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]

Context: Aging, low dehydroepiandrosterone (DHEA), and testosterone are associated with increased adiposity and metabolic risk. Treatment with these hormones may improve these abnormalities. Objective: The objective of the study was to determine effects of aging, DHEA, or testosterone replacement on adiposity, meal fat partitioning, and postabsorptive lipolysis. Design: This was a cross-sectional, 2-yr, double-blind, randomized, placebo-controlled trial. Setting: The study was conducted in the general community. Patients: Elderly women and men (≥60 yr) with low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations and young adults. Interventions: Thirty elderly women each received 50 mg DHEA or placebo daily for 2 yr. Thirty elderly men received 75 mg DHEA, 29 received 5 mg testosterone (patch), and 32 received placebo daily for 2 yr. Thirty young women and 32 young men served as controls. Main Outcome Measures: In vivo measures of meal fat storage into sc fat, postabsorptive lipolysis, and regional adiposity at baseline and after treatment. Results: At baseline, the elderly had more body fat, greater systemic lipolysis (women, P = 0.0003; men, P < 0.0001) adjusted for resting energy expenditure, greater meal fat oxidation (women, P = 0.026; men, P = 0.0025), and less meal fat storage in sc fat (women, P = 0.0139; men, P= 0.0006). Although testosterone treatment increased meal fat storage into upper- vs. lower-body fat in elderly men, neither hormone affected regional adiposity, meal fat oxidation, or systemic lipolysis. Conclusions: Aging, in the context of low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations, is associated with changes in meal fat partitioning and postabsorptive lipolysis that are not corrected by DHEA and only partly corrected by testosterone replacement. DHEA or testosterone treatment of hormone-deficient elderly does not normalize adipose tissue lipolysis, but testosterone restores a “youthful” meal fat storage pattern in elderly men.

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.

Purpose Inconsistencies and errors resulting from nonstandard processes, together with redundancies, rework, and excess workload, lead to extended time frames for clinical trial protocol development. This results in dissatisfaction among sponsors, investigators, and staff and restricts the availability of novel treatment options for patients. Methods A team of experts from Mayo Clinic formed, including Protocol Development Unit staff and management from the three Mayo Clinic campuses (Florida, Minnesota, and Arizona), a systems and procedures analyst, a quality office analyst, and two physician members to address the identified deficiencies. The current-state process was intensively reviewed, and improvement steps were taken to accelerate the development and approval of cancer-related clinical trials. The primary goal was to decrease the time from receipt of a new protocol through submission to an approving authority, such as the National Cancer Institute or institutional review board. Results Using the Define, Measure, Analyze, Improve, Control (DMAIC) framework infused with Lean waste-reduction methodologies, areas were identified for improvement, including enhancing first-time quality and processing new studies on a first-in/first-out basis. The project was successful in improving the mean turnaround time for internally authored protocols (P < .001) from 25.00 weeks (n = 41; range, 3.43 to 94.14 weeks) to 10.15 weeks (n = 14; range, 4.00 to 22.14 weeks). The mean turnaround time for externally authored protocols was improved (P < .001) from 20.61 weeks (n = 85; range, 3.29 to 108.57 weeks) to 7.79 weeks (n = 50; range, 2.00 to 20.86 weeks). Conclusion DMAIC framework combined with Lean methodologies is an effective tool to structure the definition, planning, analysis, and implementation of significant process changes.

Purpose Intensive postoperative surveillance is associated with improved survival and recommended for patients with late stage (stage IIB and III) colon cancer. We hypothesized that stage I and IIA colon cancer patients would experience similar benefits. Patients and Methods Secondary analysis of data from the Clinical Outcomes of Surgical Therapy trial was performed by analyzing results according to TNM stage; early (stage I and IIA, 537 patients) and late (stage IIB and III, 254 patients) stage disease. Five-year recurrence rates were higher in patients with late (35.7%) versus early stage disease (9.5%). Early and late stage salvage rates, recurrence patterns and methods of first detection were compared by χ2 test. Results Salvage rates for early- and late-stage disease patients with recurrence were the same (35.9% v 37%; P = .9, respectively). Median survival after second surgery after recurrence was 51.2 and 35.8 months for early- and late-stage patients, respectively. Single sites of first recurrence did not significantly differ between early and late stage, but multiple sites of recurrence occurred less often in early-stage patients (3.6% v 28.6%, for early v late, respectively; P < .001). Methods of first detection of recurrence were not significantly different: carcinoembryonic antigen (29.1% v 37.4%), computed tomography scan (23.6% v 26.4%), chest x-ray (7.3% v 12.1%), and colonoscopy (12.7% v 8.8%), for early versus late stage disease, respectively. Conclusion Patients with early-stage colon cancer have similar sites of recurrence, and receive similar benefit from postrecurrence therapy as late-stage patients; implementation of surveillance guidelines for early-stage patients is appropriate.

ABSTRACTThe sulfonamides were the first drugs with antituberculous effects. Their use was abandoned and basically forgotten with the advent of streptomycin and isoniazid combination treatment. There is a widespread belief, apparently based on testing a single isolate on questionable media, thatMycobacterium tuberculosisis resistant to trimethoprim-sulfamethoxazole (TMP-SMX). We saw a complex immunocompromised patient with tuberculosis who was initially treated with TMP-SMX without antituberculous drugs and defervesced on this treatment. An isolate ofM. tuberculosisfrom this patient was found to be sensitive to TMP-SMX. We examined how frequentlyM. tuberculosisis sensitive to TMP-SMX. Isolates were tested for susceptibility to TMP-SMX on supplemented Middlebrook 7H10 plates. We found that 43 of 44 (98%) isolates ofM. tuberculosiswere susceptible to the combination of ≤1 μg/ml of TMP and 19 μg/ml of SMX (≤1/19 μg/ml). Thus, the vast majority of ourM. tuberculosisisolates were susceptible to TMP-SMX at an MIC similar to that forMycobacterium kansasii,Mycobacterium marinum, and sensitive rapidly growing mycobacteria, organisms successfully treated with TMP-SMX as part of the treatment regimen. It is possible that TMP-SMX may be useful in treating patients with multiple-drug-resistant and extended drug-resistant tuberculosis. We feel that a clinical trial looking at the effectiveness of TMP-SMX as an antituberculous drug is worthwhile.