Recent Publications by CFE Educators

Neuroserpin is a regulator of neuronal growth and plasticity. Like other members of the serpin family, neuroserpin undergoes a large conformational change as part of its function. Unlike other serpins such as α(1)-antitrypsin, wild-type neuroserpin will polymerize under near-physiological conditions, and will spontaneously transition to the latent state. To probe the origins of this conformational lability, we have performed hydrogen exchange measurements and molecular-dynamics simulations on human neuroserpin. Hydrogen exchange indicates that neuroserpin has greater flexibility in the breach region and in β-strand 1C compared with α(1)-antitrypsin. Molecular-dynamics simulations show that the distance between the top of β-strands 3 and 5A averages 4.6 Å but becomes as large as 7.5 Å in neuroserpin while it remains stable at ∼3.5 Å in α(1)-antitrypsin. Further simulations show that the stabilizing S340A mutation suppresses these fluctuations in neuroserpin. The first principal component calculated from the simulations shows a movement of helix F away from the face of β-sheet A in neuroserpin while no such movement is evident in α(1)-antitrypsin. The increased mobility of these regions in neuroserpin relative to α(1)-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.

Progesterone receptor (PR) is strongly associated with disease prognosis and therapeutic efficacy in hormone-related diseases such as endometriosis and breast, ovarian, and uterine cancers. Receptor status is currently determined by immunohistochemistry assays. However, noninvasive PR imaging agents could improve disease detection and help elucidate pathological molecular pathways, leading to new therapies and animal disease models. A series of water-soluble PR-targeted magnetic resonance imaging (MRI) probes were synthesized using Cu(I)-catalyzed click chemistry and evaluated in vitro and in vivo. These agents demonstrated activation of PR in vitro and preferential accumulation in PR(+) compared to PR(-) human breast cancer cells with low toxicity. In xenograft tumor models, the agents demonstrated enhanced signal intensity in PR(+) tumors compared to PR(-) tumors. The results suggest that these agents may be promising MRI probes for PR(+) diseases.

CONTEXT

The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury.

OBJECTIVE

To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28.

DESIGN, SETTING, AND PARTICIPANTS

The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up.

INTERVENTIONS

Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement.

MAIN OUTCOME MEASURE

Ventilator-free days to study day 28.

RESULTS

The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001).

CONCLUSIONS

Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT00609180.

BACKGROUND AND STUDY AIMS

In routine practice, colonoscopy may fail to prevent colorectal cancer (CRC), especially in the proximal colon. A better endoscopic recognition of serrated polyps is important, as this pathway may explain some of the post-colonoscopy cancers. In this study, the endoscopic characteristics of serrated polyps were examined.

PATIENT AND METHODS

This was a cross-sectional, single-center study of all consecutive patients referred for elective colonoscopy during 1 year. The endoscopists were familiarized with the detection and treatment of nonpolypoid colorectal lesions. Serrated polyps were classified into high risk serrated polyps, defined as dysplastic or large (≥ 6 mm) proximal nondysplastic serrated polyps, and low risk serrated polyps including the remaining nondysplastic serrated polyps. Advanced colorectal neoplasms were defined as multiple (at least three),≥ 10 mm in size, high grade dysplastic adenomas or CRC.

RESULTS

A total of 2309 patients were included (46.1 % men, mean age 58.4 years), of whom 2.5 % (57) had at least one high risk serrated polyp and 13.9 % (322) had at least one advanced neoplasm. Overall, serrated polyps were more often nonpolypoid than adenomas (16.2 % vs. 11.1 %; P = 0.002). In total, 65 high risk serrated polyps were found, of which 43.1 % (28) displayed a nonpolypoid endoscopic appearance. Patients with advanced neoplasms were more likely to have synchronous high risk serrated polyps than patients without advanced neoplasms: OR 3.66 (95 % CI 2.03 - 6.61, P 0.001).

