to atherosclerosis. We investigated the association between NAFLD and coronary artery calcium (CAC) scores, determined based on noncontrast cardiac computed tomography data, in an elderly cohort.MethodsWe conducted a longitudinal, cross-sectional study of data from 250 participants (mean age, 67.6 ± 7.0 y; 43.2% men) in the Rancho Bernardo Study-a prospective population-based study of mostly white adults in suburban Southern California. We compared CAC scores, liver-to-spleen attenuation ratio, and volumes of visceral adipose tissue (VAT) at baseline and after a 5-year follow-up period.ResultsWe assigned participants to groups based on CAC scores (0, 0-10, 11-100, 101-400, and >400). Among groups, the liver-to-spleen attenuation ratio did not vary significantly, but VAT increased with CAC score (median and interquartile range values were as follows: 50.0 [33.3-77.4] cm(3), 63.0 [33.9-93.1] cm(3), 66.1 [48.2-80.2] cm(3), 69.1 [48.1-85.0] cm(3), 76.1 [53.1-108.5] cm(3) for CAC groups; P= .0054). In multivariable regression analysis, NAFLD at baseline was not associated with an increased risk of a CAC score greater than 0. Longitudinal analysis showed that visceral fat, but not hepatic steatosis, increased in participants with increasing CAC scores (interquartile range 57.1-92.4) vs 55.2 cm(3) in patients without (interquartile range 36.5-81.1, P= .0401). The proportion of patients with NAFLD decreased after the 5-year follow-up period (from 29.3% before to 14.1% afterward; P= .0081), despite increased mean CAC scores and VAT volume in patients.ConclusionsIn adults age 67.6 ± 7.0 years, the proportion with NAFLD decreased despite increasing CAC score and VAT with age. There was no clear association between NAFLD and CAC score. However, VAT was associated with baseline and increasing CAC scores. Visceral adiposity therefore might be a risk factor for coronary artery disease.

The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE=glycation) interfere with the BBB integrity and function. Here, we present data that carbonyl stress induced by methylglyoxal leads to glycation of endothelial cells and the basement membrane, which interferes with the barrier-function and with the expression of RAGE, occludin and ZO-1. Furthermore, methylglyoxal induced carbonyl stress promotes the expression of the pro-inflammatory interleukins IL-6 and IL-8. In summary, this study provides new insights into the relationship between AGE formation by carbonyl stress and brain microvascular endothelial barrier dysfunction.

Aim: During ageing, advanced glycation end products (AGEs) accumulate in extracellular matrix proteins like collagen and contribute to a decline in organ function. As skin autofluorescence (sAF) can assess subcutaneous accumulation of fluorescent AGEs, this study aimed to investigate the relationship between AGE-modified cardiac tissue collagen and AGE related sAF in coronary artery bypass surgery patients.

The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T1-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D3 by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T1-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity. Copyright © 2011 John Wiley & Sons, Ltd.

We demonstrated increased (18)F-FDG uptake in injured peripheral nerves in a model of neuropathic pain using small-animal PET/MRI.A neuropathic pain model in rats was created by spared-nerve injury of the left sciatic nerve. Sham-operated rats without nerve injury were used as a control. The presence of pain was confirmed by testing for allodynia. Sequential small-animal (18)F-FDG PET and MRI scans of the thighs were obtained and coregistered. Autoradiography was performed on harvested nerves and muscle.The group with spared-nerve injury showed the development of allodynia in the operated limb (P0.001). Increased (18)F-FDG uptake was observed on both PET/MRI (P0.001) and autoradiography (P0.005) in the operated nerve in this group. (18)F-FDG uptake in the nerves correlated well with allodynia (ρ = -0.59; P0.024).Animals with neuropathic pain show increased (18)F-FDG uptake in the affected nerve. Small-animal PET/MRI can be effectively used to localize (18)F-FDG uptake in peripheral nerves.

In addition to the well-described role of platelets in thrombosis, a growing body of evidence implicates platelets in diverse inflammatory responses. We recently showed platelets can contribute to the pathophysiology of inflammatory arthritis via IL-1– containing microparticles. In this study, we demonstrate that platelets, and not platelet microparticles, actively contribute to synovitis via production of proinflammatory prostacyclin in an autoimmune arthritis model. Using both genetic and pharmacologic approaches, we establish that paracrine production of prostacyclin proceeds in the absence of cyclooxygenase-2. Furthermore, we also demonstrate that prostacyclin generation can arise via transcellular collaboration between platelets and fibroblast-like synoviocytes. In addition to shedding light on an unappreciated pathway of lipid synthesis in arthritis, we further delineate a novel effector activity by which platelets can contribute to inflammatory disease.

Aim During ageing, advanced glycation end-products (AGEs) accumulate in extracellular matrix proteins like collagen and contribute to a decline in organ function. As skin autofluorescence (sAF) can assess subcutaneous accumulation of fluorescent AGEs, this study aimed to investigate the relationship between AGE-modified cardiac tissue collagen and AGE-related sAF in coronary artery bypass graft (CABG) surgery patients. Methods Between January 2011 and January 2012, data from 72 consecutive male patients undergoing isolated CABG were prospectively recorded. Collagen fractions were isolated from the right atrial appendages of these patients by proteolysis and collagenase digestion. Collagen was quantified by hydroxyproline assay, and AGEs by AGE-related intrinsic fluorescence; sAF was measured using an autofluorescence reader. Results Biochemical analysis showed that the insoluble cardiac collagen fraction contained the highest amounts of accumulated AGEs; the AGE-related intrinsic fluorescence of this fraction increased with age ( P =0.0001), blood glucose ( P =0.002), HbA 1c ( P =0.01) and sAF ( P =0.008). Conclusion This study demonstrated for the first time a relationship between cardiac tissue glycation and AGE-related sAF. In addition, cardiac tissue glycation was associated with age, blood glucose and long-term glucose values in patients with coronary artery disease.

