Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E -/- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS

Large third-order electronic polarizability of a conjugated porphyrin polymer

Degenerate four-wave mixing measurements, using 45 ps pulses at 1064 nm, have been used to determine the magnitude of the third-order optical susceptibility tensor for thin films of a conjugated porphyrin polymer. The time dependence of the signals indicates that the dominant response is fast relative to the duration of the optical pulses. It is shown that a response on this time scale cannot be consistent with a mechanism in which resonant absorption is significant, and therefore that the primary component of the susceptibility must correspond to an instantaneous electronic polarization. The microscopic polarizability per macrocycle of the polymer is approximately 3 orders of magnitude greater than that of the monomer - a result that indicates the role of inter-macrocycle conjugation in the nonlinearity. This appears to be the largest one-photon-off-resonance third-order optical susceptibility reported for any organic material

Degenerate four-wave mixing studies of butadiyne-linked conjugated porphyrin oligomers

The third-order electronic susceptibilities have been measured in solution for a series of conjugated porphyrin oligomers, and for a conjugated polymer of this type. At 1064 nm, the non-resonant susceptibilities of the oligomers and the polymer are large (χ (3)≈10 -17-10 -16 m 2 V -2), have comparable real and imaginary parts, and the real part is negative in sign. The molecular susceptibility per ring chromophore, (γ/N), shows a linear dependence upon chain length, N. We propose a general mechanism for the enhancement of the third-order susceptibilities in conjugated porphyrin based materials due to two-photon resonance with charge transfer states