Whole-body System Research Articles

Full field-of-view, high-resolution, photon-counting detector CT: technical assessment and initial patient experience

We report a comprehensive evaluation of a full field-of-view (FOV) photon-counting detector (PCD) computed tomography (CT) system using phantoms, and qualitatively assess image quality in patient examples. A whole-body PCD-CT system with 50 cm FOV, 5.76 cm z-detector coverage and two acquisition modes (standard: 144 × 0.4 mm collimation and ultra-high resolution (UHR): 120 × 0.2 mm collimation) was used in this study. Phantoms were scanned to assess image uniformity, CT number accuracy, noise power spectrum, spatial resolution, material decomposition and virtual monoenergetic imaging (VMI) performance. Four patients were scanned on the PCD-CT system with matched or lower radiation dose than their prior clinical CT scans performed using energy-integrating detector (EID) CT, and the potential clinical impact of PCD-CT was qualitatively evaluated. Phantom results showed water CT numbers within ±5 HU, and image uniformity measured between peripheral and central regions-of-interests to be within ±5 HU. For the UHR mode using a dedicated sharp kernel, the cut-off spatial frequency was 40 line-pairs cm−1, which corresponds to a 125 μm limiting in-plane spatial resolution. The full-width-at-half-maximum for the section sensitivity profile was 0.33 mm for the smallest slice thickness (0.2 mm) using the UHR mode. Material decomposition in a multi-energy CT phantom showed accurate material classification, with a root-mean-squared-error of 0.3 mg cc−1 for iodine concentrations (2–15 mg cc−1) and 14.2 mg cc−1 for hydroxyapatite concentrations (200 and 400 mg cc−1). The average percent error for CT numbers corresponding to the iodine concentrations in VMI (40–70 keV) was 2.75%. Patient PCD-CT images demonstrated better delineation of anatomy for chest and temporal bone exams performed with the UHR mode, which allowed the use of very sharp kernels not possible with EID-CT. VMI and virtual non-contrast images generated from a patient head CT angiography exam using the standard acquisition mode demonstrated the multi-energy capability of the PCD-CT system.

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture

Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK. Two species contribute simultaneously to the drug PK: drugs that dissociate from DcNP (Part 1) and drugs retained in DcNP (Part 2, presented separately). Here, we describe the PBPK modeling of the nanoparticle-free drugs. The free-drug model was built on subcutaneous injections of suspended lopinavir, ritonavir, and tenofovir in NHP, and validated by external experiments. A novelty was the design of a lymphatic network as part of a whole-body PBPK system which included major lymphatic regions: the cervical, axillary, hilar, mesenteric, and inguinal nodes. This detailed/regionalized description of the lymphatic system and mononuclear cells represents an unprecedented level of prediction that renders the free-drug model extendible to other small-drug molecules targeting the lymphatic system at both the regional and cellular levels.

Systems analysis of the mechanisms governing the cardiovascular response to changes in posture and in peripheral demand during exercise

Blood flows and pressures throughout the human cardiovascular system are regulated in response to various dynamic perturbations, such as changes to peripheral demands in exercise, rapid changes in posture, or loss of blood from hemorrhage, via the coordinated action of the heart, the vasculature, and autonomic reflexes. To assess how the systemic and pulmonary arterial and venous circulation, the heart, and the baroreflex work together to effect the whole-body responses to these perturbations, we integrated an anatomically-based large-vessel arterial tree model with the TriSeg heart model, models capturing nonlinear characteristics of the large and small veins, and baroreflex-mediated regulation of vascular tone and cardiac chronotropy and inotropy. The model was identified by matching data from the Valsalva maneuver (VM), exercise, and head-up tilt (HUT). Thirty-one parameters were optimized using a custom parameter-fitting tool chain, resulting in an unique, high-fidelity whole-body human cardiovascular systems model. Because the model captures the effects of exercise and posture changes, it can be used to simulate numerous clinical assessments, such as HUT, the VM, and cardiopulmonary exercise stress testing. The model can also be applied as a framework for representing and simulating individual patients and pathologies. Moreover, it can serve as a framework for integrating multi-scale organ-level models, such as for the heart or the kidneys, into a whole-body model. Here, the model is used to analyze the relative importance of chronotropic, inotropic, and peripheral vascular contributions to the whole-body cardiovascular response to exercise. It is predicted that in normal physiological conditions chronotropy and inotropy make roughly equal contributions to increasing cardiac output and cardiac power output during exercise. Under upright exercise conditions, the nonlinear pressure-volume relationship of the large veins and sympathetic-mediated venous vasoconstriction are both required to maintain preload to achieve physiological exercise levels. The developed modeling framework is built using the open Modelica modeling language and is freely distributed.

