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The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice. The rate of repair declines with age; however, exposure to young circulations can rejuvenate fracture repair, but how this is accomplished is unknown. Here, the authors identify proteins, including low-density lipoprotein receptor-related protein 1 (Lrp1), as being secreted from young macrophages and rejuvenating fracture repair in mice.

Objective The aim of this study was to systematically review the literature to evaluate the clinical performance of integrated 18 F-FDG PET/MR as compared with 18 F-FDG PET/CT in oncologic imaging. Methods The literature was searched using MEDLINE and EMBASE via OVID. Studies comparing the diagnostic accuracy of integrated 18 F-FDG PET/MR and 18 F-FDG PET/CT in the diagnosis, staging/restaging, assessment of treatment response, or evaluation of metastasis in patients with suspected or diagnosed cancers were deemed eligible for inclusion. Risk of bias and applicability concerns were assessed using the QUADAS-2 tool. Results Twenty studies met the inclusion criteria. The overall quality of the studies was rated favorably with bias or applicability concerns in a few studies. Our review suggests that 18 F-FDG PET/MR performs comparably to 18 F-FDG PET/CT in the detection of local lymph node and distant metastases and superiorly in determining the local extent of tumor. SUV obtained from 18 F-FDG PET/MR correlated highly with those obtained from 18 F-FDG PET/CT. Conclusions Based on early evidence, 18 F-FDG PET/MR is comparable to 18 F-FDG PET/CT in the clinical scenarios examined in this review. The potential for interchangeability of 18 F-FDG PET/MR with 18 F-FDG PET/CT will vary by indication and the body site that is being imaged, with PET scanners integrated with MRI predicted to provide greater detail in the evaluation of local tumor extent, where 18 F-FDG PET/CT can be limited.

BACKGROUND: Air pollution is associated with respiratory symptoms, lung function decrements, and hospitalizations. However, there is little information about the influence of air pollution on lung injury. OBJECTIVE: In this study we investigated acute effects of air pollution on pulmonary function and airway oxidative stress and inflammation in asthmatic children. METHODS: We studied 182 children with asthma, 9-14 years of age, for 4 weeks. Daily ambient concentrations of sulfur dioxide, nitrogen dioxide, ozone, and particulate matter or = 2.5 microm in aerodynamic diameter (PM(2.5)) were monitored from two stations. Once a week we measured spirometry and fractional exhaled nitric oxide (FeNO), and determined thiobarbituric acid reactive substances (TBARS) and 8-isoprostane--two oxidative stress markers--and interleukin-6 (IL-6) in breath condensate. We tested associations using mixed-effects regression models, adjusting for confounding variables. RESULTS: Interquartile-range increases in 3-day average SO2 (5.4 ppb), NO2 (6.8 ppb), and PM(2.5) (5.4 microg/m3) were associated with decreases in forced expiratory flow between 25% and 75% of forced vital capacity, with changes being -3.1% [95% confidence interval (CI), -5.8 to -0.3], -2.8% (95% CI, -4.8 to -0.8), and -3.0% (95% CI, -4.7 to -1.2), respectively. SO2, NO2, and PM(2.5) were associated with increases in TBARS, with changes being 36.2% (95% CI, 15.7 to 57.2), 21.8% (95% CI, 8.2 to 36.0), and 24.8% (95% CI, 10.8 to 39.4), respectively. Risk estimates appear to be larger in children not taking corticosteroids than in children taking corticosteroids. O3 (5.3 ppb) was not associated with health end points. FeNO, 8-isoprostane, and IL-6 were not associated with air pollutants. CONCLUSION: Air pollution may increase airway oxidative stress and decrease small airway function of asthmatic children. Inhaled corticosteroids may reduce oxidative stress and improve airway function.

