Publications

Functional characterization of noncoding sequences is crucial for understanding the human genome and learning how genetic variation contributes to disease. 3' untranslated regions (UTRs) are an important class of noncoding sequences, but their functions remain largely uncharacterized. We developed a method for massively parallel functional annotation of sequences from 3' UTRs (fast-UTR) and used this approach to measure the effects of a total of >450 kilobases of 3' UTR sequences from >2,000 human genes on steady-state mRNA abundance, mRNA stability and protein production. We found widespread regulatory effects on mRNA that were coupled to effects on mRNA stability and protein production. Furthermore, we discovered 87 novel cis-regulatory elements and measured the effects of genetic variation within known and novel 3' UTR motifs. This work shows how massively parallel approaches can improve the functional annotation of noncoding sequences, advance our understanding of cis-regulatory mechanisms and quantify the effects of human genetic variation.

PURPOSE

We identified rates of and risk factors for complications after colpocleisis using the American College of Surgeons NSQIP® database.

MATERIALS AND METHODS

Women treated with Le Fort colpocleisis from 2005 to 2011 were identified in the database. Primary outcomes were 30-day complication rates. Secondary outcomes were risk factors for complications and the impact of age and a concomitant sling on morbidity. Clinical and procedural characteristics were compared using the chi-square test and 1-way ANOVA.

RESULTS

We identified 283 women, of whom 23 (8.1%) experienced complications. The most common complication was urinary tract infection in 18 women (6.4%). There was 1 death for a 0.4% mortality rate. Increased complications were associated with age less than 75 years (p = 0.03), chronic obstructive pulmonary disease (p = 0.03), hemiplegia (p = 0.03), disseminated cancer (p = 0.03) and open wound infection (p = 0.02). Six patients (2.1%) required return to the operating room within 30 days. Complication rates did not differ based on operative time (p = 0.78), inpatient status (p = 0.24), resident involvement (p = 0.35), concomitant sling placement (p = 0.81) or anesthesia type (p = 0.27). Women undergoing colpocleisis without (191) and with (92) a sling had similar baseline characteristics. Colpocleisis without and with a sling had similar rates of complications (7.9% vs 8.7%, p = 0.81), urinary tract infection (5.8% vs 7.6%, p = 0.55), return to the operating room (2.1% vs 2.2%, p = 0.97) and mortality (0% vs 1.1%, p = 0.15).

CONCLUSIONS

Mortality and complication rates after colpocleisis are low with urinary tract infection being the most common postoperative complication. Concomitant sling placement does not increase 30-day complication rates.

BACKGROUND

Fulminant myocarditis (FM) is often a self-resolving entity if the patient survives the acute illness. Venoarterial extracorporeal membrane oxygenation (ECMO) has been used successfully for treatment of cardiogenic shock or cardiac arrest due to FM. However, clinical outcomes are not well understood, in part because of small study sizes. In the absence of large clinical trials, performance of pooled analysis represents the best method for ascertaining survival rates for ECMO.

METHODS

A systematic Medline search was conducted on ECMO for the treatment of FM, updated up to November 2012. Studies with n ≥10 published in the year 2000 or later that reported survival to hospital discharge for FM requiring ECMO were included. Studies that reported only on pediatric patients were excluded. The smaller of studies with overlapping patients were excluded. Cochran Q and I(2) were calculated and reported.

RESULTS

Six studies were included in the analysis, encompassing 170 patients. The minimum and maximum reported rates of survival to hospital discharge were 60.0% and 87.5%, respectively. The cumulative rate was 115/170. The calculated Cochran Q value was 3.63, which was not significant for heterogeneity. The I(2) value was 0%. The pooled estimate rate was 66.9% with a 95% confidence interval of 59.4%-73.7%.

CONCLUSION

More than two-thirds of patients with FM and either cardiogenic shock and/or cardiac arrest survive to hospital discharge with ECMO. These findings could be used in the risk-benefit analysis when initiation of a cardiopulmonary bypass system is being considered for FM.

While raised levels of monocyte chemoattractant protein 1 (MCP-1) have been observed in patients with chronic muscle pain, direct evidence for its role as an algogen in skeletal muscle is still lacking. In the rat, MCP-1 induces a dose-dependent mechanical hyperalgesia lasting for up to 6weeks. Following recovery, rats exhibited a markedly prolonged hyperalgesia to an intramuscular injection of prostaglandin E2, hyperalgesic priming. Intrathecal pretreatment with isolectin B4 (IB4)-saporin, which selectively destroys IB4-positive (IB4+) nociceptors, markedly decreased MCP-1-induced hyperalgesia and prevented the subsequent development of priming. To evaluate the involvement of MCP-1 in stress-induced chronic pain we administered, intrathecally, antisense (AS) or mismatch oligodeoxynucleotides directed against CCR2 (the canonical receptor for MCP-1) mRNA, during the exposure to water-avoidance stress, a model of stress-induced persistent muscle pain. The AS treatment attenuated this hyperalgesia, whereas IB4-saporin abolished water-avoidance stress-induced muscle hyperalgesia and prevented stress-induced hyperalgesic priming. These results indicate that MCP-1 induces persistent muscle hyperalgesia and a state of latent chronic sensitization to other algogens, by action on its cognate receptor on IB4+ nociceptors. Because MCP-1 also contributes to stress-induced widespread chronic muscle pain, it should be considered as a player in chronic musculoskeletal pain syndromes.