Increased Monocyte-Derived CD11b+ Macrophage Subpopulations Following Cigarette Smoke Exposure Are Associated With Impaired Bleomycin-Induced Tissue Remodelling.

RationaleThe accumulation of macrophages in the airways and the pulmonary interstitium is a hallmark of cigarette smoke-associated inflammation. Notably, pulmonary macrophages are not a homogenous population but consist of several subpopulations. To date, the manner in which cigarette smoke exposure affects the relative composition and functional capacity of macrophage subpopulations has not been elucidated.MethodsUsing a whole-body cigarette smoke exposure system, we investigated the impact of cigarette smoke on macrophage subpopulations in C57BL/6 mice using flow cytometry-based approaches. Moreover, we used bromodeoxyuridine labelling plus Il1a-/- and Il1r1-/- mice to assess the relative contribution of local proliferation and monocyte recruitment to macrophage accumulation. To assess the functional consequences of altered macrophage subpopulations, we used a model of concurrent bleomycin-induced lung injury and cigarette smoke exposure to examine tissue remodelling processes.Main ResultsCigarette smoke exposure altered the composition of pulmonary macrophages increasing CD11b+ subpopulations including monocyte-derived alveolar macrophages (Mo-AM) as well as interstitial macrophages (IM)1, -2 and -3. The increase in CD11b+ subpopulations was observed at multiple cigarette smoke exposure timepoints. Bromodeoxyuridine labelling and studies in Il1a-/- mice demonstrated that increased Mo-AM and IM3 turnover in the lungs of cigarette smoke-exposed mice was IL-1α dependent. Compositional changes in macrophage subpopulations were associated with impaired induction of fibrogenesis including decreased α-smooth muscle actin positive cells following intratracheal bleomycin treatment. Mechanistically, in vivo and ex vivo assays demonstrated predominant macrophage M1 polarisation and reduced matrix metallopeptidase 9 activity in cigarette smoke-exposed mice.ConclusionCigarette smoke exposure modified the composition of pulmonary macrophage by expanding CD11b+ subpopulations. These compositional changes were associated with attenuated fibrogenesis, as well as predominant M1 polarisation and decreased fibrotic activity. Overall, these data suggest that cigarette smoke exposure altered the composition of pulmonary macrophage subpopulations contributing to impaired tissue remodelling.

Inhalation of Tungsten Metal Particulates Alters the Lung and Bone Microenvironments Following Acute Exposure.

Inhalation of tungsten particulates is a relevant route of exposure in occupational and military settings. Exposure to tungsten alloys is associated with increased incidence of lung pathologies, including interstitial lung disease and cancer. We have demonstrated, oral exposure to soluble tungsten enhances breast cancer metastasis to the lungs through changes in the surrounding microenvironment. However, more research is required to investigate if changes in the lung microenvironment, following tungsten particulate exposure, can drive tumorigenesis or metastasis to the lung niche. This study examined if inhalation to environmentally relevant concentrations of tungsten particulates caused acute damage to the microenvironment in the lungs and/or systemically using a whole-body inhalation system. Twenty-four female BALB/c mice were exposed to Filtered Air, 0.60 mg/m3, or 1.7 mg/m3 tungsten particulates (<1 µm) for 4 h. Tissue samples were collected at days 1 and 7 post-exposure. Tungsten accumulation in the lungs persisted up to 7 days post-exposure and produced acute changes to the lung microenvironment including increased macrophage and neutrophil infiltration, increased levels of proinflammatory cytokines interleukin 1 beta and C-X-C motif chemokine ligand 1, and an increased percentage of activated fibroblasts (alpha-smooth muscle actin+). Exposure to tungsten also resulted in systemic effects on the bone, including tungsten deposition and transient increases in gene expression of proinflammatory cytokines. Taken together, acute whole-body inhalation of tungsten particulates, at levels commonly observed in occupational and military settings, resulted in changes to the lung and bone microenvironments that may promote tumorigenesis or metastasis and be important molecular drivers of other tungsten-associated lung pathologies such as interstitial lung disease.

