Citations

Purpose We tested the hypothesis that the preimplantation mechanical properties of BioCleanse‐treated bone–patellar tendon–bone (BPTB) allografts are not significantly different from those of untreated specimens. Methods For this controlled laboratory study, specimens were harvested as central third or hemi‐BPTB units from both knees of 17 cadaveric tissue donors (11 men and 6 women) aged 19 to 88 years. Donor‐matched specimens (20 per group) were randomly assigned to either BioCleanse‐treated or untreated control groups. Specimens were subjected to 25 minutes of pretensioning at 89 N and then cyclically loaded under longitudinal tension between 50 N and 250 N for 1,000 cycles at 1 Hz, followed by ramp to failure at 50 mm/min. Results No statistically significant difference was found between untreated and BioCleanse‐treated specimens in stiffness (235.3 ± 37.6 N/mm v 222.3 ± 53.4 N/mm, P = .37), cyclic creep (0.38 ± 0.42 mm v 0.40 ± 0.26 mm, P = .81), maximum force (1,685.7 ± 471.6 N v 1,807.0 ± 657.8 N, P = .47), or ultimate stress (29.0 ± 9.8 MPa v 29.0 ± 12.8 MPa, P = .98). Conclusions The preimplantation mechanical properties of BPTB allografts treated with BioCleanse are not significantly different from those of untreated controls. Clinical Relevance This laboratory study compares the biomechanical properties of chemically treated allografts, which are currently being used in anterior cruciate ligament reconstruction, with those of nontreated fresh‐frozen allografts.

Abstract High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

Cerebral white matter hyperintensities on brain MRI (leukoaraiosis) are associated with increased risk of stroke and dementia. To assess the relationships of blood pressure level and circadian pattern with leukoaraiosis, we obtained 24-hour ambulatory blood pressure recordings and brain magnetic resonance images in 343 white and 267 black adults who were members of sibships that had ≥2 siblings with essential hypertension. In multiple linear regression models, factors associated with greater leukoaraiosis in both racial groups included age ( P ≤0.002), homocysteine levels ( P ≤0.006), and brain volume ( P ≤0.008). In blacks, ambulatory blood pressure measures associated with greater leukoaraiosis were higher awake, asleep, and 24-hour systolic and diastolic levels ( P ≤0.009 for each). In addition, there was a trend for smaller nocturnal declines in systolic and diastolic levels (ie, nondipping patterns) to be associated with greater leukoaraiosis, and all of these associations, except nondipping of diastolic level, remained or became significant after controlling for office blood pressure ( P <0.05 for each). In whites, among ambulatory blood pressure measures, only higher asleep diastolic levels trended toward association with greater leukoaraiosis. However, similar to findings in blacks, nondipping of systolic and diastolic ambulatory blood pressure levels were each associated with greater leukoaraiosis ( P ≤0.008), and all of these associations remained or became significant after controlling for office blood pressure ( P ≤0.009 for each). Higher ambulatory blood pressure levels and a nondipping circadian pattern contribute to greater leukoaraiosis volume after controlling for office blood pressure.

Background— Mechanisms purported to contribute to the pathophysiology of heart failure with normal ejection fraction (HFnlEF) include diastolic dysfunction, vascular and left ventricular systolic stiffening, and volume expansion. We characterized left ventricular volume, effective arterial elastance, left ventricular end-systolic elastance, and left ventricular diastolic elastance and relaxation noninvasively in consecutive HFnlEF patients and appropriate controls in the community. Methods and Results— Olmsted County (Minn) residents without cardiovascular disease (n=617), with hypertension but no heart failure (n=719), or with HFnlEF (n=244) were prospectively enrolled. End-diastolic volume index was determined by echo Doppler. End-systolic elastance was determined using blood pressure, stroke volume, ejection fraction, timing intervals, and estimated normalized ventricular elastance at end diastole. Tissue Doppler e′ velocity was used to estimate the time constant of relaxation. End-diastolic volume (EDV) and Doppler-derived end-diastolic pressure (EDP) were used to derive the diastolic curve fitting (α) and stiffness (β) constants (EDP=αEDV β ). Comparisons were adjusted for age, sex, and body size. HFnlEF patients had more severe renal dysfunction, yet smaller end-diastolic volume index and cardiac output and increased EDP compared with both hypertensive and healthy controls. Arterial elastance and ventricular end-systolic elastance were similarly increased in hypertensive controls and HFnlEF patients compared with healthy controls. In contrast, HFnlEF patients had more impaired relaxation and increased diastolic stiffness compared with either control group. Conclusions— From these cross-sectional observations, we speculate that the progression of diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease.

Caveolar endocytosis is an important mechanism for the uptake of certain pathogens and toxins and also plays a role in the internalization of some plasma membrane (PM) lipids and proteins. However, the regulation of caveolar endocytosis is not well understood. We previously demonstrated that caveolar endocytosis and β1-integrin signaling are stimulated by exogenous glycosphingolipids (GSLs). In this study, we show that a synthetic GSL with nonnatural stereochemistry, β-d-lactosyl-N-octanoyl-l-threo-sphingosine, (1) selectively inhibits caveolar endocytosis and SV40 virus infection, (2) blocks the clustering of lipids and proteins into GSLs and cholesterol-enriched microdomains (rafts) at the PM, and (3) inhibits β1-integrin activation and downstream signaling. Finally, we show that small interfering RNA knockdown of β1 integrin in human skin fibroblasts blocks caveolar endocytosis and the stimulation of signaling by a GSL with natural stereochemistry. These experiments identify a new compound that can interfere with biological processes by inhibiting microdomain formation and also identify β1 integrin as a potential mediator of signaling by GSLs.

Background— Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored. Methods and Results— We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even >1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81; P =0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02; P =0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted P <0.001 for trend) and new diabetes (adjusted P <0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes. Conclusions— In stable coronary artery disease, an elevated hs-CRP level, even >1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition.

Abstract Rationale Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution. Objectives We sought to identify genes associated with CT scan distribution of emphysema in individuals without α1-antitrypsin deficiency but with severe COPD. Methods We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution. Measurements and Main Results Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of −950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005). Conclusions Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.