Abnormal collagen fibrils in cartilage of matrilin-1/matrilin-3-deficient mice

Matrilins are oligomeric extracellular matrix adaptor proteins mediating interactions between collagen fibrils and other matrix constituents. All four matrilins are expressed in cartilage and mutations in the human gene encoding matrilin-3 (MATN3) are associated with different forms of chondrodysplasia. Surprisingly, however, Matn3-null as well as Matn1- and Matn2-null mice do not show an overt skeletal phenotype, suggesting a dominant negative pathomechanism for the human disorders and redundancy/compensation among the family members in the knock-out situation. Here, we show that mice lacking both matrilin-1 and matrilin-3 develop an apparently normal skeleton, but exhibit biochemical and ultrastructural abnormalities of the knee joint cartilage. At the protein level, an altered SDS-PAGE band pattern and a clear up-regulation of the homotrimeric form of matrilin-4 were evident in newborn Matn1/Matn3 and Matn1 knock-out mice, but not in Matn3-null mice. The ultrastructure of the cartilage matrix after conventional chemical fixation was grossly normal; however, electron microscopy of high pressure frozen and freeze-substituted samples, revealed two consistent observations: 1) moderately increased collagen fibril diameters throughout the epiphysis and the growth plate in both single and double mutants; and 2) increased collagen volume density in Matn1(-/-)/Matn3(-/-) and Matn3(-/-) mice. Taken together, our results demonstrate that matrilin-1 and matrilin-3 modulate collagen fibrillogenesis in cartilage and provide evidence that biochemical compensation might exist between matrilins.

Patients with erythrophobia (fear of blushing) show abnormal autonomic regulation in mental stress conditions

OBJECTIVE: The objective of this study was to analyze the autonomic functions of patients with erythrophobia. METHODS: Forty patients with a diagnosis of erythrophobia (female/male ratio 18/22) without any other organic lesions and 20 healthy volunteers (female/male ratio 10/10) were assessed. Clinical evaluation was performed using a modified version of semistructured interviews. Autonomic testing was performed by means of spectral analysis of heart rate and continuous blood pressure by sparse discrete Fourier transformation at rest and under mental stress. RESULTS: There were no significant difference between the two samples in age, sex distribution, BMI, resting systolic, or diastolic blood pressure, nor was there a difference in autonomic baseline functioning between the 40 patients with erythrophobia and the control subjects. On the other hand, patients with erythrophobia consistently showed higher pulse rates (88 +/- 20 vs. 78 +/- 9 bpm, p <.05), higher total heart rate power values (8.40 +/- 0.63 vs. 8.07 +/- 1.02 p <.05), higher midfrequency spectral values (7.38 +/- 0.66 vs. 7.02 +/- 1.18, p <.01), higher high-frequency spectral values (6.89 +/- 0.86 vs. 6.48 +/- 1.44, p <.05), and lower baroreceptor sensitivity (8.62 +/- 8.16 vs. 11.65 +/- 4.42, p <.005) than the healthy subjects. ANOVA showed a significant group interaction (p <.0001) between the samples. CONCLUSIONS: This study provides evidence for abnormal autonomic functioning in patients with erythrophobia when under mental stress.

Virtual reality ultrasound imaging of the normal and abnormal fetal central nervous system

OBJECTIVES: In fetal ultrasound imaging, teaching and experience are of paramount importance to improve prenatal detection rates of fetal abnormalities. Yet both aspects depend on exposure to normal and, in particular, abnormal 'specimens'. We aimed to generate a number of simple virtual reality (VR) objects of the fetal central nervous system for use as educational tools. METHODS: We applied a recently proposed algorithm for the generation of fetal VR object movies to the normal and abnormal fetal brain and spine. Interactive VR object movies were generated from ultrasound volume data from normal fetuses and fetuses with typical brain or spine anomalies. Pathognomonic still images from all object movies were selected and annotated to enable recognition of these features in the object movies. RESULTS: Forty-six virtual reality object movies from 22 fetuses (two with normal and 20 with abnormal brains) were generated in an interactive display format (QuickTime) and key images were annotated. The resulting .mov files are available for download from the website of this journal. CONCLUSIONS: VR object movies can be generated from educational ultrasound volume datasets, and may prove useful for teaching and learning normal and abnormal fetal anatomy.

The absence of angiopoietin-2 leads to abnormal vascular maturation and persistent proliferative retinopathy

Angiopoietin-2 (Ang-2) antagonises the maturing effect of angiopoietin-1 (Ang-1) on blood vessels, and cooperates with VEGF to induce neovascularisation. In knockout mice, Ang-2 displayed a specific role in postnatal angiogenic remodelling. Here, we demonstrate that mice deficient in Ang-2 fail to form a proper spatial retinal vascular network. The retinal vasculature was characterised by reduced large vessel numbers and defects forming the superficial periphery mostly on the arteriolar site, and the secondary and tertiary deep capillary network. Hypoxia in the retinal periphery induced a four-fold VEGF upregulation and active endothelial proliferation for up to 60 days. Concomitantly, retinal digest preparations showed increased arteriolar (+33%) and capillary diameters (+90%), and fluorescein angiograms revealed leakiness of neovascular front. At one year of age, persistent preretinal vessels were non-leaky in accordance with a relative increase in the ratio of Ang-1 to VEGF. Taken together, the data suggest that Ang-2 has an important function in the spatial configuration of the three-dimensional retinal vasculature. Secondarily, prolonged VEGF activity results in a model of persistent proliferative retinopathy.

Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve

BACKGROUND The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 2 trial demonstrated a significant reduction in subsequent coronary revascularization among patients with stable angina and at least 1 coronary lesion with a fractional flow reserve ≤0.80 who were randomized to percutaneous coronary intervention (PCI) compared with best medical therapy. The economic and quality-of-life implications of PCI in the setting of an abnormal fractional flow reserve are unknown. METHODS AND RESULTS We calculated the cost of the index hospitalization based on initial resource use and follow-up costs based on Medicare reimbursements. We assessed patient utility using the EQ-5D health survey with US weights at baseline and 1 month and projected quality-adjusted life-years assuming a linear decline over 3 years in the 1-month utility improvements. We calculated the incremental cost-effectiveness ratio based on cumulative costs over 12 months. Initial costs were significantly higher for PCI in the setting of an abnormal fractional flow reserve than with medical therapy ($9927 versus $3900, P<0.001), but the $6027 difference narrowed over 1-year follow-up to $2883 (P<0.001), mostly because of the cost of subsequent revascularization procedures. Patient utility was improved more at 1 month with PCI than with medical therapy (0.054 versus 0.001 units, P<0.001). The incremental cost-effectiveness ratio of PCI was $36 000 per quality-adjusted life-year, which was robust in bootstrap replications and in sensitivity analyses. CONCLUSIONS PCI of coronary lesions with reduced fractional flow reserve improves outcomes and appears economically attractive compared with best medical therapy among patients with stable angina.

Merger decisions and executive stock ownership in acquiring firms

This study supports the proposition that managerial welfare affects merger decisions. The abnormal stock returns experienced by bidder firms, from the time of the announcement of a merger bid through the stockholder approval date, are positively relaterd to the percentage of own-company stock held by the senior management of the bidder. The results suggest that substantial amounts of own-company share ownership help align the interests of stockholders and management.