Dynamic tracking and identification of tissue-specific secretory proteins in the circulation of live mice

Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell and tissue types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validate iSLET in a whole-body system, we express iSLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liver iSLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together, iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.

Assessment on the lung injury of mice posed by airborne PM2.5 collected from developing area in China and associated molecular mechanisms by integrated analysis of mRNA-seq and miRNA-seq

Some epidemiological evidences showed exposure of airborne fine particulate matter (PM2.5) was associated with lung dysfunction. However, the adverse effects of PM2.5 from mid-scale city of China on the respiratory system were unknown. Correspondingly, the mechanisms, especially the epigenetic mechanism regulated by miRNAs, involved in PM2.5-induced lung injury has not been fully understood. In this study, male Balb/C mice were exposed to PM2.5 collected from mid-scale city (Baoji), China for 8 weeks (mean concentration 298.52 ± 25.86 μg/m3 at exposure chamber) using a whole-body exposure system. The carbon component was the main ingredient (45.80%) of PM2.5 followed by ions (43.19%). Meanwhile, the sum concentrations of polycyclic aromatic hydrocarbons (PAHs) and n-alkanes (C18-C33) were 570.48 and 2029.13 ng/m3 in the exposure chamber, respectively. Obvious lung injury including pulmonary inflammation and fibrosis (p < 0.05 compared with the control) were found from PM2.5 exposure group determined by micro-CT and histopathological assays, respectively, suggesting the health risk posed by PM2.5 from mid-scale city of China should be concerned. The integrated analysis between mRNA-seq and miRNA-seq revealed the differentially expression genes in lung tissues were enriched in immune pathways including B cell receptor signaling (p = 0.078) and cell adhesion molecules (CAMs) (p = 0.0068). The expression profiles of the genes and corresponding mRNAs involved into the immune pathways determined by RT-qPCR analysis were consistent with them conducted by transcriptome. Moreover, the expression levels of the proteins (i.e., CD19, CD81, PIK3CD, and CD22) involved into B cell receptor signaling pathway from exposure group were 1.71- to 6.948- folds compared with the control, validating the results of the genes expression profiles. Further, canonical correlation analysis (CCA) and multiple correlation analysis between the target genes and components of PM2.5 documented the organic compounds (i.e., Benzo(a)pyrene (p = 0.012) and octadecane (p = 0.05)) and inorganic elements (i.e., Cl-, Ti, Al, and Zn) was the key environmental factors. Cd19, Pik3cd, and Cd8b1 might be the key genes for lung dysfunction induced by PM2.5 illuminated using interactive analysis (p < 0.05). This work for the first time showed the adverse effects of PM2.5 in mid-scale city in China on respiratory system should be concerned, and the associated epigenetic mechanism regulated by miRNA were revealed. These results may provide new insight into the development of future assessment on the air pollution associated respiratory disease.

