Potentially lethal damage (PLD) repair has been defined as that property conferring the ability of cells to recover from DNA damage depending on the postirradiation environment. Using a novel cyclin ...dependent kinase 1 inhibitor RO-3306 to arrest cells in the G^sub 2^ phase of the cell cycle, examined PLD repair in G^sub 2^ in cultured Chinese hamster ovary (CHO) cells. Several CHO-derived DNA repair mutant cell lines were used in this study to elucidate the mechanism of DNA double-strand break repair and to examine PLD repair during the G^sub 2^ phase of the cell cycle. While arrested in G^sub 2^ phase, wild-type CHO cells displayed significant PLD repair and improved cell survival compared with cells released immediately from G^sub 2^ after irradiation. Both the radiation-induced chromosomal aberrations and the delayed entry into mitosis were also reduced by G^sub 2^-holding PLD recovery. The PLD repair observed in G^sub 2^ was observed in nonhomologous end-joining (NHEJ) mutant cell lines but absent in homologous recombination mutant cell lines. From the survival curves, G^sub 2^-NHEJ mutant cell lines were found to be very sensitive to gamma-ray exposure when compared to G^sub 2^/homologous recombination mutant cell lines. Our findings suggest that after exposure to ionizing radiation during G^sub 2^, NHEJ is responsible for the majority of non-PLD repair, and conversely, that the homologous recombination is responsible for PLD repair in G^sub 2^.
Potentially lethal damage (PLD) repair has been defined as that property conferring the ability of cells to recover from DNA damage depending on the postirradiation environment. Using a novel cyclin ...dependent kinase 1 inhibitor RO-3306 to arrest cells in the G sub( 2) phase of the cell cycle, examined PLD repair in G sub( 2) in cultured Chinese hamster ovary (CHO) cells. Several CHO-derived DNA repair mutant cell lines were used in this study to elucidate the mechanism of DNA double-strand break repair and to examine PLD repair during the G sub( 2) phase of the cell cycle. While arrested in G sub( 2) phase, wild-type CHO cells displayed significant PLD repair and improved cell survival compared with cells released immediately from G sub( 2) after irradiation. Both the radiation-induced chromosomal aberrations and the delayed entry into mitosis were also reduced by G sub( 2)-holding PLD recovery. The PLD repair observed in G sub( 2) was observed in nonhomologous end-joining (NHEJ) mutant cell lines but absent in homologous recombination mutant cell lines. From the survival curves, G sub( 2)-NHEJ mutant cell lines were found to be very sensitive to gamma-ray exposure when compared to G sub( 2)/homologous recombination mutant cell lines. Our findings suggest that after exposure to ionizing radiation during G sub( 2), NHEJ is responsible for the majority of non-PLD repair, and conversely, that the homologous recombination is responsible for PLD repair in G sub( 2).
This article summarizes the work done within the Colargol project during CEMRACS 2012. The aim of this project is to compare the implementations of high order finite element methods for compressible ...flows that have been developed at ONERA and at INRIA for about one year, within the Aghora and Aerosol libraries.
Cet article résume le travail effectué durant le projet Colargol pendant le CEMRACS 2012. Le but de ce projet est de comparer les implémentations de méthodes d’éléments finis d’ordre élevé pour les fluides compressibles devéloppées à l’ONERA et à l’INRIA depuis environ un an dans les bibliothèques Aghora et Aerosol.
The long-term impact of persistent pulmonary vascular obstruction after pulmonary embolism (PE) remains unknown. Based on ventilation-perfusion lung scan performed at discharge and 3 months after a ...first PE, we aimed to investigate the prognostic value on 5-year adverse events of (1) residual pulmonary vascular obstruction (RPVO) at discharge (DIS-RPVO), (2) RPVO at 3 months (3M-RPVO), and (3) relative change in RPVO between the 2 scans (RC-RPVO). We performed a prospective, multicenter cohort study from January 2007 to December 2009 including patients who survived at least 3 months after a PE. RC-RPVO was defined as (DIS-RPVO − 3M-RPVO)/DIS-RPVO. The primary end point was a combined end point at 5 years, composed of all-cause death, recurrent venous thromboembolism, chronic thromboembolic pulmonary hypertension, heart failure, and rehospitalization for cardiac causes. Receiver-operating characteristic curves were computed to define thresholds of DIS-RPVO, 3M-RPVO, and RC-RPVO predictive of the primary combined end point at 5 years. Overall, 241 patients were included (high-risk PE: 11.2%, intermediate-risk PE: 51.8%, low-risk PE: 37%). Mean DIS-RPVO was 27.9 ± 15.1%, mean 3M-RPVO was 10.3 ± 10.8%, and mean RC-RPVO was 61.7 ± 33.4%. At 5 years, 112 patients (46.5%) experienced the combined end point. Both 3M-RPVO ≥15% and RC-RPVO ≤37.5% were independently related to the occurrence of the combined end point at 5 years (p = 0.01 and p = 0.02, respectively). DIS-RPVO did not predict long-term adverse events. In conclusion, RC-RPVO ≤37.5% and 3M-RPVO ≥15% were independently related to the occurrence of adverse events 5 years after a first PE.
To characterize electromyographic abnormalities according to symptoms (asymptomatic, fatigue, pseudobotulism) reported 1 month after botulinum toxin injection.
