Citations

AbstractThe AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)

Previous results following subfascial endoscopic perforator vein surgery were reported to be worse in post-thrombotic syndrome than in limbs with primary valvular incompetence. This report comprises a larger patient cohort with longer follow-up. The goal of this study was to determine if subfascial endoscopic perforator vein surgery is justified in patients with postthrombotic venous insufficiency. The clinical data of 91 consecutive patients who underwent subfascial endoscopic perforator vein surgery with or without superficial reflux ablation over a 7-year period from May 1993 to June 2000 were retrospectively analyzed. Fifty-four females and 37 males (median age, 53 years; range, 20-77) underwent 103 subfascial endoscopic perforator vein surgery procedures. Forty-two limbs were classified as C6 (active ulcer), 34 as C5 (healed ulcer), and 24 as C4 (lipodermatosclerosis). Thirty procedures were performed in post-thrombotic limbs. Concomitant superficial reflux ablation was performed in 74 limbs (72%); saphenous vein stripping had been previously performed in 29 (28%). Deep venous incompetence was present in 89% of limbs; 13% had venous outflow obstruction on plethysmography. Cumulative ulcer healing in post-thrombotic limbs was not significantly different from limbs with primary valvular incompetence; 30-, 60-, and 90-day healing rates were 44%, 72%, and 72% vs 39%, 70%, and 87%, respectively (p = 0.35). On univariate analysis, the presence of ulcer greater than 2 cm in diameter was associated with delayed ulcer healing (p = 0.02). Cumulative ulcer recurrence in all limbs was 4%, 20%, and 27% at 1, 3, and 5 years, respectively. Ulcer recurrence in post-thrombotic limbs was higher than in limbs with primary valvular incompetence at 1, 3, and 5 years; 16%, 47%, and 56% vs 0%, 8%, and 15%, respectively (p = 0.001). Recurrent ulcers were small, superficial, and easier to heal. Clinical improvement was significant even in post-thrombotic limbs; median clinical score decreased from 9.5 to 3 (p=0.001), and median outcome score was +2 (mean 1.9; range, -I to 3). Median clinical score in patients with primary valvular incompetence improved from 6 to 1.5 (p = 0.0001). Subfascial endoscopic perforator vein surgery with superficial reflux ablation promoted ulcer healing, improved clinical outcome, and resulted in a low long-term ulcer recurrence rate in limbs with primary valvular incompetence. Despite good clinical outcome in post-thrombotic limbs, ulcer recurrence was high. These results imply that the role of subfascial endoscopic perforator vein surgery with superficial reflux ablation in patients with post-thrombotic limbs continues to be controversial.

Background— The long-term natural history of lone atrial fibrillation is unknown. Our objective was to determine the rate and predictors of progression from paroxysmal to permanent atrial fibrillation over 30 years and the long-term risk of heart failure, thromboembolism, and death compared with a control population. Methods and Results— A previously characterized Olmsted County, Minnesota, population with first episode of documented atrial fibrillation between 1950 and 1980 and no concomitant heart disease or hypertension was followed up long term. Of this unique cohort, 76 patients with paroxysmal (n=34), persistent (n=37), or permanent (n=5) lone atrial fibrillation at initial diagnosis met inclusion criteria (mean age at diagnosis, 44.2±11.7 years; male, 78%). Mean duration of follow-up was 25.2±9.5 years. Of 71 patients with paroxysmal or persistent atrial fibrillation, 22 had progression to permanent atrial fibrillation. Overall survival of the 76 patients with lone atrial fibrillation was 92% and 68% at 15 and 30 years, respectively, similar to 86% and 57% survival for the age- and sex-matched Minnesota population. Observed survival free of heart failure was slightly worse than expected ( P =0.051). Risk for stroke or transient ischemic attack was similar to the expected population risk during the initial 25 years of follow-up but increased thereafter ( P =0.004), although CIs were wide. All patients who had a cerebrovascular event had developed ≥1 risk factor for thromboembolism. Conclusions— Comorbidities significantly modulate progression and complications of atrial fibrillation. Age or development of hypertension increases thromboembolic risk.

Background Propofol infusion syndrome is first manifest by unexplained metabolic acidosis. Its incidence is unknown. Methods Charts of all patients undergoing nonsurgical, catheter radiofrequency ablation for atrial flutter or fibrillation from 1999 through 2001 at Mayo Clinic Rochester, who received propofol and had an arterial blood gas drawn during the procedure, were reviewed retrospectively for metabolic acidosis, prospectively defined as base excess -2 or less. Of 301 radiofrequency ablation cases, 55 had an arterial blood gas. Virtually all radiofrequency ablation patients received propofol, so they could not be used as nonpropofol controls. Instead, all carotid endarterectomy patients in 2000 who did not receive propofol and had an arterial blood gas drawn after anesthetic induction and before surgical incision were used as a comparator group. Results In propofol radiofrequency ablation patients with no apparent cause of metabolic acidosis besides propofol, 13 of 55 (24%) had base excess of -2 or less, versus 22 of 267 carotid patients (8.2%) (P<0.01). Maximal negative base excess was -4.2+/-1.7 in these propofol patients and was not correlated with propofol dose, age, or fluid dose, versus base excess of -3.2+/-1.5 in carotid patients (P>0.05). Propofol patients received prolonged anesthetics (7 h) and high-dose propofol (20 mg/kg). Conclusions This is the first incidence estimate of metabolic acidosis during prolonged propofol infusion and suggests that it is not rare. The study is limited by its retrospective nature and by the lack of baseline arterial blood gas data and will require confirmation by prospective study.