Advanced glycation endproducts (AGEs) represent a non-enzymatic posttranslational protein modification. AGEs are generated by a series of chemical reactions of free reducing monosaccharides, such as glucose, fructose or metabolites of the monosaccharide metabolism with amino groups of proteins. After oxidation, dehydration and condensation, stable AGE-modifications are formed. AGE-modified proteins accumulate in all cells and tissues as a normal feature of ageing and correlate with the glucose concentration in the blood. AGEs are increased in diabetic patients and play a significant role in the pathogenesis of most age-related neural disorders, such as Alzheimer's disease. We examined the role of AGEs on neurite outgrowth of PC12 cells. We induced the formation of AGEs using the reactive carbonyl compound methylglyoxal (MGO) as a physiological metabolite of glucose. We found that AGE-modification of laminin or collagen interfered with adhesion but not with neurite outgrowth of PC12 cells. Furthermore, the AGE-modification of PC12 cell proteins reduced NGF-induced neurite outgrowth. In conclusion, our data show that AGEs negatively influence neural plasticity.

Background: Advanced glycation end products (AGEs) seem to be involved in ageing as well as in the development of cardiovascular diseases. During ageing, the AGEs accumulate in matrix proteins like collagen and fibronectin inducing tissue stiffness. The Bypass operation is the most common intervention in patients suffering from coronary heart disease. However as the majority of the patients are older than 60, the graft material (vein or artery) of these patients is probably enriched on AGE-modifications. To which extent these modifications may affect the quality and functionality of bypass graft material and the heart function after operation is unknown. We analyzed the AGE-modifications in the collagen from the right atrium and residual bypass graft material (saphenous vein and internal thoracic artery) to elucidate in which extension the collagen of graft material is AGE-modified. Methods: Collagen type I and III (soluble fraction) were isolated from veins, arteries and the right atrium by proteolysis with pepsin. The residual insoluble fraction was extracted by digestion with collagenase type I and proteinase K. Collagen was quantified by 4-hydroxyproline assay and AGEs by the AGE intrinsic fluorescence (360nm excitation and 440nm emission). Results: The AGE fluorescence in patient material (vein, atrium) increased with patients age (p=0.0025). Decreasing amounts of extracted insoluble collagen correlate with increased AGE fluorescence (p=0.0001). Comparing vein, artery and atrium of the same patients we isolated equal levels of soluble and insoluble collagen in arteries and atriums, whereas only in veins increased amounts of soluble collagen were extracted in comparison to the insoluble fraction (p

Objective To report our experience with minocycline-induced autoimmunity (MIA) in children, with an emphasis on the potential for chronicity. Study design Retrospective cohort study of patients with development of rheumatologic symptoms while receiving minocycline between 1996 and 2006. Results Twenty-seven children were diagnosed with MIA at a single pediatric rheumatology practice. The mean age at onset was 16.5 ± 1.39 years. The mean duration of minocycline use before diagnosis was 13.0 ± 10.8 months. All patients presented with constitutional symptoms. Twenty-two had polyarthralgia, and 17 had polyarthritis, mostly affecting hands and feet. On the basis of disease duration after discontinuation of minocycline, we divided subjects into 3 categories: transient, intermediate, and chronic. Seven patients had development of chronic autoimmune disease that was still active at last follow-up, a mean of 31.6 ± 13.0 (13-48) months after onset. Six patients followed an intermediate course, with resolution of symptoms within 12 months, and 14 patients had symptoms that resolved rapidly on discontinuation of minocycline. All patients with a chronic course had evidence of arthritis at presentation. Conclusion A substantial proportion of children with MIA had development of chronic symptoms with the potential for significant morbidity. Physicians who prescribe minocycline should be aware of its propensity for inducing potentially serious autoimmune phenomena.

Advanced glycation end products (AGEs) seem to be involved in ageing as well as in the development of cardiovascular diseases. Accumulation of AGEs contribute to tissue stiffness and organ dysfunction by crosslinking extracellular matrix proteins like collagen. We aimed to assess whether AGE-modified cardiac tissue collagen and AGE related skin autofluorescence may reflect the cardiac function and have a prognostic value for the outcome of coronary artery bypass surgery patients. Therefore, AGE-modifications in collagen from 72 male patients undergoing isolated coronary artery bypass graft (CABG) surgery were analyzed. Collagen fractions were isolated from the right atrial auricle and the residual bypass graft material (saphenous vein) of these patients and quantified by 4-hydroxyproline assay. AGE modifications were determined by the AGE intrinsic fluorescence (excitation 360nm/emission 440nm). The skin autofluorescence (sAF) as a non-invasive parameter was measured using the AGE reader. The non-extractable collagen contained the highest amounts of AGEs and positively correlates with the patients age (p=0.0001), blood glucose level (p=0.002), HbA1c level (p=0.01) and sAF (p=0.008). The right atrial auricle collagen showed significantly more modifications compared to vein graft material of the same patient (p=0,001). Skin autofluorescence positively correlates with AGE content in cardiac tissue (p=0.01) and therefore could be used as a predictor of tissue stiffness in patients with coronary heart disease.