7 Tesla Chlorine (35Cl) and Sodium (23Na) MR Imaging of an Enchondroma.

We demonstrated the feasibility of 7 Tesla sodium (23Na) and chlorine (35Cl) MRI of a solitary enchondroma. For this, we established dedicated sequences on a 7-Tesla whole-body system with the following key parameters for 35Cl MRI: TE/TR = 0.35/60 ms, TRO = 5 ms, α = 90°, Δx3 = (6 mm)3, 3averages, Tacq = 30 min and for 23Na MRI: TE/TR = 0.4/101 ms, TRO = 10ms; α = 90°; Δx3 = (1.9 mm)3, 3 averages, Tacq = 30 min 18 s. The measured apparent Na+ concentration was 255 mmol/l and was approximately 7-fold higher than the apparent Cl- concentration with about 36 mmol/l. Additionally, repeated proton MRI examinations demonstrated constant but subtle growth (≈0.65 ml/year) over 14 years. In conclusion, enchondromas obviously have a high contrast-to-noise ratio when compared with the normal bone marrow in 23Na and 35Cl MRI, which may contribute to detection and differentiation in unclear or subtle cases. KEY POINTS:: · High magnetic field strengths (e. g., 7 Tesla) enable sodium (23Na) and chlorine (35Cl) MRI of solitary cartilage-forming tumors like enchondromas with nominal spatial resolutions of (1.9 mm)3 (23Na MRI) and (6 mm)3 (35Cl MRI).. · Measured median tumoral apparent Na+ and Cl- concentrations were nearly 13 times higher and 3 times higher than in normal muscle tissue, respectively.. · Enchondromas have a high contrast-to-noise-ratio when compared with the normal bone marrow in 23Na and 35Cl MRI, which may contribute to detection and differentiation in unclear or subtle cases.. CITATION FORMAT: · Weber M, Seyler L, Nagel AM. 7 Tesla Chlorine (35Cl) and Sodium (23Na) MR Imaging of an Enchondroma. Fortschr Röntgenstr 2021; 193: 1207 - 1211.

1.5 vs 3 Tesla Magnetic Resonance Imaging: A Review of Favorite Clinical Applications for Both Field Strengths-Part 1.

Whole-body magnetic resonance imaging (MRI) systems with a field strength of 3 T have been offered by all leading manufacturers for approximately 2 decades and are increasingly used in clinical diagnostics despite higher costs. Technologically, MRI systems operating at 3 T have reached a high standard in recent years, as well as the 1.5-T devices that have been in use for a longer time. For modern MRI systems with 3 T, more complexity is required, especially for the magnet and the radiofrequency (RF) system (with multichannel transmission). Many clinical applications benefit greatly from the higher field strength due to the higher signal yield (eg, imaging of the brain or extremities), but there are also applications where the disadvantages of 3 T might outweigh the advantages (eg, lung imaging or examinations in the presence of implants). This review describes some technical features of modern 1.5-T and 3-T whole-body MRI systems, and reports on the experience of using both types of devices in different clinical settings, with all sections written by specialist radiologists in the respective fields.This first part of the review includes an overview of the general physicotechnical aspects of both field strengths and elaborates the special conditions of diffusion imaging. Many relevant aspects in the application areas of musculoskeletal imaging, abdominal imaging, and prostate diagnostics are discussed.

Long-term clinical outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy using the CyberKnife® robotic radiosurgery system for vestibular schwannoma.

The study aimed to evaluate the long-term clinical outcomes of patients with vestibular schwannoma (VS) treated with stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HSRT) with frameless robotic whole-body radiosurgery system (CyberKnife® ). This retrospective analysis of prospectively collected data included 123 consecutive patients with VS treated at the Radiosurgery center, Ramathibodi Hospital, Bangkok, Thailand. SRS was recommended for patients with unserviceable hearing and Koos grade I-III tumors, and HSRT for patients with serviceable hearing or Koos grade III-IV tumors. Between March 2009 and December 2015, 23 patients (19%) were treated with SRS, whereas 100 (81%) received HSRT. The commonly used regimen was 12Gy in one fraction for SRS and 18Gy in three fractions for HSRT. After a median follow-up of 72 months (range: 12-123 months), the 5-year and 8-year progression-free survival (PFS) rates for the whole cohort were 96% and 92%, respectively. The PFS was not significantly different between the SRS and HSRT groups (p=0.23). Among 28 patients with serviceable hearing in the HSRT group, the 5-year and 8-year hearing preservation rates were 87% and 65%, respectively. The rate of nonauditory complications was 14%. Koos grade III/IV was a predictor of disease progression and was associated with nonauditory complications. SRS and HSRT with the CyberKnife® system provided excellent long-term tumor control with a low rate of nonauditory complications. HSRT may result in acceptable hearing preservation rates.