Background: Air pollution is associated with respiratory symptoms, lung function decrements, and hospitalizations. However, there is little information about the influence of air pollution on lung injury. Objective: In this study we investigated acute effects of air pollution on pulmonary function and airway oxidative stress and inflammation in asthmatic children. Methods: We studied 182 children with asthma, 9-14 years of age, for 4 weeks. Daily ambient concentrations of sulfur dioxide, nitrogen dioxide, ozone, and particulate matter ≤ 2.5 μm in aerodynamic diameter$({\\rm PM}_{2.5})$were monitored from two stations. Once a week we measured spirometry and fractional exhaled nitric oxide$({\\rm Fe}_{{\\rm NO}})$, and determined thiobarbituric acid reactive substances (TBARS) and 8-isoprostane-two oxidative stress markers-and interleukin-6 (IL-6) in breath condensate. We tested associations using mixed-effects regression models, adjusting for confounding variables. Results: Interquartile-range increases in 3-day average SO₂ (5.4 ppb), NO₂ (6.8 ppb), and${\\rm PM}_{2.5}$(5.4 μg/m³) were associated with decreases in forced expiratory flow between 25% and 75% of forced vital capacity, with changes being -3.1% [95% confidence interval (CI), -5.8 to -0.3], -2.8% (95% CI, -4.8 to -0.8), and -3.0% (95% CI, -4.7 to -1.2), respectively. SO₂, NO₂, and${\\rm PM}_{2.5}$were associated with increases in TBARS, with changes being 36.2% (95% CI, 15.7 to 57.2), 21.8% (95% CI, 8.2 to 36.0), and 24.8% (95% CI, 10.8 to 39.4), respectively. Risk estimates appear to be larger in children not taking corticosteroids than in children taking corticosteroids. O₃ (5.3 ppb) was not associated with health end points.${\\rm Fe}_{{\\rm NO}}$, 8-isoprostane, and IL-6 were not associated with air pollutants. Conclusion: Air pollution may increase airway oxidative stress and decrease small airway function of asthmatic children. Inhaled corticosteroids may reduce oxidative stress and improve airway function.

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors that lack the ability to metastasize. There are no directed therapies or standard treatment plan, and chemotherapeutics, radiation, and surgery often have temporary effects. The majority of desmoid tumors are related to T41A and S45F mutations of the beta-catenin encoding gene ( CTNNB1 ). Using broad spectrum metabolomics, differences were investigated between paired normal fibroblast and desmoid tumor cells from affected patients. There were differences identified, also, in the metabolomics profiles associated with the two beta-catenin mutations, T41A and S45F. Ongoing drug screening has identified currently available compounds which inhibited desmoid tumor cellular growth by more than 50% but did not affect normal fibroblast proliferation. Two drugs were investigated in this study, and Dasatinib and FAK Inhibitor 14 treatments resulted in unique metabolomics profiles for the normal fibroblast and desmoid tumor cells, in addition to the T41A and S45F. The biochemical pathways that differentiated the cell lines were aminoacyl-tRNA biosynthesis in mitochondria and cytoplasm and signal transduction amino acid-dependent mTORC1 activation. This study provides preliminary understanding of the metabolic differences of paired normal and desmoid tumors cells, their response to desmoid tumor therapeutics, and new pathways to target for therapy.

Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The beta-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of beta-catenin signaling in bone repair. Western blot analysis showed significant up-regulation of beta-catenin during the bone healing process. Using a beta-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that beta-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/beta-catenin pathway) inhibited beta-catenin signaling and the healing process, suggesting that WNT ligands regulate beta-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized beta-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific beta-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of beta-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated beta-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. These results demonstrate that beta-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of beta-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, beta-catenin positively regulates osteoblasts. This is a different function for beta-catenin than has previously been reported during development. Activation of beta-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.

Significance Current genomic and biochemical analysis revealed mutations in isocitrate dehydrogenase ( IDH ) genes associated with several neoplasms and a novel enzymatic activity of IDH mutations to catalyze α-ketoglutarate to d -2-hydroxyglutarate, contributing to tumorigenesis. We identified a broad range of IDH1 mutations, including a previously unidentified IDH1 -R132Q mutation, in cartilage tumors. Cartilage-specific Col2a1-Cre/ERT2;Idh1-R132 mutant knock-in mice developed multiple enchondroma-like lesions. These data show that mutant Idh in growth-plate cells causes persistence of chondrocytes, giving rise to enchondromas adjacent to the growth cartilage in bone. Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes ( IDH1 and IDH2 ) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1 -R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d -2-hydroxyglutarate ( d -2HG). Mice expressing Idh1 -R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1 -R132Q or 2HG treatment. Col2a1-Cre; Idh1 -R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d -2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

