Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006.

BACKGROUND: Recently, epidemiological and clinical data have revealed important changes with regard to clinical adenovirus infection, including alterations in antigenic presentation, geographical distribution, and virulence of the virus. METHODS: In an effort to better understand the epidemiology of clinical adenovirus infection in the United States, we adopted a new molecular adenovirus typing technique to study clinical adenovirus isolates collected from 22 medical facilities over a 25-month period during 2004-2006. A hexon gene sequence typing method was used to characterize 2237 clinical adenovirus-positive specimens, comparing their sequences with those of the 51 currently recognized prototype human adenovirus strains. In a blinded comparison, this method performed well and was much faster than the classic serologic typing method. RESULTS: Among civilians, the most prevalent adenovirus types were types 3 (prevalence, 34.6%), 2 (24.3%), 1 (17.7%), and 5 (5.3%). Among military trainees, the most prevalent types were types 4 (prevalence, 92.8%), 3 (2.6%), and 21 (2.4%). CONCLUSIONS: For both populations, we observed a statistically significant increasing trend of adenovirus type 21 detection over time. Among adenovirus isolates recovered from specimens from civilians, 50% were associated with hospitalization, 19.6% with a chronic disease condition, 11% with a bone marrow or solid organ transplantation, 7.4% with intensive care unit stay, and 4.2% with a cancer diagnosis. Multivariable risk factor modeling for adenovirus disease severity found that age <7 years (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4-7.4), chronic disease (OR, 3.6; 95% CI, 2.6-5.1), recent transplantation (OR, 2.7; 95% CI, 1.3-5.2), and adenovirus type 5 (OR, 2.7; 95% CI, 1.5-4.7) or type 21 infection (OR, 7.6; 95% CI, 2.6-22.3) increased the risk of severe disease.     

Quantitative Characterization of Epicardial Wave Fronts During Regional Ischemia and Elevated Extracellular Potassium Ion Concentration

This study applied zero-delay wave number spectral estimation as a means of quantifying the changes in activation and recovery sequences of propagating plane waves on the epicardial surface of in situ porcine hearts during regional hyperkalemia and ischemia. Unipolar electrograms (104) were recorded from the left ventricular surface of nine hearts using a plaque electrode array with 1 mm spatial sampling intervals. The objectives were (1) to define a set of parameters capable of quantifying the spatial and temporal changes in measured extracellular potentials associated with localized ischemia prior to the onset of conduction block; (2) to elevate regional levels of extracellular potassium ion concentration and quantify potential changes due to this known physiologic manipulation; and (3) to use quantitative parameters to make statistical comparisons in order to distinguish wave fronts during normal, ischemic and hyperkalemic conditions. Results showed that the parameters of wave number and average temporal frequency and the associated power, as determined from the wave number spectrum, provided statistically significant (p < 0.05) quantification of changes in wave front features during normal and ischemic or hyperkalemic conditions. The results were consistent with results obtained from conventional time–space domain methods like isochronal mapping and electrograms, with the advantage of a quantitative result enabling simple comparisons and trend analysis for large numbers of heart beats. © 1998 Biomedical Engineering Society. PAC98: 8759Wc, 8722Fy, 8780+s     

c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression

c-Myc promotes cell growth and transformation by ill-defined mechanisms. c-myc(-/-) mice die by embryonic day 10.5 (E10.5) with defects in growth and in cardiac and neural development. Here we report that the lethality of c-myc(-/-) embryos is also associated with profound defects in vasculogenesis and primitive erythropoiesis. Furthermore, c-myc(-/-) embryonic stem (ES) and yolk sac cells are compromised in their differentiative and growth potential. These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. However, c-Myc is also required for the proper expression of other angiogenic factors in ES and yolk sac cells, including angiopoietin-2, and the angiogenic inhibitors thrombospondin-1 and angiopoietin-1. Finally, c-myc(-/-) ES cells are dramatically impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes develop are poorly vascularized. Therefore, c-Myc function is also necessary for the angiogenic switch that is indispensable for the progression and metastasis of tumors. These findings support the model wherein c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.     

Determination of glomerular size-selectivity in the normal rat with Ficoll.

Diffusion studies in vitro indicate that Ficoll behaves more like an ideal spherical molecule than does dextran, suggesting that Ficoll would be a better probe of glomerular pore size than the commonly used dextran. To examine the differences between these macromolecules in vivo, the fractional clearances of tritiated Ficoll and dextran were measured over a wide range of molecular sizes (Stokes-Einstein radius, rs, from 19 to 65 A) in normal euvolemic Munich-Wistar rats. Whole-kidney and single-nephron hemodynamic conditions were characterized through a combination of clearance and micropuncture measurements. The fractional clearance, or sieving coefficient (theta), for dextran significantly exceeded that of Ficoll at all molecular sizes examined, theta for dextran being approximately 10 times that for Ficoll for rs greater than 30 A. Thus, the results with Ficoll imply a more size-restrictive barrier than do the results with dextran. The values of theta for Ficoll approximated previously reported values for uncharged globular proteins. Although theta for Ficoll at rs = 35 A was much smaller than the corresponding value for dextran, it was still approximately 30 times greater than typical values of the filtrate-to-plasma concentration ratio reported for serum albumin (a polyanion) in the rat, in agreement with the concept that glomerular charge-selectivity normally plays an important role in the prevention of albuminuria. Three membrane-pore models were compared in their ability to represent the dextran and Ficoll sieving data. A lognormal pore-size distribution in parallel with a nonselective "shunt" pathway was found to be more effective than either an isoporous membrane with a shunt or a purely lognormal distribution. On the basis of these laboratory results and computations, Ficoll may be preferred over dextran in future studies of glomerular size-selectivity.     

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.