Ambient fine particulate matter exposure disrupts circadian rhythm and oscillation of the HPA axis in a mouse model

Emerging evidence supports that exposure to ambient fine particulate matter (PM2.5) is associated with the metabolic syndrome. As the main neuroendocrine axis in mammals, the hypothalamic-pituitary-adrenal (HPA) axis's circadian rhythm (CR) plays an essential role in regulating metabolic homeostasis. Our previous studies found that ambient PM2.5 exposure caused CR disorder of the critical enzymes involved in lipid metabolism in mouse liver and adipose tissues. However, the impact of ambient PM2.5 exposure on the HPA axis is not fully illustrated yet. Male C57BL/6 mice were randomly exposed to ambient PM2.5 or filtered air for ten weeks via a whole-body exposure system. Rhythmic oscillations of clock genes in the hypothalamus and adrenal gland were characterized. The effects of ambient PM2.5 exposure on clock gene expression and rhythmic expression of molecules related to glucocorticoid synthesis were also examined. Firstly, a more robust CR of clock genes was demonstrated in the adrenal gland than that in the hypothalamus. Secondly, PM2.5 exposure significantly inhibited the expression of Clock at ZT8 in the hypothalamus. However, both circadian oscillation and expression levels of Bmal1, Cry1, Cry2, and Rorα were increased significantly by ambient PM2.5 exposure in the adrenal gland. Moreover, abnormal rhythmic oscillation patterns of corticotropin-releasing hormone and adrenocorticotropic hormone were observed after ambient PM2.5 exposure, with no change at the expression levels. Finally, the expression of Cyp11b1 was markedly decreased at ZT0 in the adrenal gland of PM2.5 exposed mice. Our findings provide new insights into the ambient PM2.5 exposure-induced metabolic syndrome from the perspective of CR disturbances.

The effect of electronic cigarettes exposure on learning and memory functions: behavioral and molecular analysis

Objective: Electronic cigarettes (ECIGs) are battery-powered devices that emit vaporized solutions for the user to inhale. ECIGs are marketed as a less harmful alternative to combustible cigarettes. The current study examined the effects of ECIG aerosol exposure on learning and memory, expression of brain derived neurotrophic factor (BDNF), and the activity of antioxidant enzymes in the hippocampus. Methods: Male Wistar rats were exposed to ECIG aerosol, by a whole-body exposure system, 1 h/day for 1 week, 4 weeks, and 12 weeks. Spatial learning and memory were tested using the Radial Arm Water Maze (RAWM). Hippocampal BDNF protein level, and oxidative stress biomarkers (GPx, SOD, GSH, GSSG, GSH/GSSG ratio) were also assessed. Results: ECIG aerosol exposure for 4 and 12 weeks impaired both short- and long- term memory and induced reductions in the hippocampus BDNF, SOD and GPx activities, and GSH/GSSG ratio (p < 0.05). No changes in any examined biomarkers were observed after 1-week exposure to ECIG aerosol (p > 0.05). Conclusions: ECIG aerosol exposure impaired functional memory and elicited changes in brain chemistry that are consistent with reduced function and oxidative stress.

Dance Motion Capture Based on Data Fusion Algorithm and Wearable Sensor Network

In this paper, through an in-depth study and analysis of dance motion capture algorithms in wearable sensor networks, the extended Kalman filter algorithm and the quaternion method are selected after analysing a variety of commonly used data fusion algorithms and pose solving algorithms. In this paper, a sensor-body coordinate system calibration algorithm based on hand-eye calibration is proposed, which only requires three calibration poses to complete the calibration of the whole-body sensor-body coordinate system. In this paper, joint parameter estimation algorithm based on human joint constraints and limb length estimation algorithm based on closed joint chains are proposed, respectively. The algorithm is an iterative optimization algorithm that divides each iteration into an expectation step and a great likelihood step, and the best convergence value can be found efficiently according to each iteration step. The feature values of each pose action are fed into the algorithm for model learning, which enables the training of the model. The trained model is then tested by combining the collected gesture data with the algorithmic model to recognize and classify the gesture data, observe its recognition accuracy, and continuously optimize the model to achieve accurate recognition of human gesture actions.

