Citations

Background and Purpose— We sought to determine the vascular risk factors and demographic features associated with the severity and location of intracranial stenosis. Methods— Data on patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial were used for the analyses. Demographic features and vascular risk factors were compared in patients with moderate stenosis (n=336) versus severe stenosis (n=225) and according to the location of intracranial stenosis (middle cerebral, internal carotid, basilar, or vertebral artery). Results— History of a lipid disorder (77% in severe vs 67% in moderate, P =0.01), metabolic syndrome (63% in severe vs 53% in moderate, P =0.05), and diabetes (43% in severe vs 35% in moderate, P =0.04) were more common in patients with severe intracranial stenosis by univariate analyses. A history of a lipid disorder was independently associated with severe stenosis (odds ratio=1.62; 95% CI, 1.09 to 2.42; P =0.02). The distribution of stenosis location differed among age groups ( P =0.0015), sexes ( P =0.0001), races ( P =0.0243), qualifying events ( P =0.0156), diabetes ( P =0.0030), coronary artery disease ( P =0.0030), and hyperlipidemia ( P =0.054). Patients with basilar artery stenoses were older and more likely to have hyperlipidemia. Patients with middle cerebral artery stenoses were more likely to be women and black. Patients with internal carotid artery stenoses were more likely to have diabetes. Patients with vertebral artery stenoses were more likely to have coronary artery disease. Conclusions— History of a lipid disorder had the strongest association with severity of intracranial stenosis and should be the target of prevention therapies. Different locations of intracranial stenoses are associated with different vascular risk factors and demographic features, suggesting that there may be a difference in the underlying pathophysiology of stenoses among the intracranial arteries.

Abstract Type I alveolar epithelial cells (ATIs) are very large, thin cells, which extend across several air sacs and cover more than 95% of the alveolar surface area. ATIs are the target of many insults, including ventilator-induced lung injury, and are generally considered terminally differentiated cells arising from type II cell (ATII) lineage. ATIs have proven difficult to harvest and maintain in primary culture, which is why much of ATI biology has been inferred from studies on ex vivo, ATII-derived, so-called ATI-like cells. We report on a modified approach to rat ATI harvest and primary culture, which yielded the following observations: (1) rat ATI can be harvested and maintained with a high degree of purity in primary culture; (2) in vitro growth characteristics of primary ATIs differ from those of ATII-derived ATI-like cells; ATIs, but not ex vivo, ATII-derived ATI-like cells, are capable of cell division; (3) ATIs readily repair plasma membrane wounds without the subsequent loss of their ability to divide; (4) ATI monolayers heal scratch wounds primarily by cell spreading and migration. Although the ability of ATIs to divide may be limited to the in vitro environment, we do believe that their role in alveolar wound repair deserves to be revisited, and the molecular control of ATI–ATII plasticity further explored.

The objective of our paper was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two-level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters.

Abstract Background: Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. Methods: This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model. Results: In the log additive model, two linked (r2 = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r2 = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements. Conclusions: Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non–multivitamin users. Impact: This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population. Cancer Epidemiol Biomarkers Prev; 19(7); 1812–21. ©2010 AACR.

Abstract Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival.

Purpose Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. Patients and Methods The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Results Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. Conclusion The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.