Abstract High-risk susceptibility genes explain &lt;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]

Background— Heart failure (HF) is a progressive disorder associated with frequent morbidity and mortality. An American Heart Association/American College of Cardiology staging classification of HF has been developed to emphasize early detection and prevention. The prevalence of HF stages and their association with mortality are unknown. We sought to estimate HF stage prevalence in the community and to measure the association of HF stages with mortality. Methods and Results— A population-based, cross-sectional, random sample of 2029 Olmsted County, Minnesota, residents aged ≥45 years was identified. Participants were classified by medical record review, symptom questionnaire, physical examination, and echocardiogram as follows: stage 0, healthy; stage A, HF risk factors; stage B, asymptomatic cardiac structural or functional abnormalities; stage C, HF symptoms; and stage D, severe HF. In the cohort, 32% were stage 0, 22% stage A, 34% stage B, 12% stage C, and 0.2% stage D. Mean B-type natriuretic peptide concentrations (in pg/mL) increased by stages: stage 0=26, stage A=32, stage B=53, stage C=137, and stage D=353. Survival at 5 years was 99% in stage 0, 97% in stage A, 96% in stage B, 75% in stage C, and 20% in stage D. Conclusions— The present study provides prevalence estimates and prognostic validation for HF staging in a community cohort. Of note, 56% of adults ≥45 years of age were classified as being in stage A (risk factors) or B (asymptomatic ventricular dysfunction). HF staging underscores the magnitude of the population at risk for progression to overt HF.

Objective: The five-factor model of personality was used to describe the correlates of smoking abstinence. Methods: Following treatment in the Mayo Clinic Nicotine Dependence Center, the six month abstinence status was determined by self-report. Sixteen months to 2.4 years following the initial treatment evaluation, and 10 months to 1.9 years after the abstinence status was determined, 475 patients were mailed a Neuroticism, Extraversion, Openness, Five-Factor Inventory questionnaire. Ninety-nine abstinent and 151 smoking patients returned a completed questionnaire. Results: Multivariate analysis showed that low scores on neuroticism and openness were associated with tobacco abstinence. In addition, high scores on neuroticism and low scores on agreeableness and conscientiousness were associated with predictors of poor outcome including greater number of cigarettes smoked per day, initiation of smoking prior to age 18, and a Fagerström Test for Nicotine Dependence score of ≥ 6. Conclusions: Personality characteristics as predictors of smoking abstinence following treatment warrant further investigation in prospective clinical trails. Treatment matching using personality profiling as a guide may be a valuable tool for improving abstinence rates following treatment for nicotine dependence.

Experiments were designed to determine the effects of nicotine treatment on the functions of saphenous veins used for coronary artery bypass grafts in dogs. Dogs received either no treatment or transdermal nicotine for 5 weeks at doses of 11 mg, 22 mg or 44 mg/day. Saphenous veins were removed and suspended for the measurement of isometric force in organ chambers. Endothelium was removed mechanically from some rings. N G -mono-methyl-l-arginine (l-NMMA; 10 - 4 M) was used to inhibit the production of nitric oxide. Contractions to alpha 2 -adrenergic stimulation were decreased in veins from dogs treated with a 22-mg/day dose of transdermal nicotine. In addition, endothelium-dependent relaxations to adenosinediphosphate (10 - 8 -10 - 4 M) and the calcium ionophore A23,187 (10 - 8 -10 - 6 M) were decreased in veins from dogs with a 22-mg/day dose and increased in veins from dogs treated with a 44-mg/day dose. These relaxations were inhibited by l-NMMA. Plasma concentrations of oxidized products of nitric oxide were decreased only in dogs treated with 22 mg/day of nicotine. The relaxation of rings without endothelium (direct response on the smooth muscle) to nitric oxide were not altered by nicotine treatment. These results suggest that the short-term treatment of dogs with intermediate (22 mg/day) but not low (11 mg/day) or high (44 mg/day) doses of transdermal nicotine decreases the endothelial function of veins used for coronary artery bypass grafts. Therefore, changes in plasma products of nitric oxide and endothelium-depen-dent relaxations mediated by nitric oxide are related to the dose of nicotine treatment.