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Duffy, Mitchell J. ; Duffy, Mitchell James: Development of translational optical imaging strategies to assess inflammatory biomarkers in rheumatoid arthritis. 2018
Inhalt
Content
Abstract
Introduction
Rheumatoid Arthritis
Causes of Rheumatoid Arthritis
List of Figures
Inflammation
Cartilage and Bone Destruction
Diagnosis
Laboratory Values
Management
Role of Imaging in Arthritis
Imaging Modalities
Optical Imaging
Fluorescence Reflectance Imaging
Biomarkers for imaging of inflammation in RA
S100A9
Structure and Function
Role of S100A8/A9 in RA
Initiation and Leukocyte Invasion
Cartilage and Bone Destruction
Imaging Strategies for S100 alarmins
Matrix Metalloproteinases
Structure and Function
Role of MMPs in RA
Inflammation, Invasion and Synovitis
Remodelling and Degradation
Imaging strategies for MMP activity
Animal Models of Rheumatoid Arthritis
Aim
List of Tables
Materials and Methods
Materials
Fluorescent labels
Chemicals
Acknowledgements
Consumables
Antibodies
Primary Antibodies
Secondary Antibodies
Equipment
Software
Methods
Mice
Collagen-induced arthritis (CIA)
FRI Imaging
Imaging Analysis
Immunohistochemistry
H&E staining
Immunofluorescence Staining
Mac-3 / MRP14 Double Staining Immunofluorescence
Statistical Analysis
Experimental Setup
Onset group
Resolution group
Results
Curriculum Vitae
Onset phase
Imaging results show individual inflammation of paws in CIA
Two subtypes of disease progression identified
Both fast and slow responders show statistically elevated S100A8/A9 and MMP levels on the day of peak inflammation
S100A8/A9 and MMP SBRs correlate and are elevated in paws with high clinical scores
Resolution phase
Imaging results show inflammation resolution and low SBRs at late time point regardless of paw clenching
Imaging of the resolution of a highly inflamed state shows decreasing levels of inflammatory biomarkers.
Histology
Morphological findings
Analysis Methods
Immunohistochemistry corroborates target presence beginning at clinical score 2
Late stage disease shows little S100A8/A9 and MMP expression despite high clinical scores
Single joint inflammation case study
Why employ the signal to background ratio?
Thresholded SBR Inflammatory Area Analysis Method
Thresholded SBR Inflammatory Fraction Analysis Method
Receiver Operating Characteristic for optimal threshold determination
Discussion
Multiplexing small molecule probes provided novel insight into concurrent expression of MMPs and S100A8/A9
No time shift between the expression of S100A8/A9 and MMPs was found
Histology corroborated S100A9 and MMP-9 imaging data
Division of onset phase CIA mice into fast and slow responding groups
The clinical score reflects externally observable markers of inflammation
Choice of analysis method and use of signal to background ratio
Blood concentration of tracer is lower in CIA mice
Thresholded SBR Area and Fraction analyses considered
ROC curves indicate limited applicability of thresholding methods
FRI in the clinic
Photoacoustic imaging of Naphthalocyanine labelled ligands presents a 3D diagnostic opportunity
Conclusions and Outlook
References
Appendix
A Abbreviations