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Background and purpose: Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in b-cells. Here we examine whether the lowering of blood glucose levels in the rat by small molecule glucokinase activators (GKAs) can be predicted from in vitro enzyme potencies and plasma compound exposure. Experimental approach: We developed an insulin resistant and hyperinsulinemic animal model, the high fat fed female Zucker (fa/fa) rat (HFFZ), and measured the acute in vivo glucose-lowering efficacy of a number of GKAs in an oral glucose tolerance test. Key results: Four GKAs (at 1 to 30 mg kg À1 ), with different in vitro enzyme potencies, dose-dependently improved oral glucose tolerance in HFFZ rats (10-40% decrease glucose area under the curve (AUC) from vehicle control). The extent of glucose lowering, or the pharmacodynamic (PD) effect, of a GKA was directly related to the total compound concentration in the plasma; the pharmacokinetic (PK) measurement. This PK-PD relationship was extended across a series of GKAs by accounting for differences in protein binding and in the in vitro potency. Conclusions and implications: When the unbound GKA compound level is greater than the in vitro enzyme potency there was significant blood glucose lowering in vivo. This latter relationship was upheld in non-diabetic Wistar rats orally dosed with a GKA. The robust and predictive nature of the PK-PD relationship for GKAs may prove of value in testing these agents in early human clinical studies.

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The aim of this study was to establish the reproducibility of sequential three-dimensional (3D) ultrasound reconstructions of an identified segment of the carotid artery bifurcation in asymptomatic subjects. A freehand acquisition, compound reconstruction, 3D ultrasound system was used on three occasions, over a period of 1 year. The lumen of the vessel was reconstructed to provide a volume measurement and a rotatable 3D structure representation that could be examined for geometrical correspondence. The four subjects differed significantly in the visualized 3D geometry of the vessel bifurcation. There was good correspondence in the sequential reconstructions for each individual in both the 3D geometry and in the measured lumen volume, with an overall coefficient of variation of 5% and no evidence of deterioration in correlation with time.

We present the case of a rock climber with a rupture of the A3 flexor sheath pulley. The diagnosis was confirmed with Colour Doppler Imaging (CDI) and with B-mode ultrasound imaging, and the surgical repair was evaluated in the same way. Vertical displacement of the flexor tendon meant that using CDI measurements of the longitudinal movements was not possible. However, using computer analysis of digitized B-mode images from texture patterns identified in the tendons, the vertical and longitudinal components of movement during flexion were calculated. The repair of the pulley was shown to produce tendon movement ratios nearer those of the control digit of the opposite hand.