Endovascular repair or surveillance of patients with small AAA.

OBJECTIVE: To compare the outcome of patients with small abdominal aortic aneurysms (AAA) treated in a prospective trial of endovascular aneurysm repair (EVAR) to patients randomized to the surveillance arm of the UK Small Aneurysm Trial. METHOD: All patients with small AAA (< or = 5.5 cm diameter) treated with a stent graft (EVARsmall) in the multicenter AneuRx clinical trial from 1997 to 1999 were reviewed with follow up through 2003. A subgroup of patients (EVARmatch) who met the age (60-76 years) and aneurysm size (4.0-5.5 cm diameter) inclusion criteria of the UK Small Aneurysm Trial were compared to the published results of the surveillance patient cohort (UKsurveil) of the UK Small Aneurysm Trial (NEJM 346:1445, 2002). Endpoints of comparison were aneurysm rupture, fatal aneurysm rupture, operative mortality, aneurysm related death and overall mortality. The total patient years of follow-up for EVAR patients was 1369 years and for UK patients was 3048 years. Statistical comparisons of EVARmatch and UKsurveil patients were made for rates per 100 patient years of follow up (/100 years) to adjust for differences in follow-up time. RESULTS: The EVARsmall group of 478 patients comprised 40% of the total number of patients treated during the course of the AneuRx clinical trial. The EVARmatch group of 312 patients excluded 151 patients for age < 60 or > 76 years and 15 patients for AAA diameter < 4 cm. With the exception of age, there were no significant differences between EVARsmall and EVARmatch in pre-operative factors or post-operative outcomes. In comparison to the UKsurveil group of 527 patients, the EVARmatch group was slightly older (70 +/- 4 vs. 69 +/- 4 years, p = 0.009), had larger aneurysms (5.0 +/- 0.3 vs. 4.6 +/- 0.4 cm, p < 0.001), fewer women (7 vs. 18%, p < 0.001), and had a higher prevalence of diabetes and hypertension and a lower prevalence of smoking at baseline. Ruptures occurred in 1.6% of EVARmatch patients and 5.1% of UKsurveil patients; this difference was not significant when adjusted for the difference in length of follow up. Fatal aneurysm rupture rate, adjusted for follow up time, was four times higher in UKsurveil (0.8/100 patient years) than in EVARmatch (0.2/100 patient years, p < 0.001); this difference remained significant when adjusted for difference in gender mix. Elective operative mortality rate was significantly lower in EVARmatch (1.9%) than in UKsurveil (5.9%, p < 0.01). Aneurysm-related death rate was two times higher in UKsurveil (1.6/100 patient years) than in EVARmatch (0.8/100 patient years, p = 0.03). All-cause mortality rate was significantly higher in UKsurveil (8.3/100 patient years) than in EVARmatch (6.4/100 patient years, p = 0.02). CONCLUSIONS: It appears that endovascular repair of small abdominal aortic aneurysms (4.0-5.5 cm) significantly reduces the risk of fatal aneurysm rupture and aneurysm-related death and improves overall patient survival compared to an ultrasound surveillance strategy with selective open surgical repair.     

Further characterization of ts1-8, a mutant of herpes simplex virus type 1.

Our initial characterization of a herpes simplex virus type 1, temperature sensitive host shutoff mutant, called ts1-8, revealed that it has a low plaquing efficiency and exhibits a defect in the shutoff of host polypeptide synthesis and host DNA replication at the nonpermissive temperature of 39.5 degrees C. Using intratypic marker rescue experiments the ts plaquing mutation was mapped to a 557 bp region. Sequence analysis and complementation studies revealed that the low plaquing efficiency phenotype is due to a mutation in the glycoprotein B gene converting Pro-357 to Ser. This novel tsgB mutation is located in a conserved region of gB and it is distinct from the delayed host shutoff mutation (dhs).     

Fusion and Matrix Protein Gene Sequence Analysis of Paramyxoviruses of Type 1(PMV-1) Isolated from Pigeons in Slovenia

Paramyxoviruses of type 1 (PMV-l) isolated from pigeons were genetically analyzed. A part of the fusion and the matrix protein genes were amplified and sequenced, Typical amino acid sequences associated with virulence were determined at the fusion protein cleavage site in all PMV-1 isolates. All Slovene pigeon PMV-1 strains share high amino acid sequence similarity with other pigeon strains. In the phylogenetic tree, they are clustered together with pigeon PMV-1 isolates with moderate pathogenicity. Phylogenetic analysis obtained from the fusion and the matrix protein gene alignments showed the same branching order. Viruses circulating among pigeons were found to form quite unique lineage of virulent NDV strains.     

