Mec1 Is Activated at the Onset of Normal S Phase by Low-dNTP Pools Impeding DNA Replication.

The Mec1 and Rad53 kinases play a central role during acute replication stress in budding yeast. They are also essential for viability in normal growth conditions, but the signal that activates the Mec1-Rad53 pathway in the absence of exogenous insults is currently unknown. Here, we show that this pathway is active at the onset of normal S phase because deoxyribonucleotide triphosphate (dNTP) levels present in G1 phase may not be sufficient to support processive DNA synthesis and impede DNA replication. This activation can be suppressed experimentally by increasing dNTP levels in G1 phase. Moreover, we show that unchallenged cells entering S phase in the absence of Rad53 undergo irreversible fork collapse and mitotic catastrophe. Together, these data indicate that cells use suboptimal dNTP pools to detect the onset of DNA replication and activate the Mec1-Rad53 pathway, which in turn maintains functional forks and triggers dNTP synthesis, allowing the completion of DNA replication.

Infectious complications of intrathecal baclofen pump devices in a pediatric population.

BACKGROUND: Intrathecal baclofen (ITB) is an effective therapy for spasticity and dystonia in pediatric populations; however, there are associated infectious complications. METHODS: Patients who had an initial ITB device implanted at our center were followed to determine the proportion of patients with infectious and noninfectious complications, identify risk factors for infection and describe the clinical presentations, treatment and outcomes of infectious complications. RESULTS: Over the 15-year study period, 139 patients had an initial ITB device placed. The mean age at placement was 13.6 years (range: 6 months to 41 years). In the first year of follow-up, 83% had no complications or secondary procedures, 17% had at least 1 secondary procedure and 5% had an infectious complication. The median time until infection was 14 days (mean 33 ± 42 days). Patients with secondary spasticity or dystonia were more likely to have infections than patients with cerebral palsy (86% versus 14%; P < 0.0001). In the 94 patients with a first secondary procedure, 29% had at least 1 other procedure and 8% had an infection in the 1 year follow-up. Overall, 24 patients had 27 infections; 22% superficial, 33% deep and 45% organ space. Staphylococcus aureus was isolated in 50% of those with cultures obtained. Explantation was required in 59% of patients with an infection and differed by infection type: superficial (17%), deep (44%) and organ space (92%) (P = 0.004). CONCLUSIONS: Infectious complications were relatively uncommon; however, when present, frequently led to the explantation of the ITB pump device.