Background Knowledge of the inhalable particulate matter components responsible for health effects is important for developing targeted regulation. Objectives In a double-blind randomised cross-over trial of controlled human exposures to concentrated ambient particles (CAPs) and their endotoxin and (1→3)-β-D-glucan components, we evaluated acute inflammatory responses. Methods 35 healthy adults were exposed to five 130-min exposures at rest: (1) fine CAPs (∼250 µg/m3); (2) coarse CAPs (∼200 µg/m3); (3) second coarse CAPs (∼200 µg/m3); (4) filtered air; and (5) medical air. Induced sputum cell counts were measured at screening and 24 h postexposure. Venous blood total leucocytes, neutrophils, interleukin-6 and high-sensitivity C reactive protein (CRP) were measured pre-exposure, 3 and 24 h postexposure. Results Relative to filtered air, an increase in blood leucocytes 24 h (but not 3 h) postexposure was significantly associated with coarse (estimate=0.44×109 cells/L (95% CI 0.01 to 0.88); n=132) and fine CAPs (0.68×109 cells /L (95% CI 0.19 to 1.17); n=132), but not medical air. Similar associations were found with neutrophil responses. An interquartile increase in endotoxin (5.4 ng/m3) was significantly associated with increased blood leucocytes 3 h postexposure (0.27×109 cells/L (95% CI 0.03 to 0.51); n=98) and 24 h postexposure (0.37×109 cells/L (95% CI 0.12 to 0.63); n=98). This endotoxin effect did not differ by particle size. There were no associations with glucan concentrations or interleukin-6, CRP or sputum responses. Conclusions In healthy adults, controlled coarse and fine ambient particle exposures independently induced acute systemic inflammatory responses. Endotoxin contributes to the inflammatory role of particle air pollution.

The role of fludeoxyglucose F 18 positron emission tomography (PET) in the presurgical evaluation of patients with medically intractable epilepsy continues to be refined. The purpose of this study was to systematically review the literature to assess the diagnostic accuracy and utility of PET in this setting. Thirty-nine studies were identified through MEDLINE and EMBASE databases that met the inclusion criteria. In adult patients, PET hypometabolism showed a 56 to 90% agreement with seizure onset localized by intracranial electroencephalogram (pediatric: 21 to 86%). In temporal lobe epilepsy patients with good surgical outcome, PET displayed moderate to high sensitivity in localizing the seizure focus (range: 71 to 89%). The sensitivity increased by 8 to 23% when PET results were combined with magnetic resonance imaging or electroencephalogram. PET has been shown to affect patient management by improving the guidance of intracranial electrodes placement, altering the decision to perform surgery, or excluding patients from further evaluation. Utilité de la tomographie par émission de positons dans l’épilepsie. Le rôle de la tomographie par émission de positons (PET scan) au 18F fluodésoxyglucose (18F-FDG) dans l’évaluation préchirurgicale de patients présentant une épilepsie réfractaire au traitement médical est constamment raffiné. Le but de cette étude était de revoir systématiquement la littérature afin d’évaluer la précision du diagnostic et l’utilité du PET scan dans ce contexte. Nous avons identifié 39 études dans les bases de données MEDLINE et EMBASE qui rencontraient nos critères d’inclusion. Chez les patients adultes, un hypométabolisme au PET scan concordait entre 56 et 90% avec le début de la crise localisé par l’électroencéphalographie intracrânienne (patients pédiatriques: entre 21 et 86%). Chez les patients atteints d’épilepsie temporale chez qui le résultat chirurgical avait été favorable, le PET scan avait une sensibilité de modérée à élevée pour localiser le foyer épileptogène (écart : 71 à 89%). La sensibilité augmentait de 8 à 23% quand les résultats du PET scan étaient combinés à l’imagerie par résonance magnétique ou à l’électroencéphalographie. Il est démontré que le PET scan influence le traitement du patient en améliorant le guidage lors de la mise en place des électrodes intracrâniennes, en modifiant la décision de procéder à une chirurgie ou en évitant de procéder à des examens plus poussés chez certains patients.

Objective: To investigate the associations between exposure to particulate air pollution and changes in cardiovascular function and plasma mediators in seniors. Methods: We monitored daily indoor and outdoor black carbon and particulate matter ≥2.5 µm (PM2.5) and personal PM2.5 repeatedly for 28 nonsmoking seniors. We then measured their blood pressure, heart rate, and brachial artery function, and determined plasma mediators of inflammation, vascular function, and oxidative stress. We tested associations using mixed-effects models. Results: Increases in black carbon and PM2.5 were associated with increases in blood pressure, heart rate, endothelin-1, vascular endothelial growth factor, and oxidative stress marker thiobarbituric acid reactive substances, and a decrease in brachial artery diameter (P < 0.05). Conclusion: Daily exposure to particulate pollution, likely traffic-related, may result in adverse effects on cardiovascular function and blood mediators that modulate vascular system in seniors.