[35S]methionine interaction with rat liver tRNA and effect of chemical carcinogens

The interaction of [³⁵S]methionine with hepatic tRNA in normal, carcinogen-treated, and partially hepatectomized rats was studied. tRNA was preferentially labeled following [³⁵S]methionine (1.6 mCi, 25 mg/kg body wt) administration by intraperitoneal injection. The extent of [³⁵S]methionine-tRNA interaction was impaired by partial hepatectomy and by conditions having a carcinogenic potential.Presented at the Proceedings of the International Meetings on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.Supported by CNR, Progetti Finalizzati Chimica Fine ed Oncologia     

Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis

Osteoprotegerin (OPG) is a recently discovered member of the TNF receptor superfamily that acts as an important paracrine regulator of bone remodeling. OPG knockout mice develop severe osteoporosis, whereas administration of OPG can prevent ovariectomy-induced bone loss. These findings implicate a role for OPG in the development of osteoporosis. In the present study, we screened the OPG gene promoter for sequence variations and examined their association with bone mineral density (BMD) in 103 osteoporotic postmenopausal women. Single-strand conformation polymorphism analysis followed by DNA sequencing revealed a presence of four nucleotide substitutions: 209 G-->A, 245 T-->G, 889 C-->T, and 950 T-->C. The frequencies of genotypes were as follows: GG (89.3%), GA (10.7%) for 209 G-->A polymorphism; TT (89.3%), TG (10.7%) for 245 T-->G polymorphism; and TT (25.2%), TC (53.4%), CC (21.4%) for 950 T-->C polymorphism. Substitution 889 C-->T was found in only two patients. Statistically significant association of genotypes with BMD at the lumbar spine (P = 0.005) was observed for 209 G-->A and 245 T-->G polymorphisms. Haplotype GATG was associated with lower BMD as compared with GGTT haplotype. Our results suggest that 209 G-->A and 245 T-->G polymorphisms in the OPG gene promoter may contribute to the genetic regulation of BMD.     

A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study

Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G>T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen-activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis.Noonan syndrome (NS; http://www.omim.org/entry/163950?search=163950&highlight=163950) is a relatively common genetic disorder with an incidence of 1 per 1000-2500 live births (1). Clinically it is a very heterogeneous disorder, predominantly characterized by dysmorphic facial features, congenital heart defect (CHD), post-natal short stature, webbed neck, chest deformity, cryptorchidism in men, lymphatic dysplasia, variable bleeding disorders, and intellectual disability. CHD is present in 50 to 80% of affected individuals and it is also very heterogeneous (2). Most commonly found are pulmonary valve stenosis with or without dysplastic pulmonary valve and hypertrophic cardiomyopathy. Providing the CHD is not large, life expectancy is in the normal range (3). NS and CHD are regularly connected with germline KRAS mutations. We describe a patient with NS and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene.     

Engineering bone tissue from human embryonic stem cells

In extensive bone defects, tissue damage and hypoxia lead to cell death, resulting in slow and incomplete healing. Human embryonic stem cells (hESC) can give rise to all specialized lineages found in healthy bone and are therefore uniquely suited to aid regeneration of damaged bone. We show that the cultivation of hESC-derived mesenchymal progenitors on 3D osteoconductive scaffolds in bioreactors with medium perfusion leads to the formation of large and compact bone constructs. Notably, the implantation of engineered bone in immunodeficient mice for 8 wk resulted in the maintenance and maturation of bone matrix, without the formation of teratomas that is consistently observed when undifferentiated hESCs are implanted, alone or in bone scaffolds. Our study provides a proof of principle that tissue-engineering protocols can be successfully applied to hESC progenitors to grow bone grafts for use in basic and translational studies.     

The Effect of Scandium on the Structure,Microstructure and Superconductivity of Equimolar Sc-Hf-Nb-Ta-Ti-Zr Refractory High-Entropy Alloys

In this study, we investigate the scandium-containing Sc-Hf-Nb-Ta-Ti-Zr system of refractory high-entropy alloys (HEAs). Using the arc-melting method, we synthesized nine equimolar alloys (five 4-, three 5- and one 6-component), with all of them containing Sc. The alloys were characterized by XRD, electron microscopy and EDS, while superconductivity was investigated via electrical resistivity, specific heat and the Meissner effect. The results were compared to the parent Hf-Nb-Ta-Ti-Zr refractory HEAs, forming a single-phase body-centered cubic (bcc) structure and quite homogeneous microstructure. The addition of Sc produces a two-phase structure in the Sc-Hf-Nb-Ta-Ti-Zr alloys, with one phase being bcc and the other hexagonal close-packed (hcp). The hcp phase absorbs practically all Sc, whereas the Sc-poor bcc phase is identical to the bcc phase in the Hf-Nb-Ta-Ti-Zr parent system. Upon the Sc addition, the microstructure becomes very inhomogeneous. Large bcc dendrites (10–100 µm) are homogeneous in the central parts, but become a fine dispersion of sub-micron precipitates of the bcc and hcp phases close to the edges. The interdendritic regions are also a fine dispersion of the two phases. Superconductivity of the Sc-Hf-Nb-Ta-Ti-Zr alloys originates from the bcc phase fraction, which demonstrates identical superconducting parameters as the bcc Hf-Nb-Ta-Ti-Zr parent alloys, while the Sc-containing hcp phase fraction is non-superconducting.