Phenotypic and genotypic heterogeneity in familial Milroy lymphedema.

Familial Milroy lymphedema (ML) is classified as an autosomal dominant disorder characterized by peripheral edema of the lower extremities at birth or in early childhood. The variety of phenotypes are not well described, and the genomic location and functional expression of the gene or genes underlying this and related familial lymphedema syndromes remain largely unknown. In this collaborative study between the University of Arizona and the University of São Paulo, we collected clinical pedigrees on 6 ML families, carried out clinical examination of affected and unaffected individuals, and, in representative affected members of two of the families performed dynamic lymphangioscintigraphy (LAS) of the lower and upper limbs to delineate further the ML lymphangiodysplastic phenotype. To localize the gene for ML, we conducted a genome-wide search in 4 of the families using 387 polymorphic dinucleotide-repeat markers at approximate 10 cM spacing in 54 subjects (affected, unaffected bloodline relatives, and spouses). In all 6 families (86 subjects), we specifically examined the suggested linkage to the vascular endothelial growth factor (VEGF)-C receptor (Flt4) gene localized to the chromosome region 5q34-q35. The findings provide evidence for a spectrum of ML clinical and LAS phenotypes and also suggest ML locus heterogeneity.

Inhibition of normal and experimental angiotumor endothelial cell proliferation and cell cycle progression by 2-methoxyestradiol.

With rapid growth and metabolism, aggressive cancers require an extensive vascular network, termed tumor angiogenesis. The body produces a variety of natural angiogenic inhibitors, among which is the mammalian estrogen metabolite, 2-methoxyestradiol (2-MeOE2). In this study, we compared the effects of 2-MeOE2 on a human umbilical vein cell line (HUVEC-C) and on an immortal, angiotumor-producing rat sinusoidal endothelial cell line (RSE-1). In vitro, the effects of varying concentrations of 2-MeOE2 from 0.01-100.0 microM were measured with cell counts and compared to control cells. HUVEC-C had an ED50 approximately 3.5 microM with approximately 27% inhibition of cell growth whereas RSE-1 had an ED50 approximately 2.2 microM with approximately 50% inhibition of cell growth compared with controls. The lowest concentration with maximal effect was 10.0 microM 2-MeOE2 for both cell lines. Using this concentration, flow cytometric analysis of cell cycles was performed with propidium iodide stained DNA of HUVEC-C and RSE-1 at 24 and 48 hr. Both demonstrated a significant (P < 0.0001) block at G2M of the cell cycle. At 48 hr, HUVEC-C had 32% of cells in G2M (control = 9% G2M), and RSE-1 had 36% of cells in G2M (control = 18% G2M). These findings demonstrate a strong in vitro antiproliferative effect of 2-MeOE2 on normal dividing endothelial as well as angiotumor cells mediated through a cell cycle-specific block at G2M. The antiendothelial, antiangiotumor effect of 2-MeOE2 supports its potential as a therapeutic agent against solid organ cancers, benign or malignant vascular growths, and other pathologic states dependent on angiogenesis.

Chest imaging with flat-panel detector at low and standard doses: comparison with storage phosphor technology in normal patients.

The purpose of this study was to evaluate the performance of standard-dose and low-dose cesium iodide (CsI)-doted amorphous silicon (a-Si) flat-panel detector technology (FDT) as compared with storage-phosphor technology (SPT) in the depiction of relevant anatomical structures in chest radiography. In 75 patients referred for thoracic CT, digital chest radiographs were randomly obtained with either SPT at a standard dose (speed class S400, n=25), standard-dose FDT (S400, n=25) or FDT at a low dose (S800, n=25). Five radiologists evaluated the visibility of eight pulmonary and mediastinal anatomical structures using a five-point rating scale. To determine statistically significant differences between the three groups, the Mann-Whitney U-test was employed. No statistically significant differences were found in the depiction of eight criteria between SPT and standard-dose or low-dose FDT chest radiographs. The performance of FDT S400 was equal to SPT for most criteria and better for retrocardiac structures and soft tissue. FDT S800 was inferior to both SPT and FDT S400. Standard-dose FDT is equivalent to SPT in the depiction of relevant anatomical structures of the chest. Our results also indicate that a dose reduction of 50% with FDT may result in small but not significant decrease of image quality.