Metabolic Dynamics in the Prefrontal Cortex during a Working Memory Task in Young Adult Smokers

Introduction: Cigarette smoking is known to modulate brain metabolism and brain function. How the dynamics of these metabolic alterations influence the active performance of higher order cognitive tasks in smokers, compared to non-smokers, is still unclear. The present exploratory study sought to examine the impact of smoking on the “complete” metabolic profile while the participants performed a working memory (N-back) task. Methods: The study sample consisted of 40 young male healthy participants (smokers [n = 20] and non-smokers [n = 20]). Functional magnetic resonance spectroscopy data were acquired using a 3 T whole-body MR system. Data analysis was performed using Java-based Magnetic Resonance User Interface software, and metabolite ratios with respect to creatine (Cr) were calculated. Results: On a behavioural level, smokers showed worse performance (measured by d’) than non-smokers. However, we observed significant differences in the metabolite concentrations in smokers compared to non-smokers, which also changed over the course of the N-back task. A significant effect of the group was observed with smokers showing lower glutamate/Cr (Glx/Cr) and choline/Cr (Cho/Cr) ratios than non-smokers. Further, N-acetyl aspartate (NAA/Cr) and Cho/Cr ratios were significantly different during the rest and the task conditions. In addition, our results demonstrated the metabolite interactions (NAA and Cho, Glx and myo-inositol [mI], and Cho and mI). Conclusion: Further studies are necessary to shed more light on the association between smoking behaviours and metabolic alterations. However, our preliminary findings would assist in this future research to have a complete understanding of the metabolite interactions not only in smoking but also in addiction research.

Performance comparison of a dedicated total breast PET system with a clinical whole-body PET system: a simulation study

This paper presents a novel PET geometry for breast cancer imaging. The scanner consists of a ‘stadium’ (a rectangle with two semi-circles on opposite sides) shaped ring, along with anterior and posterior panels to provide high sensitivity and high spatial resolution for an imaging field-of-view (FOV) that include both breasts, mediastinum and axilla. We simulated this total-breast PET system using GATE and reconstructed the coincidence events using a GPU-based list-mode image reconstruction implementing maximum likelihood expectation-maximization (ML-EM) algorithm. The rear-panel is made up of a single layer of LSO crystals (3.2 × 3.2 × 20 mm3 each), while the ‘stadium’-shaped elongated ring and the anterior panel are made with dual-layered LSO crystals (1.6 × 1.6 × 6 mm3 each). The energy resolution and coincidence resolving time of all detectors are assumed to be 12% and 250 ps full-width-at-half-maximum, respectively. Various sized simulated lesions (4, 5, 6 mm) having 4:1, 5:1, and 6:1 lesion-to-background radioactivity concentration ratios, mimicking different biological uptakes, were strategically located throughout a volumetric torso phantom. We compared system sensitivity and lesion detectability of the dedicated total-breast PET system to a state-of-the-art clinical whole-body PET scanner. The mean sensitivity of the total-breast PET system is 3.21 times greater than that of a whole-body PET scanner in the breast regions. The total-breast PET system also provides better contrast-recovery coefficients for lesions of all sizes and lesion-to-background ratios in the breast when compared to a reference clinical whole-body PET scanner. Receiver operating characteristics (ROC) study shows the area under the ROC curve is 0.948 and 0.924 for the total-breast system and the whole-body PET scanner, respectively, in the detection of 4 mm diameter lesions with 4:1 lesion-to-background ratio. This study demonstrates our novel geometry can provide an imaging FOV larger than conventional PEM systems to simultaneously image both breasts, chest wall and axillae with significantly improved lesion detectability in the breasts when compared to a whole-body PET scanner.