Retrospective, single-center study ...comparing single-fiber electromyography (SFEMG) in the extensor digitorum communis (EDC) or orbicularis oculi (OO) muscles.
Hospital.
Four groups of adults treated for spasticity or neurologic bladder hyperactivity (N=55): control group (asymptomatic patients: n=17), fatigue group (unusual fatigue with no weakness: n=15), pseudobotulism group (muscle weakness and/or visual disturbance: n=20), and botulism group (from intensive care unit of the same hospital: n=3).
Not applicable.
Mean jitter, percentage of pathologic fibers, and percentage of blocked fibers were compared between groups.
SFEMG was abnormal for 17.6% of control patients and 75% of patients in the pseudobotulism group. There were no differences between the control and fatigue groups. Mean jitter, percentage of pathologic fibers, and percentage of blocked fibers of the EDC muscle were significantly higher in the pseudobotulism group than in the fatigue and control groups. There were no differences between groups for the OO muscle. The SFEMG results in the botulism group were qualitatively similar to those of the pseudobotulism group.
SFEMG of the EDC muscle confirmed diffusion of the toxin into muscles distant from the injection site in the pseudobotulism group. SFEMG in the OO muscle is not useful for the diagnosis of diffusion. No major signs of diffusion of botulinum toxin type A were found away from the injection site in patients with fatigue but no motor weakness. Such fatigue may be related to other mechanisms.
Summary Background In trachoma control programmes, azithromycin is distributed to treat the strains of chlamydia that cause ocular disease. We aimed to compare the effect of annual versus ...twice-yearly distribution of azithromycin on infection with these strains. Methods We did a cluster-randomised trial in 24 subdistricts in northern Ethiopia, which we randomly assigned to receive annual or twice-yearly treatment for all residents of all ages. Random assignment was done with the RANDOM and SORT functions of Microsoft Excel. All individuals were offered their assigned treatment of a single, directly observed, oral dose of azithromycin. A 6 week course of topical 1% tetracycline ointment, applied twice daily to both eyes but not directly observed, was offered as an alternative to azithromycin in patients younger than 12 months, and in patients with self-reported pregnancy, with allergy, or who refused azithromycin. Our primary, prespecified outcome was the prevalence of ocular chlamydial infection in a random sample of children aged 0–9 years at baseline and every 6 months for a total of 42 months within sentinel villages. Our analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00322972. Findings Antibiotic coverage of children aged 1–9 years was greater than 80% (range 80·9 to 93·0) at all study visits. In the groups treated annually, the prevalence of infection in children aged 0–9 years was reduced from a mean 41·9% (95% CI 31·5 to 52·2) at baseline to 1·9% (0·3 to 3·5) at 42 months. In the groups treated twice yearly, the prevalence of infection was reduced from a mean 38·3% (29·0 to 47·6) at baseline to 3·2 % (0·0 to 6·5) at 42 months. The prevalence of ocular chlamydial infection in children aged 0–9 years in groups treated annually was not different from that of the groups treated twice yearly at 18, 30, and 42 months (pooled regression p>0·99, 95 % CI −0·06 to 0·06). The mean elimination time in the twice-yearly treatment group was 7·5 months earlier (2·3 to 17·3) than that of the annual group (p=0·10, Cox proportional hazards model). Interpretation After 42 months of treatment, the prevalence of ocular infection with chlamydia was similar in the groups treated annually and twice yearly. However, elimination of infection might have been more rapid in the groups of villages that received treatment twice yearly. Funding National Institutes of Health (NEI U10 EY016214).
Radioactive copper (II) (diacetyl-bis N4-methylthiosemicarbazone) (Cu-ATSM) isotopes were originally developed for the imaging of hypoxia in tumors. Because the decay of a super(64)Cu atom is ...emitting not only positrons but also Auger electrons, this radionuclide has great potential as a theranostic agent. However, the success of super(64)Cu-ATSM internal radiation therapy would depend on the contribution of Auger electrons to tumor cell killing. Therefore, we designed a cell culture system to define the contributions to cell death from Auger electrons to support or refute our hypothesis that the majority of cell death from super(64)Cu-ATSM is a result of high-LET Auger electrons and not positrons or other low-LET radiation. Chinese hamster ovary (CHO) wild type and DNA repair-deficient xrs5 cells were exposed to super(64)Cu-ATSM during hypoxic conditions. Surviving fractions were compared with those surviving gamma-radiation, low-LET hadron radiation, and high-LET heavy ion exposure. The ratio of the D sub(10) values (doses required to achieve 10% cell survival) between CHO wild type and xrs5 cells suggested that super(64)Cu-ATSM toxicity is similar to that of high-LET Carbon ion radiation (70 keV/ mu m). gamma H2AX foci assays confirmed DNA double-strand breaks and cluster damage by high-LET Auger electrons from super(64)Cu decay, and complex types of chromosomal aberrations typical of high-LET radiation were observed after super(64)Cu-ATSM exposure. The majority of cell death was caused by high-LET radiation. This work provides strong evidence that super(64)Cu-ATSM damages DNA via high-LET Auger electrons, supporting further study and consideration of super(64)Cu-ATSM as a cancer treatment modality for hypoxic tumors.
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