Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats
Bibliographic record
Abstract
Background & Aims: Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Methods: Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. Results: In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Conclusions: Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT. Impact and implications: Hepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".