Dysregulation of breathing control through distinct molecular mechanisms of the brainstem cell population in neonatal sepsis

Introduction Neonatal sepsis is triggered by a dysregulated immune response leading to systemic inflammation and life-threatening organ dysfunction. The systemic alterations and activation of immune cells will impact the activity of neural circuits, neural and non-neuronal cell populations, including those in the brainstem involved in breathing rhythm generation and pattern. Elucidating the extent to which inflammation modulates the CNS control of breathing has eluded us due to the lack of appropriate physiological maneuvers capable of interrogating specific brainstem circuits in the neonatal period. We perform novel respiratory testing in newborn pups with unrestrained plethysmography using distinct TLR ligands to test the hypothesis that distinct forms of systemic inflammation modulate brainstem circuits in different ways. Our goal was to investigate how different systemic inflammatory insults at the neonatal period affect the brainstem by determining the contribution of neurons, astrocytes, and microglia in the breathing plasticity response. Methods CD1 mice were I.P. treated at postnatal day 5 (PD5) with LPS, or Pam3CSK4(PAM), or saline (control). Using a whole-body plethysmography system, we assessed brainstem arousal reflex. Briefly, unrestrained pups were placed inside of the chamber individually, and submitted to a room air (RA) exposure for 06 min, followed by 01 min of a gas mixture of 97%N2/3%CO2 (anoxia) repeated 05 times. Ultrasonic vocalization recordings, a measure of brainstem-spinal circuit prolonged-forced expiration, were obtained with the Avisoft SASLab Pro software. Bulk brainstem and gene expression analysis of isolated neurons, astrocytes, and microglia were performed with Clariom™ S Assay mouse and Affymetrix GeneChip Mouse Gene ST 2.0 arrays. Differential gene expression was analyzed using a cutoff of 2-fold change and P-value of 0.01 and t-test in comparison to the control. Results Respiratory frequency during the baseline phase was 176 BPM in the control group, while was founded lower in the LPS and PAM group. Tidal volume (TVb) and minute ventilation (MVb) were also diminished in both groups compared to the control. The gasp latency, or time to recover after each anoxic episode, was prolonged impairing the autoresuscitation, especially, in the PAM treated group. Vocalization function was also affected by inflammation presence resulting in a reduced number of calls per min. A robust gene modulation in the brainstem bulk of PD5 pups was caused in both inflammatory insults. The enrichment analysis showed activation of T helper cells whereas CIBERSORT analysis indicated enrichment of Treg and B cells memory. The molecular pathways activated in neurons, astrocytes, and microglia were founded distinct and specific to the TLR ligand while astrocytes exhibited a lack of responsiveness caused by PAM. Conclusions We conclude that TRLs ligands activate specific neural mechanisms that will detrimentally affect ventilatory response and the ability to autoresuscitate via a central mechanism in the course of neonatal sepsis.

Chronic air pollution exposure exaggerates obesity-induced tissue inflammation and insulin resistance by activating inflammasome

Abstract Background: Air pollution has been associated with cardiometabolic diseases such as obesity and insulin resistance. However, the underlying mechanisms were not fully understood. In this study, we examined the role of NLRP3 inflammasome in chronic air pollution-induced tissue inflammation and insulin resistance. Methods: 8 weeks old male WT and NLRP3−/− mice were exposed to filtered air (FA) or concentrated ambient particles (CAPS) in a small animal whole-body exposure system with or without high fat diet for 6 hours/day, 5 days/week, for a total of 12 weeks (n= 5–8 per group). Results: CAPS exposure enhanced insulin resistance in the WT mice but not in the NLRP3−/− mice. Cytokine array and ELISA assays indicated that IL-1β secretion was increased in the culture supernatant of macrophages isolated from CAPS-exposed WT mice, compared to that of FA-exposed mice. Electronic microscopy showed particulate deposites in the peritoneal macrophages isolated from the peritoneal cavity of CAPS-exposed animals. The gene expression of Nlrp3 and Il-1β, the rate-limiting factor of NLRP3 inflammasome activation, were also increased in CAPS-exposed WT mice. Deficiency of NLRP3 blocked CAPS exposure-induced lung inflammation, inflammatory gene expression, and IL-1β secretion in mice. Subsequent ex vivo experiments by culturing macrophages with particulate matters indicate that air pollution particles not only initiate the transcription of Nlrp3 and Il-1β, the first signal for inflammasome activation, but also induce the activation of caspase-1, the second signal for inflammasome activation. Conclusions: Our data suggest that NLRP3 inflammasome activation mediates air pollution-induced tissue inflammation and insulin resistance.

