AbstFact--In this study, we analyzed blood flow through a model stenosis with Reynolds numbers ranging from 300 to 3,600 using both experimental and numerical methods. The jet produced at the throat was turbulent, leading to an axisymmetric region of slowly recirculating flow. For higher Reynolds numbers, this region became more disturbed and its length was reduced. The numerical predictions were confirmed by digital particle image velocimetry and used to describe the fluid dynamics mechanisms relevant to prior measurements of platelet deposition in canine blood flow (R. T. Schoephoerster et al., Atheroscleros& and Thromboshr 12:1806-1813. Actual deposition onto the wall was dependent on the wall shear stress distribution along the stenosis, increasing in areas of flow recirculation and reattachment. Platelet activation potential was analyzed under laminar and turbulent flow conditions in terms of the cumulative effect of the varying shear and elongational stresses, and the duration platelets are exposed to them along individual platelet paths. The cumulative product of shear rate and exposure time along a platelet path reached a value of 500, half the value needed for platelet activation under constant shear (J. M. Ramstack et al., Journal of Biomechanics 12: 113-125, 1979).

The restenosis or occlusion that frequently follows balloon angioplasty is poorly understood. Thus, the pathophysiological response to angioplasty of the common carotid artery in 38 heparinized normal pigs was investigated by quantification of the 111In-labeled platelet deposition and histological and electron microscopic examination from 1 hour to 60 days after angioplasty. At 1 hour, the following findings were noted: complete endothelial denudation in all arteries, marked platelet deposition (44.7 +/- 20.7 X 10(6)/cm2), mural thrombus in seven of 10 pigs, and a medial tear extending through the internal elastic lamina in nine of 18 arteries. All nine arteries with tears had associated mural thrombus and severe platelet deposition (76 X 10(6)/cm2); in contrast, the nine arteries without a tear had no mural thrombus and much lower platelet deposition (6 X 10(6)/cm2). Necrosis of medial smooth muscle cells was evident at 24 hours. Platelet deposition remained high at 24 hours (40.5 +/- 20.6 X 10(6)/cm2), but was markedly reduced at 4 days (4.4 +/- 1.5 X 10(6)/cm2), coincident with partial regrowth of endothelium or periluminal lining cells. No significant platelet deposition was noted at 7 days, when the endothelial cell type of regrowth was largely complete. Intimal proliferation of smooth muscle cells was mild and patchy at 7 days, significantly greater and more uniform at 14 days, and unchanged at 30 and 60 days after angioplasty. Complete thrombotic occlusion occurred in four (11%) of the 38 pigs. A significant stenosis present at 30 days after angioplasty was shown by histological examination to be due to organization of mural thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

Distinct mutations in the centrosomal-cilia protein CEP290 lead to diverse clinical findings in syndromic ciliopathies. We show that CEP290 localizes to the transition zone in ciliated cells, precisely to the region of Y-linkers between central microtubules and plasma membrane. To create models of CEP290-associated ciliopathy syndromes, we generated Cep290(ko/ko) and Cep290(gt/gt) mice that produce no or a truncated CEP290 protein, respectively. Cep290(ko/ko) mice exhibit early vision loss and die from hydrocephalus. Retinal photoreceptors in Cep290(ko/ko) mice lack connecting cilia, and ciliated ventricular ependyma fails to mature. The minority of Cep290(ko/ko) mice that escape hydrocephalus demonstrate progressive kidney pathology. Cep290(gt/gt) mice die at mid-gestation, and the occasional Cep290(gt/gt) mouse that survives shows hydrocephalus and severely cystic kidneys. Partial loss of CEP290-interacting ciliopathy protein MKKS mitigates lethality and renal pathology in Cep290(gt/gt) mice. Our studies demonstrate domain-specific functions of CEP290 and provide novel therapeutic paradigms for ciliopathies.

Laminar and turbulent numerical simulations of steady flow in an aneurysm model were carried out over Reynolds numbers ranging from 300 to 3600. The numerical simulations are validated with Digital particle Image Velocimetry (DPIV) measurements, and used to study the fluid dynamic mechanisms that characterize aneurysm deterioration, by correlating them to in vitro blood platelet deposition results. It is shown that the recirculation zone formed inside the aneurysm cavity creates conditions that promote thrombus formation and the viability of rupture. Wall shear stress values in the recirculation zone are around one order of magnitude less than in the entrance zone. The point of reattachment at the distal end of the aneurysm is characterized by a pronounced wall shear stress peak. As the Reynolds number increases in laminar flow, the center of the recirculation region migrates toward the distal end of the aneurysm, increasing the pressure at the reattachment point. Under fully turbulent flow conditions (Re = 3600) the recirculation zone inside the aneurysm shrinks considerably. The wall shear stress values are almost one order of magnitude larger than those for the laminar cases. The fluid dynamics mechanisms inferred from the numerical simulation were correlated with measurements of blood platelet deposition, offering useful explanations for the different morphologies of the platelet deposition curves.