Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6.

Humans and mice lacking Lrp5 have low BMD. To evaluate whether Lrp5 and Lrp6 interact genetically to control bone or skeletal development, we created mice carrying mutations in both Lrp5 and the related gene Lrp6. We found that compound mutants had dose-dependent deficits in BMD and limb formation, suggesting functional redundancy between these two genes in bone and limb development. INTRODUCTION: Lrp5 and Lrp6 are closely related members of the low density lipoprotein receptor family and are co-receptors for Wnt ligands. While Lrp5 mutations are associated with low BMD in humans and mice, the role of Lrp6 in bone formation has not been analyzed. MATERIALS AND METHODS: To address whether Lrp5 and Lrp6 play complimentary roles in bone and skeletal development, we created mice with mutations in both genes. We inspected limbs of mice from the different genotypic classes of compound mutants to identify abnormalities. DXA and muCT were used to evaluate the effect of mutations in Lrp5 and Lrp6 on BMD and microarchitecture. RESULTS: Mice heterozygous for mutations in Lrp6 and either heterozygous or homozygous for a mutation in Lrp5 (Lrp6(+/-);Lrp5(+/-) or Lrp6(+/-);Lrp5(-/-)) display limb defects with incomplete penetrance and variable expression. DXA analysis showed that BMD decreased as mice progressively were more deficient in Lrp5 and Lrp6. Lrp6(+/-);Lrp5(-/-) mice were more severely affected than Lrp6(+/+);Lrp5(-/-) mice, whereas Lrp6(+/-);Lrp5(+/-) mice had statistically higher BMD than Lrp6(+/+);Lrp5(-/-) mice and lower BMD compared with wildtype mice and mice heterozygous for either mutation alone. CONCLUSIONS: Lrp6 and Lrp5 genetically interact in limb development in mice. Furthermore, heterozygosity for an inactivating mutation in Lrp6 further reduces BMD in both male and female mice lacking Lrp5.     

Migraine therapy: relationship between serotonergic contractile receptors in canine and rabbit saphenous veins to human cerebral and coronary arteries

Canine and rabbit vascular contractile responses to serotonergic agonists have been used to predict antimigraine efficacy for several antimigraine agents, including sumatriptan. The purpose of the present study was to establish the assumed predictive value of contractile responses in canine and rabbit saphenous veins to contractile efficacy for a series of agonists in human cerebral and coronary arteries and to understand better the receptors mediating such responses. The canine and rabbit saphenous veins contracted similarly (both qualitatively and quantitatively) to series of structurally diverse serotonergic agonists, suggesting that the receptors mediating serotonin-induced contractility in these tissues were similar. In addition, the contractile potency (estimated as EC₅₀ values) for these structurally diverse serotonergic agonists in either the rabbit or canine saphenous vein significantly correlated with contractile potency for these agonists in human cerebral arteries. Thus, to the extent that contractile responsiveness of human cerebral arteries may predict antimigraine agents, contractile responses of the rabbit and/or canine saphenous vein may be useful surrogates for antimigraine efficacy. In addition, the contractile potency for this series of serotonergic agonists in the rabbit and/or canine saphenous vein significantly correlated with contractile potency of these agonists in human coronary arteries. These data suggest that the use of the saphenous vein to identify potent vasoconstrictors will also reveal agents capable of contracting human coronary arteries, a liability for using this approach to evaluate promising antimigraine therapies.     

Palpable solid breast masses: retrospective single- and multimodality evaluation of 201 lesions

The diagnostic virtues and limitations of single- and multimodality testing in the evaluation of solid palpable breast masses were studied. Two hundred one consecutive patients who had a solid palpable breast mass and who underwent biopsy between September 1982 and July 1986 were included for blinded retrospective analysis of their physical examination, mammographic, ultrasonographic (US), thermographic, and pathologic characteristics. Benign breast disease was diagnosed histologically in 106 women, while carcinoma was established in 95. The sensitivities of physical examination, mammography, US, and thermography were 0.88, 0.94, 0.78, and 0.49, respectively. US alone had the highest sensitivity in correct diagnosis of a benign solid breast mass and had the highest accuracy (0.84). Use of four modalities increased the preoperative diagnostic true-positive rate to 0.97, with some decline in specificity. Multimodality testing seems particularly beneficial in pre- and perimenopausal patients.     

Percutaneous angioscopy. Work in progress

The cardiovascular applications of flexible fiber-optic technology are imminent because of recent advances in miniaturization. In the work described here, angioscopy, or vascular endoscopy, was performed in the cadaveric aorta and in the systemic and pulmonary circulations of the canine model and selected human patients. Subsequent to our development of percutaneous techniques, clinical trials have ranged from lower-extremity venoscopy to aortic-root arterioscopy. Angioscopy could be clinically useful because of relative or absolute contraindications to iodinated contrast material. The ability to see in color and three dimensions may afford some other advantages to angioscopy over conventional angiography.     

Focal nodular hyperplasia and hepatic adenoma: comparison of angiography, CT, US, and scintigraphy

The authors reviewed 23 cases of focal nodular hyperplasia and 13 cases of hepatic adenoma, all of which were confirmed pathologically. All solitary masses that exhibited normal or increased uptake of technetium 99m-sulfur colloid were shown to be hyperplasia; while previous criteria such as a central blood supply on angiograms or a central scar on computed tomography (CT) or ultrasound (US) scans were helpful, they were relatively infrequent. A mass that was slightly hypodense and homogeneous on a CT or US scan and highly vascular with an intense capillary stain on an angiogram was almost always hyperplasia. Acute hemorrhage within a focal hepatic tumor was common in adenoma but did not occur in hyperplasia.