Effect of E‐liquid Base Solution (Vegetable Glycerin or Propylene Glycol) on Aortic Function in Mice

The effects of vaping with electronic cigarettes (e-cigs) on cardiovascular health are still under investigation. An important question that still remains unknown is the role of individual constituents within the e-liquid used for vaping. In this study, we examine the sole effect of either vegetable glycerin (VG) or propylene glycol (PG), without the presence of any flavors or nicotine, on aortic reactivity. Healthy C57BL/6J mice were exposed to e-cig vapor for 4 weeks (5d/wk, 1-hour/day, 60 puffs/day) to e-cig aerosol from either 100% VG or 100% PG e-liquid using a whole-body chamber exposure system (SCIREQ InExpose). Control mice were exposed to ambient air. E-cig aerosol was produced by a Joyetech eGRIP OLED device at 17.5 watts, with 5-second puff duration. Mice were sacrificed >24 hours after their final exposure, and thoracic aortas were excised, cleaned of perivascular adipose tissue, and were cut into 2mm ring segments. Aortic rings were mounted on wire myograph system (DMT, AD Instruments) containing warm aerated Krebs-Henseleit buffer solution. The vessels were pre-constricted with 50 µL of U46619 [7.5e-9 M], and then exposed to a serial dilution of methacholine [MCh 10-9 to 10-5 M] to assess endothelial-dependent (EDD) vasodilation, and separately to serial dilutions of sodium nitroprusside [SNP 10-9 to 10-5 M] to assess endothelium-independent (EID) vasodilation. In PG-exposed mice, max aortic EDD was reduced by 18±2% (P<0.05) compared to controls, and reduced by 14±2% (P<0.05) compared to VG-exposed mice. VG-exposed mice were not significantly different compared to controls. Maximal aortic EID was slightly impaired in PG- mice compared to control (8±2% P<0.05) and VG (5±1% P<0.05) groups. In summary, chronic exposure to e-cig aerosol from PG in the base solution resulted in aortic EDD and EID dysfunction, however VG-exposed mice were not affected. These data suggest that both endothelial-dependent and -independent mechanisms are adversely affected by PG, and therefore vaping with PG in the base solution alone poses a significant risk for adverse cardiovascular health effects.

Dynamic flux balance analysis of whole-body metabolism for type 1 diabetes.

Type 1 diabetes (T1D) mellitus is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that induce organ-wide, long-term metabolic effects. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify therapeutic interventions but is limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model of organ-specific regulation and metabolism that highlighted chronic inflammation as a hallmark of the disease, identified processes related to neurodegenerative disorders and suggested calcium channel blockers as adjuvants for diabetes control. In addition, whole-body modeling of a patient population allowed for the assessment of between-individual variability to insulin and suggested that peripheral glucose levels are degenerate biomarkers of the internal metabolic state. Taken together, the organ-resolved, dynamic modeling approach enables modeling and simulation of metabolic disease at greater levels of coverage and precision and the generation of hypothesis from a molecular level up to the population level.

Socioeconomic factors and outcome in knee osteoarthritis: a scoping literature review

Purpose: Given the increasing prevalence and burden of knee osteoarthritis world-wide, the research community is challenged to identify factors that predict its onset and progression with the ultimate aim to mechanistically understand disease and develop targeted interventions. Traditionally, risk factors for knee osteoarthritis are considered ‘local’ to the joint or ‘systemic’ referring to whole-body systems. However, there are clear indications in the scientific literature that contextual factors such as socioeconomic position merit consideration.