Citations

Background —Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1α and ECE-1β), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation. Methods and Results —Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I–treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1α and ECE-1β immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8±0.6 versus 8.4±1.2 pmol/mL, P <0.05), ECE-1 activity was attenuated (68±3% versus 32±8%, P <0.05), aortic tissue ET-1 concentrations were reduced (4.6±0.5 versus 3.2±0.3 pg/mg protein, P <0.05), and atheroma formation was attenuated (62±6% versus 34±5%, P <0.01) by NEP-I. Conclusions —These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

Abstract Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%–49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking. Cancer Epidemiol Biomarkers Prev; 21(6); 988–92. ©2012 AACR.

Abstract Background: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. Methods: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. Results: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001). Conclusions: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. Impact: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules. Cancer Epidemiol Biomarkers Prev; 21(5); 786–92. ©2012 AACR.

SummaryBackgroundPast studies with ulcerative colitis (UC) patients indicate that disease activity strongly predicts health‐related quality of life (HRQL).AimTo examine the degree to which daily treatment with MMX mesalazine predicts improved HRQL for patients with active UC and with stable HRQL for patients with quiescent UC.MethodsData from two phases of a multicentre open‐label trial were examined. In the acute phase, 132 patients with mild‐to‐moderate active UC received MMX mesalazine 2.4–4.8 g/day for 8 weeks, while 206 patients with quiescent UC received MMX mesalazine 2.4 g/day for a 12‐month maintenance phase. Disease‐specific HRQL was measured at baseline and endpoint of each phase using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Repeated‐measures anova models examined baseline‐endpoint changes in SIBDQ, stool frequency (SF), and rectal bleeding severity (RBS). Correlations assessed the associations between SIBDQ and SF/RBS scores, while ancova techniques tested the sensitivity of SIBDQ to disease recurrence.ResultsSIBDQ scores significantly increased for active mild‐to‐moderate UC patients following 8 weeks of treatment, while SIBDQ scores remained stable for quiescent UC patients following 12 months of treatment. Changes in SIBDQ scores correlated significantly with changes in SF and RBS scores. Patients with recurrent UC at maintenance phase endpoint had significantly lower SIBDQ scores than nonrecurrent patients.ConclusionsDaily MMX mesalazine therapy was associated with significant improvement in disease‐specific HRQL for patients with mild‐to‐moderate active UC and with the maintenance of HRQL for patients with quiescent UC. In both patient groups, HRQL was significantly associated with disease activity.

ABSTRACTThe Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry (MS) instruments were evaluated for the identification of nonfermenting Gram-negative bacilli (NFGNB) by a blinded comparison to conventional biochemical or molecular methods. Two hundred NFGNB that were recovered from cultures from cystic fibrosis patients in the University of Iowa Health Care (UIHC) Microbiology Laboratory between 1 January 2006 and 31 October 2010 were sent to Mayo Clinic for analysis with the Bruker Biotyper (software version 3.0) and to bioMérieux for testing with Vitek MS (SARAMIS database version 3.62). If two attempts at direct colony testing failed to provide an acceptable MALDI-TOF identification, an extraction procedure was performed. The MS identifications from both of these systems were provided to UIHC for comparison to the biochemical or molecular identification that had been reported in the patient record. Isolates with discordant results were analyzed by 16S rRNA gene sequencing at UIHC. After discrepancy testing, the Bruker Biotyper result agreed with the biochemical or molecular method, with 72.5% of isolates to the species level, 5.5% to the complex level, and 19% to the genus level (3% not identified). The level of agreement for Vitek MS was 80% species, 3.5% complex, 6% genus, and 3.5% family (7% not identified). Both MS systems provided rapid (≤3 min per isolate) and reliable identifications. The agreement of combined species/complex/genus-level identification with the reference method was higher for the Bruker Biotyper (97% versus 89.5%,P= 0.004) but required an extraction step more often. Species-level agreement with the reference method was similar for both MS systems (72.5% and 80%,P= 0.099).

Background: Fresh-stored osteochondral allografts have been used successfully to resurface large chondral and osteochondral defects of the knee. However, there are limited data available for the return to athletic activity. Purpose: To review the rate of return to athletic activity after osteochondral allograft transplantation in the knee and to identify any potential risk factors for not returning to sport. Study Design: Case series; Level of evidence, 4. Methods: Forty-three athletes were treated with fresh-stored osteochondral allograft transplantation for symptomatic large chondral or osteochondral defects of the knee from 2000 to 2010. The average age of the athletes (30 men, 13 women) was 32.9 years (range, 18-49 years). Patients were prospectively evaluated by International Knee Documentation Committee (IKDC), activities of daily living scale of the Knee Injury and Osteoarthritis Outcome Score (KOOS), Marx Activity Rating Scale, and Cincinnati Sports Activity Scale scores. A multivariable regression analysis was performed to identify potential risk factors for failure to return to sport at the preinjury level. Results: At an average 2.5-year follow-up, limited return to sport was possible in 38 of 43 athletes (88%), with full return to the preinjury level achieved in 34 of 43 athletes (79%). In these 34 athletes, time to return to sport was 9.6 ± 3.0 months. Age ≥25 years ( P = .04) and preoperative duration of symptoms greater than 12 months (odds ratio, 37; P = .003) negatively affected the ability to return to sport. In the athletes who returned to their previous level of competition, IKDC ( P < .001), KOOS ( P = .02), and Marx Activity Rating Scale ( P < .001) scores were all significantly greater than in those athletes who did not return to sport. Conclusion: Osteochondral allograft transplantation in an athletic population for chondral and osteochondral defects in the knee allows for a high rate of return to sport. Risk factors for not returning to sport included age ≥25 years and preoperative duration of symptoms ≥12 months.

Background: Many researchers have previously explored the correlation between surgical flow disruptions (distractions and interruptions) and error in cardiac surgery, however there is no reliable tool to prospectively categorize surgical flow disruptions and the conditions that predispose a surgical team to error. Methods and Results: Two independent raters of different medical and human factors expertise observed 12 cardiovascular operations and iteratively designed a tool to characterize surgical flow disruptions and the latent factors that contribute to error. Categories to characterize surgical flow disruptions were based on human factors models of human error. Following the design period, both raters observed 10 surgical cases using the tool, to assess validity and inter-rater reliability. Rating agreement (weighted kappa) for each category across the 10 surgeries was moderate to very high, resulting in strong inter-rater reliability for each category on the surgical flow disruption tool (SFDT). Conclusions: This research depicts the development and utility of a tool to analyze surgical flow disruptions in the cardiovascular operating room with satisfactory inter-rater reliability. This tool is an important first step in systematically categorizing and measuring surgical flow disruptions and their impact on patient safety in the operating room.