The role of APC/C(Cdh1) in replication stress and origin of genomic instability.

It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

Postural post-dural puncture headache. A prospective randomised study and a meta-analysis comparing two different 0.40 mm O.D. (27 g) spinal needles.

BACKGROUND: To compare the incidence of postural post-dural puncture headache (PPDPH) after spinal anaesthesia using two different 0.40 mm O.D. (27 g) spinal needles: pencil-point needle and Quincke needle. In addition, a meta-analysis of studies comparing small bore spinal needles with regard to development of PPDPH was performed. METHODS: Clinical study: A prospective randomised double-blind study was set up to investigate PPDPH after using 0.40 mm pencil-point (Pencan, B. Braun) or Quincke (Spinocan, B. Braun) spinal needle. Postoperatively on day 5 to 7 a telephone interview was conducted in order to reveal postoperative complications such as headache and backache. PPDPH was considered present when the headache was new to the patient, and demonstrated posture dependence. Meta-analysis: Electronic database search and manual search of relevant literature were performed in order to find randomised control trials comparing equal sized (outer diameter, O.D.) spinal needles with different bevel shape. Only studies with a proper method and not merely presented as an abstract were included in addition to the present clinical study. RESULTS: Out of 313 patients randomised, 301 were completely followed up, 153 in the pencil-point group and 148 in the Quincke group. The two groups were comparable regarding surgical procedures and demographic data. Of 15 patients suffering from PPDPH, 12 were found in the Quincke group, and 3 in the pencil-point group. The difference was 6.1% (95% CI from 1.2 to 12.5%). The meta-analysis of 1131 patients gave a relative risk of developing PPDPH of 0.38 (95% CI from 0.19 to 0.75) in the pencil-point group compared to the Quincke group. CONCLUSION: A pencil-point-shaped spinal needle will significantly reduce PPDPH compared with Quincke-type spinal needles, also when small bore needles (0.40 mm O.D.) are used.

Postural post-dural puncture headache after spinal and epidural anaesthesia. A randomised, double-blind study.

BACKGROUND: This study was conducted in order to investigate the effect of patient expectation in the development of postural post-dural puncture headache (PPDPH). METHODS: 224 patients less than 55 years scheduled for minor non-obstetric surgery were randomised to receive single-injection spinal (SA) or epidural (EA) anaesthesia. A 27-g Quinke needle was used for SA and a 18-g Tuohy needle for EA. Patients, operating team and postoperative ward personnel were all blinded to the anaesthetic given and so was an independent observer responsible for follow-up after 5-7 days. The occurrence of headache, backache and other complaints was recorded. Headache was classified as PPDPH or non-PPDPH, and duration and intensity of the headache was registered. The quality of anaesthesia was directly evaluated by the surgeon using a VAS scale from 1 (excellent) to 10 (very poor) and indirectly by the supplemental use of opioid analgesia and general anaesthesia in the two groups. RESULTS: 212 patients, 103 SA and 109 EA, with a mean age of 36.7 years, could be fully evaluated. The groups were comparable with regards to age, sex and surgical procedure performed. Headache occurred in 44 patients postoperatively. PPDPH was diagnosed in 16 patients (15.5%) in the SA group and 2 (1.8%) in the EA group (P = 0.0014). Non-PPDPH occurred in 13 patients in each group. PPDPH had significantly greater mean intensity and duration than non-PPHPH. More patients in the EA group had postoperative backache (31.2%) than in the SA group (22.3%), but this difference was not statistically significant. More patients in the EA received general anaesthesia and opioid analgesia than in the SA group, and the surgeon's rating was on average 1.3 in the SA group compared to 2.5 in the EA group (P = 0.0003). CONCLUSIONS: SA gave more headache but superior quality of surgical anaesthesia compared with EA. Dural puncture, and not expectation, is the major cause of PPDPH.