CONCLUSIONS

High risk serrated polyps are frequently nonpolypoid and are associated with synchronous advanced colorectal neoplasms. Advanced colorectal neoplasms may therefore be considered red flags for the presence of high risk serrated polyps. Detection, diagnosis, and treatment of high risk serrated lesions may be important targets to improve the quality of colonoscopic cancer prevention.

Urticaria affects nearly 25% of the population at some time in their lives. In a subset of children, urticaria will develop into a chronic condition that can greatly affect quality of life. Although numerous causes and triggers are proposed for chronic urticaria (CU) in children, ranging from infections, allergens, and medications to physical factors and autoimmune disease, the exact etiology is not always identifiable. Accordingly, a large subset of cases are designated "chronic idiopathic urticaria." Because of the clinical complexities of CU, as well as the confusing literature on this topic, we have developed a conceptual framework based on the cumulative evidence to assist with the categorization, clinical evaluation, and treatment of CU in children.

BACKGROUND AND AIMS

Current efforts to prevent colorectal cancer focus on the detection and removal of neoplasms. Nonpolypoid colorectal neoplasms (NP-CRN) have a subtle appearance that can be difficult to recognize during colonoscopy. Endoscopists must first be familiar with the patterns of NP-CRN in order to detect and diagnose them. We studied the adenoma detection rates of endoscopists who had trained to detect NP-CRN, versus endoscopists who had not.

DESIGN

Retrospective Nested Case Control Study.

SETTING

Outpatient Screening Colonoscopy.

PARTICIPANTS

Adult Veterans.

INTERVENTION

Proficiency in the features and diagnosis of NP-CRN.

MAIN OUTCOMES MEASUREMENTS

Adenoma detection.

RESULTS

In total, 462 patients had screening colonoscopies-267 by colonoscopists who had trained in the features and diagnosis of NP-CRN. Patient characteristics were similar between groups-the majority were men with a mean age of 62 ± 6 years. Neoplasia was more prevalent (45.7 vs. 34.9%; p = 0.02) in patients evaluated by the trained compared to the conventionally trained group. Trained colonoscopists had a higher adenoma detection rate (0.76 vs. 0.54 adenomas per patient, p 0.001); removed a higher proportion of neoplasia (77 vs. 35%, p 0.001); and more frequently diagnosed NP-CRN lesions (OR 2.98, 95% CI: 1.46-6.08) compared to colonoscopists without supplemental training.

CONCLUSIONS

Endoscopists who are proficient in the detection of NP-CRN had significantly higher adenoma detection rates-of both polypoid and flat adenomas-compared to endoscopists without training, and were more specific in resection of adenomatous over hyperplastic lesions.

OBJECTIVE

To investigate the relationship of lower urinary tract symptoms (LUTS) to urinary tract infection, prostatitis, sexually transmitted infection, lifetime sexual partner count, and recreational drug use in a population of men who have sex with men. LUTS in men are a source of considerable morbidity, distress, and medical expense.

METHODS

We conducted a cross-sectional, Internet-based survey of urinary quality-of-life outcomes in men who have sex with men. The main outcome was the International Prostate Symptom Score (IPSS), classified as none/mild (IPSS 0-7), moderate/severe (IPSS 8-35), or severe (IPSS 20-35). The participants were also asked whether they ever sought medical attention for urinary problems.

RESULTS

The survey web site was accessed by 2783 men, of whom 2348 (84.3%) completed the questionnaire. The median age was 39 years (range 18-81). Age, depression, human immunodeficiency virus infection, gonorrhea, syphilis, prostatitis, and prescription drug abuse were all associated with LUTS. Men who sought medical attention for LUTS were more likely to report older age, diabetes, depression, gonorrhea, urinary tract infection history, and prostatitis.

CONCLUSION

Specific infectious conditions of the urinary tract and depressive symptoms are independent predictors of LUTS in men who have sex with men. Although LUTS are often multifactorial, a common unifying explanation for our finding could be the effects of local and systemic inflammation on the lower urinary tract.