A recombinant plasmid composed of segments of herpes simplex virus and simian virus 40 viral DNA inserted into the bacterial plasmid pBR322 was microinjected into pronuclei of fertilized mouse oocytes. The embryos were implanted in the oviducts of pseudopregnant females and allowed to develop to term. DNA from newborn mice was evaluated by the Southern blotting technique for the presence of DNA homologous to the injected plasmid. Two of 78 mice in one series of injections showed clear homology, though the injected sequences had been rearranged. Band intensities from the two positive mice were consistent with the presence of donor DNA in most or all of the cells of the newborns. These results demonstrate that genes can be introduced into the mouse genome by direct insertion into the nuclei of early embryos. This technique affords the opportunity to study problems of gene regulation and cell differentiation in a mammalian system by application of recombinant DNA technology.

Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK-0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed.

Timed performance-based measures have a wide range of test-retest reliability. Performance-based protocols that reflect familiar tasks with discrete starting and ending points may achieve higher reliability than tasks that are unfamiliar to subjects or may have ambiguous elements in them.

Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.

AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD‐6972, in healthy subjects and subjects with type 2 diabetes (T2DM).MethodsIn the single ascending dose study, LGD‐6972 (2‐480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD‐6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD‐6972 daily for 14 days.Results LGD‐6972 had linear plasma pharmacokinetics consistent with once‐daily dosing that was comparable in healthy and T2DM subjects. Dose‐dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD‐6972 also reduced plasma glucose in the postprandial state. Dose‐dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD‐6972 was well tolerated at the doses tested without dose‐related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia.ConclusionInhibition of glucagon action by LGD‐6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD‐6972 after 14 days of dosing supports continued clinical development.

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