Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques.

Background And Purpose: Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear.

Methods: This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2-3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta>4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage.

Flanking nucleotide specificity for DNA mismatch repair-deficient frameshifts within activin receptor 2 (ACVR2).

We previously demonstrated that exonic selectivity for frameshift mutation (exon 10 over exon 3) of ACVR2 in mismatch repair (MMR)-deficient cells is partially determined by 6 nucleotides flanking 5' and 3' of each microsatellite. Substitution of flanking nucleotides surrounding the exon 10 microsatellite with those surrounding the exon 3 microsatellite greatly diminished heteroduplex (A(7)/T(8)) and full (A(7)/T(7)) mutation, while substitution of flanking nucleotides from exon 3 with those from exon 10 enhanced frameshift mutation. We hypothesized that specific individual nucleotide(s) within these flanking sequences control ACVR2 frameshift mutation rates.

Both microsatellite length and sequence context determine frameshift mutation rates in defective DNA mismatch repair.

It is generally accepted that longer microsatellites mutate more frequently in defective DNA mismatch repair (MMR) than shorter microsatellites. Indeed, we have previously observed that the A10 microsatellite of transforming growth factor beta type II receptor (TGFBR2) frameshifts -1 bp at a faster rate than the A8 microsatellite of activin type II receptor (ACVR2), although both genes become frameshift-mutated in >80% of MMR-defective colorectal cancers. To experimentally determine the effect of microsatellite length upon frameshift mutation in gene-specific sequence contexts, we altered the microsatellite length within TGFBR2 exon 3 and ACVR2 exon 10, generating A7, A10 and A13 constructs.

BCR-ABL-transformed GMP as myeloid leukemic stem cells.

During blast crisis of chronic myelogenous leukemia (CML), abnormal granulocyte macrophage progenitors (GMP) with nuclear beta-catenin acquire self-renewal potential and may function as leukemic stem cells (Jamieson et al. N Engl J Med, 2004). To develop a mouse model for CML-initiating GMP, we expressed p210(BCR-ABL) in an established line of E2A-knockout mouse BM cells that retain pluripotency in ex vivo culture.

Mutation rates of TGFBR2 and ACVR2 coding microsatellites in human cells with defective DNA mismatch repair.

Microsatellite instability promotes colonic tumorigenesis through generating frameshift mutations at coding microsatellites of tumor suppressor genes, such as TGFBR2 and ACVR2. As a consequence, signaling through these TGFbeta family receptors is abrogated in DNA Mismatch repair (MMR)-deficient tumors. How these mutations occur in real time and mutational rates of these human coding sequences have not previously been studied.

Aortic arch atheroma.

Severe atheroma of the aortic arch has now been established as an important risk factor and mechanism for stroke and peripheral embolism. The odds ratio for stroke or peripheral embolism in patients with severe arch atheroma is greater than four, and for mobile atheroma it is greater than 12. The prevalence of severe arch atheroma among patients presenting with acute ischaemic stroke, at over 20%, is in the same order as that of atrial fibrillation and carotid atherosclerosis.

Is white matter involved in patients entered into typical trials of neuroprotection?

Background And Purpose: One of the reasons for the failure of trials of neuroprotection in stroke may be the lack of white matter (WM) protection. However, whether patients entered into typical neuroprotection trials have WM involved in the ischemic process is unknown. We studied patients who were enrolled in neuroprotection trials at our center and used a neuroimaging coregistration approach to determine whether final infarcts involved WM and, if so, in what proportion.

Identification of frame-shift intermediate mutant cells.

Frame-shift mutations at microsatellites occur as a time-dependent function of polymerase errors followed by failure of postreplicational mismatch repair. A cell-culture system was developed that allows identification of intermediate mutant cells that carry the mutation on a single DNA strand after the initial DNA polymerase errors. A plasmid was constructed that contained 13 repeats of a poly(dC-dA).

Weight gain in captive chimpanzee infants: Comparisons by sex, rearing, and colony.

Weight gain has been monitored for 13 years in a mixed longitudinal study of captive chimpanzee growth and development. This report presents results of a comparative analysis of weight relative to age in 175 animals during the first 24 months in four sex/rearing groups (hand-reared females, hand-reared males, mother-reared females, and mother-reared males) from three colonies with different physical, nutritional, and social environments (Primate Foundation of Arizona, University of Texas M.D.