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The objective of this study was to evaluate the pathology time course of the LRRK2 knockout rat model of Parkinson's disease at 1-, 2-, 4-, 8-, 12-, and 16-months of age. The evaluation consisted of histopathology and ultrastructure examination of selected organs, including the kidneys, lungs, spleen, heart, and liver, as well as hematology, serum, and urine analysis. The LRRK2 knockout rat, starting at 2-months of age, displayed abnormal kidney staining patterns and/or morphologic changes that were associated with higher serum phosphorous, creatinine, cholesterol, and sorbitol dehydrogenase, and lower serum sodium and chloride compared to the LRRK2 wild-type rat. Urinalysis indicated pronounced changes in LRRK2 knockout rats in urine specific gravity, total volume, urine potassium, creatinine, sodium, and chloride that started as early as 1- to 2-months of age. Electron microscopy of 16-month old LRRK2 knockout rats displayed an abnormal kidney, lung, and liver phenotype. In contrast, there were equivocal or no differences in the heart and spleen of LRRK2 wild-type and knockout rats. These findings partially replicate data from a recent study in 4-month old LRRK2 knockout rats and expand the analysis to demonstrate that the renal and possibly lung and liver abnormalities progress with age. The characterization of LRRK2 knockout rats may prove to be extremely valuable in understanding potential safety liabilities of LRRK2 kinase inhibitor therapeutics for treating Parkinson's disease.

Mesenchymal stromal cells (MSCs) have the potential to treat many myocardial diseases. We investigated whether these multipotent stem cells derived from bone marrow could be administered safely into the coronary circulation of healthy dogs. We injected about 0·5 million cells per kg bodyweight of early passage autologous MSCs into the left circumflex coronary artery of anaesthetised dogs. During administration, we noted ST segment elevation and T wave changes characteristic of acute myocardial ischaemia. 7 days later, macroscopic and microscopic evidence of myocardial infarction was noted. Histological sections of myocardium showed several scattered regions of dense fibroplasia accompanied by macrophage infiltrates only in areas where the MSCs were observed. We also noted raised plasma concentrations of cardiac troponin I and collagen fibril deposition in the lesions. These findings show acute myocardial ischaemia and subacute myocardial microinfarction after intracoronary arterial injection of MSCs into dogs. Published online March 2, 2004 http://image.thelancet.com/extras/03let12261web.pdf

Trefoil factors are small, protease-resistant proteins first discovered in the gastrointestinal tract and found to be important in restitution and repair after epithelial loss. This has been well defined in the gastrointestinal tract, but their expression during injury, repair and postnatal development in the lung have not been studied. The first chapter discusses previous research conducted on trefoil factors in the gastrointestinal tract with respect to development, mucosal injury and repair and the limited studies in the lung to date. Chapter two focuses on the expression profile of trefoil factors after terminal bronchiolar injury in mice using a well-defined model of Clara cell injury and repair after naphthalene. TFF1 and TFF3 mRNA increased at various times after acute injury, after proliferation and during differentiation, occasionally indicating potential opposing effects. The third chapter examines the trefoil factor expression in the developing airways of mice and Rhesus macaques at various times during postnatal development. The mRNA of all three trefoil factors were found in the airways of mice. Their expression decreased with age with different factors predominating at different ages. TFF1 and TFF3 protein was expressed in both mice and macaque airway epithelium, primarily in Clara cells and mucous cells respectively. Ciliated cell expression was present in the proximal and midlevel airways of mice, but was not apparent in distal airways. TFF1 expression was cytoplasmic in mice but was in Clara and ciliated cell nuclei of Rhesus macaques, which decreased with age as mucous cell cytoplasm signal increased. TFF3 was present in the mucous cell cytoplasm in all ages of monkeys, found in airways, submucosal glands and glandular ducts. TFF2 protein was never present in Rhesus macaques and was not evaluated in mice. The fourth chapter assessed the TFF1 and TFF3 protein expression in 3, 6 and 12 month Rhesus macaques exposed to ozone without and with recovery. TFF3 was expressed in ciliated cells of proximal bronchi. This was most apparent in 3 and 12 month animals. Six month monkeys exposed to fresh air also had ciliated cell staining, which was not apparent in ozone exposed animals.