Citations

Abstract Microcephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (γH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH2 terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks. [Cancer Res 2009;69(13):5531–6]

Background: Intravenous sodium bicarbonate (SB) administration during cardiopulmonary arrest (CPA) is intended to counteract lactic acidosis due to hypoxia, poor perfusion, and anaerobic metabolism. Despite a lack of documented efficacy and a level III recommendation from the American Heart Association, SB is widely used during resuscitation events. SB has both theoretical and measurable adverse effects. Excess or poorly timed administration during a CPA may elevate a patient's pH, inducing alkalemia. Despite decades of controversy surrounding use of this drug, the prevalence of SB-induced alkalemia has not been previously documented. Objective: To estimate the prevalence of SB-induced alkalemia in inpatients after CPA and to investigate the pattern of SB administration. Methods: Medical records were retrospectively reviewed with attention to SB administration and arterial blood gas (ABG) data. After application of inclusion and exclusion criteria to 264 CPA patients, the study group comprised 88 patients. When measured, il PCO 2 and pH were above normal limits after SB administration, we concluded that SB contributed to the alkalemia. Results: Twenty-seven (31 %) patients received SB without any ABG data, and 70 (79%) patients received at least one empiric SB dose. Of the 61 patients with ABG data, alkalemia occurred in 10, a prevalence of 16%. Administration of SB increased pH in only 9 (15%) other CPA patients and had no effect in the 42 (69%) remaining patients. Conclusions: Administration of SB during CPA was causally linked with inducing alkalemia in 16% of patients. Early collection of ABG samples may assist in optimizing pH during CPA and thus reduce unwarranted empiric use of SB.