Mechanisms underlying seizures and hypothermia during busulphan administration
Bibliographic record
Abstract
Abstract Busulphan (Bu) is used as a part of the conditioning regimen prior to HSCT. Neurotoxicity is one of Bu major adverse-effects. We investigated the kinetics of busulphan and its metabolites (tetrahydothiophene, tetrahydrothiophene-1-oxide, sulfolane, 3-OH-sulfolane) in patients and mice as well as the mechanisms underlying CNS-toxicity in mice. Busulphan metabolites were detectable in plasma and urine up to 72-h after the last Bu-dose. Sulfolane levels were high and reached maximum concentration at the time-point reported for the convulsions’ occurrence. Mice were treated with either busulphan or one of its metabolites, separately. Sulfolane treated-mice showed the highest brain exposure (AUC brain /AUC plasma ). Seizures and hypothermia were observed after sulfolane administration, accompanied with a significant decrease in calbindin-28k concentrations in the brain. Behavior changes but no signs of convulsions were seen in mice treated with lower sulfolane doses. Moreover, a reduction of spontaneous events during whole-cell patch clamp recordings from pyramidal neurons was observed following bath application of sulfolane. In conclusion, these are the first results showing that sulfolane is the major cause of seizures and hypothermia. Sulfolane concentration in plasma mirrors its concentration in the brain. The role of calbindin-D28K in CNS-toxicity and susceptibility to future neurodegenerative diseases should be investigated.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".