Cyclin-dependent kinases are critical regulators of eukaryotic DNA replication. We show that the S-phase cyclin Clb5 binds stably and directly to the origin recognition complex (ORC). This ...interaction is mediated by an "RXL" target sequence, or "Cy" motif, in the Orc6 subunit that is recognized by the "hydrophobic patch" region on Clb5. The Clb5-Orc6 interaction requires replication initiation, and is maintained throughout the remainder of S phase and into M phase. Eliminating the Clb5-Orc6 interaction has no effect on initiation of replication but instead sensitizes cells to lethal overreplication. We propose that Clb5 binding to ORC provides an origin-localized replication control switch that specifically prevents reinitiation at replicated origins.
Background Porcine bioprosthesis (bioroots) are an attractive surgical strategy for ascending aorta and arch replacement. This study evaluated the perioperative and late outcomes using this strategy ...for proximal aortic aneurysmal disease. Methods Between March 1998 and November 2009, 170 patients (40% women; median age, 70 years) underwent proximal thoracic aortic replacement using the Freestyle (Medtronics Inc, Minneapolis, MN) bioroot, with graft extension in 149 (87.6%). Aneurysmal etiology included degenerative-atherosclerotic (91.2%), acute dissection (5.3%), and chronic dissection (3.5%); 78% had greater than moderate aortic insufficiency. Surgical procedures were bioroot alone or with aortoplasty (12.3%), bioroot with ascending aortic graft (38.2%), bioroot with hemiarch graft (44.1%), and bioroot with total arch (5.3%). Hypothermic circulatory arrest was required in 49%. Results The 30-day mortality was 4.7% (n = 8). The overall complication rate was 58% (n = 100), including stroke (6.5%), renal failure (9.2%), respiratory failure (25.9%), and postoperative bleeding (7.6%). Mean hospitalization was 10.5 ± 7.3 days; 38 were discharged to a rehabilitation facility (23.5%). Predictors of 30-day/hospital death were coronary artery disease ( p = 0.0003), renal insufficiency ( p < 0.0001), emergent/urgent procedure ( p = 0.02), and hypothermic circulatory arrest ( p = 0.002). The 1-year, 5-year, and 10-year survivals were 90%, 80%, and 35% respectively. Freedom from endocarditis and reoperation was 96% at 1 year and 94% and 95% at 5 years, respectively. Conclusions Proximal thoracic aortic replacement using a porcine bioroot as part of the repair can be achieved with low perioperative mortality and acceptable late survival in a predominantly elderly population.
Category:
Pain Management, Anesthetic Advances
Introduction/Purpose:
The number of opioid prescriptions in the United States has significantly increased over the past 20 years, including those given ...after low-risk surgery. Unintentional opioid overdoses have also dramatically risen. Excess pills are widely acknowledged as a source of diversion, which accounts for up to 40% of opioid-related overdoses. In the foot and ankle literature, there are no studies looking at the quantity of pain medications that should be prescribed following outpatient surgery. Furthermore, with the increasing use of peripheral nerve blocks, their effect on quantities of narcotics needed after these surgeries have not been explored. This study aims to determine prescribing patterns for common outpatient foot and ankle surgery and whether patients are over or under-prescribed opioids and if so, by how much.
Methods:
57 patients undergoing outpatient foot and ankle surgeries were prospectively enrolled. Patients received a spinal neuraxial block and a long-acting popliteal peripheral nerve block, and did not receive ketorolac perioperatively. Patients were excluded if they had a history of chronic pain, or were currently using opioids or muscle relaxers. Enrolled patients received a standard post-operative prescription regimen of 60 tablets of narcotics, 3 days of scheduled ibuprofen, aspirin 81 mg twice a day (or alternate based on risk factors) for DVT prophylaxis, and ondansetron taken as needed. Patients used a pain diary to record when their block wore off and the quantity of narcotic taken. They received surveys at post-operative day (POD) 3, 7, and 14 detailing how many days they took the medication and how many pills were consumed, how their actual pain compared to their expected level of pain, and if they were satisfied with their pain control.
Results:
At POD 3, compared to their expected level of pain 36 patients had less pain, 15 had the same pain, and 3 had more pain than expected. The mean pain score was 4. Patients first started feeling the block wear off at 0.9 days. Patients averaged 10.3 pills of narcotics in the first 3 days and rated their overall satisfaction with pain control at 8.5. Between days 4-7, patients took an average of 7 pills, and on POD 7, 22 patients were still taking narcotics. At POD 14, patients experienced 74.4% relief of pain compared to their expected pain, and rated their overall satisfaction at 8.2. Patients had an average of 33.5 remaining pills on POD 14 and 13 patients (22.8%) were still taking narcotics.
Conclusion:
Patients receiving spinal and long-acting popliteal blocks, followed by the prescription regimen described above had excellent pain control after outpatient foot and ankle surgeries. Patients had a high level of satisfaction with their pain control, with many patients describing better pain relief than expected. However, 60 tablets of narcotics were excessive in most cases. We suggest that in patients receiving spinal and long-acting popliteal blocks, 30 tablets of a narcotic would cover the pain needs of most patients. This would provide a small excess in case of need, but would help minimize the risk of narcotic related complications and diversion.
The efflux pump P-glycoprotein (ATP-binding cassette B1, multidrug resistance MDR 1, P-gp) has long been known to contribute to MDR against cancer chemotherapeutics. We describe the development of a ...dual-fluorescent cell line system to allow multiplexing of drug-sensitive and P-gp-mediated MDR cell lines. The parental OVCAR-8 human ovarian carcinoma cell line and the isogenic MDR NCI/ADR-RES subline, which stably expresses high levels of endogenous P-gp, were transfected to express the fluorescent proteins Discosoma sp. red fluorescent protein DsRed2 and enhanced green fluorescent protein, respectively. Co-culture conditions were defined, and fluorescent barcoding of each cell line allowed for the direct, simultaneous comparison of resistance to cytotoxic compounds in sensitive and MDR cell lines. We show that this assay system retains the phenotypes of the original lines and is suitable for multiplexing using confocal microscopy, flow cytometry, or laser scanning microplate cytometry in 1,536-well plates, enabling the high-throughput screening of large chemical libraries.
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