The mechanism by which hyperthermia sensitizes mammalian cells to ionizing radiation remains to be elucidated, but an overwhelming amount of circumstantial evidence suggests that heat radiosensitization might be mediated by inhibition of double-strand break repair, particularly after exposure of irradiated cells to heat treatments in excess of about 43 degrees C. In mammalian cells, double-strand break repair usually occurs via two pathways, non-homologous end-joining and homologous recombination. Several reports suggest a role for non-homologous end-joining in heat radiosensitization, while others implicate homologous recombination as a target. However, cell lines that are compromised in either the non-homologous end-joining or homologous recombination pathway are still capable of being radiosensitized, suggesting that heat affects both pathways. Indeed, several of the proteins involved in one or both of these pathways have been observed to undergo alterations or translocation after unirradiated or irradiated cells are exposed to heat shock. The work summarized in this review implicates proteins of the Mre11/Rad50/Nbs1 complex as targets for heat radiosensitization.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons within the brain and spinal cord are lost, leading to paralysis and death. Recently, a correlation has been reported between head trauma and the incidence of ALS. Furthermore, new invasive neurosurgical studies are being planned which involve inserting needles directly to the spinal cord. We therefore tested whether acute trauma to the spinal cord via a knife wound injury would lead to accelerated disease progression in rodent models of ALS (SOD1G93A rats). A longitudinal stab injury using a small knife was performed within the lumbar spinal cord region of presymptomatic SOD1G93A rats. Host glial activation was detected in the lumbar area surrounding a micro-knife lesion at 2 weeks post-surgery in both wild type and SOD1G93A animals. However, there was no sign of motor neuron loss in the injured spinal cord of any animal and normal motor function was maintained in the ipsilateral limb. These results indicate that motor neurons in pre-symptomatic G93A animals are not affected by an invasive puncture wound injury involving reactive astrocytes. Furthermore, acute trauma alone does not accelerate disease onset or progression in this ALS model which is important for future strategies of gene and cell therapies directly targeting the spinal cord of ALS patients.
Extracorporeal membrane oxygenation (ECMO) is a low-volume, high-risk modality of care. Clinical specialists (CS) who manage ECMO circuit emergencies vary in background and approach to circuit emergencies based on institutional training standards, leading to variation that may impact the quality of care. Validated checklists to assess CS performance are crucial to eliminate disparities and improve efficiency. This study focused on the development and validation of checklists to evaluate the clinical performance of ECMO CS in three ECMO circuit emergencies. A research team with diverse clinical background from our institution developed the first iteration of three ECMO emergency checklists: (1) venous air, (2) arterial air, and (3) oxygenator failure. A modified Delphi technique with a panel of 11 national content experts in ECMO was used to develop content validity evidence. Rating scales from 1 to 7 were used to evaluate each checklist item. The response rate for three rounds of Delphi was 100%. Items with mean score >4 were kept, and new item recommendations were added based on comments from the panel. The venous air, arterial air, and oxygenator failure checklists were revised from 10, 13, and 9 items to 12, 12, and 10 items, respectively. A Cronbach’s α of 0.74 during the second round of responses indicated an acceptable degree of agreement. This study demonstrated content validation of three ECMO emergency checklists to assess performance of ECMO CS using a consensus-based Delphi technique. Future validity evidence should be acquired by implementing these checklists in the simulation environments.
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