ApoA-I induction represents a potential novel strategy to reduce cardiovascular risk, by generating nascent HDL particles. These studies will provide early evaluation of the effects of RVX-208 on lipids and atherosclerotic plaque.

Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC -the gene encoding SP-C -SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.

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As early as the 15th century Swedes noticed that rocks in their harbors were slowly rising out of the sea [Ekman, 1991]. These local observations were not sufficient to distinguish whether the rocks were rising or the sea level falling. Later, it was realized that Fennoscandia was still rebounding from the last Ice Age. This historical observation is still relevant today. How can you know whether a point on the Earth's surface is slowly moving up, down, or horizontally? One must relate local measurements to a stable and accurate reference frame, one whose scale is much larger than the problem at hand. We remain concerned with sea‐level variations, but present‐day studies recognize that change must be measured from a global point of view and with respect to a globally well‐defined reference frame. Thus, the regional and national geodetic datums developed over the past 200 years are inappropriate for studying global‐level problems.

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