Deathly decision: the clinical dilemma
One of the most difficult and sensitive clinical decisions that any physician has to make is the declaration of death. In some cases the diagnosis is facilitated by the fact that the patient is no longer breathing and the heart has stopped but other cases are less clear.
When a patient is being kept alive by a ventilator that keeps the heart beating and oxygen circulating, other signs are required to establish brain death and the condition of the brain stem comes into play. This part of the brain, which is joined to the spinal cord, encompasses the nerve connections of the sensory and motor systems for the rest of the body. If a particular set of tests finds no activity within the brain stem, the patient can be declared clinically dead because the core functions of the body will have stopped working and cannot be restarted.
Another challenge for doctors is predicting the fate of deeply comatose patients. Will they recover, move into a persistent vegetative state, or die? The dearth of clinical predictors and the poor understanding of the mechanisms involved make this a difficult call.
However, there has been recent progress. A team of Taiwanese scientists has discovered a novel clinical marker that is related specifically to brain stem death. It is located in the rostral ventrolateral medulla (RVLM), part of the brain stem that is the primary regulator of the sympathetic nervous system. It appears that there is an elaborate relationship between pro-life and pro-death programs that ultimately determines the fate of the patient.
Now that same team has examined the proteome of the RVLM to see if there are any molecular clues hidden in this neural component.
Abundant antioxidant proteins: playing a role in brain death?
Samuel Chan and colleagues from the Center for Translational Research in Biomedical Sciences at the Chang Gung Memorial Hospital-Kaohsiung Medical Center, and the National Sun Yat-sen University, Kaohsiung, examined brain tissue from rats. They collected RVLM and compared its proteome with that of the cerebral cortex, which is defunct under the persistent vegetative state.
The proteins from each section were extracted and separated by 2D gel electrophoresis with silver staining. Using image analysis, 693 and 581 proteins were resolved for RVLM and cerebral cortex, respectively, with strongly comparable distribution patterns. Nearly 86% of the protein spots were matched between the two tissue types.
The proteins with different abundances between the two samples were extracted from the gels and identified by mass spectrometry following digestion with trypsin and matching of the peptides against a database.
One particular group of antioxidant proteins was present in much higher abundance in the RVLM tissue than the cerebral cortex. They included thioredoxin, mitochondrial manganese superoxide dismutase (MnSOD) and several peroxiredoxins. Real-time PCR confirmed that the increased abundances were present at the mRNA level.
The elevated levels of antioxidant proteins were accompanied by raised amounts of tissue oxygen and increased amounts of ATP, which were almost double those in the cerebral cortex. In addition, ATP synthase subunits alpha and beta were also markedly elevated.
The team interpreted these observations as support for the assignment of RVLM as a region of the brain with a high metabolic energy requirement. This fits with earlier reports that associated the steady reduction in neuronal activity in RVLM during brain death with bioenergetic failure.
In addition, these findings support each other. Augmented levels of oxygen and elevated metabolic energy production would logically require greater amounts of antioxidant proteins to counteract the higher risk of oxidative stress and provide a safeguard mechanism against brain death.
Although the molecular pathways associated with the higher levels of antioxidant proteins were not established in this project, the results should prove useful in helping to understand the origins and progression of brain death.
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
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