Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase.

Checkpoints maintain the order of cell cycle events during DNA damage or incomplete replication. How the checkpoint response is tailored to different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in budding yeast occurs by Rad53-dependent inhibition of the initiation factors Sld3 and Dbf4. Despite this, we show here that Rad53 phosphorylates both of these substrates throughout the cell cycle at the same sites as in S-phase, suggesting roles for this pathway beyond S-phase. Indeed, we show that Rad53-dependent inhibition of Sld3 and Dbf4 limits re-replication in G2/M, preventing gene amplification. In addition, we show that inhibition of Sld3 and Dbf4 in G1 prevents premature initiation at all origins at the G1/S transition. This study redefines the scope of the 'S-phase checkpoint' with implications for understanding checkpoint function in cancers that lack cell cycle controls.

Cardiovascular medication errors in children.

OBJECTIVES: We sought to describe pediatric cardiovascular medication errors and to determine patients and medications with more-frequently reported and/or more-harmful errors. METHODS: We analyzed cardiovascular medication error reports from 2003-2004 for patients <18 years of age, from the US Pharmacopeia MEDMARX database. Reports were stratified according to harm score (A, near miss; B-D, error, no harm; E-I, harmful error). Proportions of harmful reports were determined according to drug class and age group. "High-risk" drugs were defined as antiarrhythmics, antihypertensives, digoxin, and calcium channel blockers. RESULTS: A total of 147 facilities submitted 821 reports with community hospitals predominating (70%). Mean patient age was 4 years (median: 0.9 years). The most common error locations were NICUs, general care units, PICUs, pediatric units, and inpatient pharmacies. Drug administration, particularly improper dosing, was implicated most commonly. Severity analysis showed 5% "near misses," 91% errors without harm, and 4% harmful errors, with no reported fatalities. A total of 893 medications were cited in 821 reports. Diuretics were cited most frequently, followed by antihypertensives, angiotensin inhibitors, beta-adrenergic receptor blockers, digoxin, and calcium channel blockers. Calcium channel blockers, phosphodiesterase inhibitors, antiarrhythmics, and digoxin had the largest proportions of harmful events, although the values were not statistically significantly different from those for other drug classes. Infants <1 year of age accounted for 50% of reports. Proportions of harmful events did not differ according to age. CONCLUSIONS: Infants <1 year of age were most frequently reported in cardiovascular medication errors reaching inpatients, in a national, voluntary, error-reporting database. Proportions of harmful errors were not significantly different by age or cardiovascular medication. Most errors were related to medication administration, largely due to improper dosing.

Laser recanalization of the subclavian vein.

We report the use of a long wire and introducer as a rail for the laser recanalization of a chronically occluded subclavian vein following extraction of a fractured permanent pacing lead. This allowed new pacing leads to be placed through the previously occluded vessel.