Research news and notes

1. Early reperfusion with balloon angioplasty for myocardial infarctions 

Advances in coronary care often precede development in cerebrovascular care by several years. Thus, if we want to see our future, it pays to read Cardiology news.

A recent review article in the New England Journal of Medicine [2] describes the effectiveness of primary percutaneous coronary intervention (PCI). According to the article, current data support PCI as opposed to fibrinolysis when both procedures are available immediately upon patient's arrival to the hospital. However, many institutions cannot provide PCI or perform it in a timely fashion. Fibrinolytic therapy for myocardial infarction is also best administered early, within 2 to 3 hours of the onset of symptoms. Little benefit is seen from fibrinolytic therapy administered after 12 hours or more. Probably with time, there is both irreversible necrosis of more tissue, and the clot is more organized and difficult to break up. Primary PCI is even more time dependent. The initial goal for PCI was treatment within 120 minutes or less; 150 minutes of treatment was considered OK. Mortality was 5.7% with delays of 120 to 150 minutes, and 7.4% with delays of a little more than 150 minutes. Now, it is evident that further shortening the time to treatment is very beneficial. When administered within the first 90 minutes, in-hospital mortality in a large study of 29 222 patients was only 3.0%.

When adjusted for differences in patient characteristics, each 15-minute reduction in door-to-balloon time from 150 to less than 90 minutes was associated with 6.3 fewer deaths per 1000 patients treated. The following is the summary regarding selection of reperfusion therapy: PCI is better, but as PCI-related delays increase, its advantage disappears. The current recommendations are fibrinolytic therapy within 30 minutes of arrival at the hospital when door-to-balloon time of more that 90 minutes is anticipated.

The article goes ahead to describe strategies to minimize time to treatment. The authors recommend a single-call system to activate the PCI team, with emergency department bypass for appropriate patients, having a ready suite in addition to those used for electives, and many other approaches. These are excellent ideas for stroke treatment as well. However, the greatest challenge is the reduction of the overall time from the onset of symptoms to treatment. Here, stroke is at a disadvantage relative to myocardial infarction. Delays in seeking medical attention are common. The awareness of brain attack is the key. It is our job to educate our patients and promote accelerated care for stroke patients.

2. Autophagy in the brain keeps it healthy 

The term autophagy refers to a lysosomal degradation pathway that keeps the cells clear of damaged, harmful, or unneeded molecules. Autophagy helps protect against diseases such as cancer and neural degeneration [1]. Indeed, most neural degenerative diseases are associated with inappropriate accumulation of protein degradation products. Genetic studies in mice demonstrated that inadequate autophagy can lead to accumulation of protein aggregates and neurodegeneration [3]. A recent study by Simonsen et al [3] from the Salk Institute (La Jolla, CA, USA) showed for the first time that increasing the expression of genes related to autophagy can be beneficial. The authors worked in the drosophila model. In wild-type flies, the expression of autophagy-related genes declines with age, and mutations in the Atg8a gene (autophagy-related 8a) result in reduced life span. Insoluble proteins accumulate in the neurons, and the sensitivity to oxidative stress increases. Augmentation of the expression of Atg8a gene produces the opposite effect; the adult life span increased by 56%.

Although results in flies appear to be far removed from clinical medicine, this is an interesting finding. The basic biochemical pathways are relatively preserved in all animals. In a few years, this can be a new direction of clinical research in neurodegenerative diseases.

3. Pluripotent stem cell lines derived from human somatic cells 

One of the key traits of human embryonic stem (ES) cells is their ability to differentiate into any tissue. Because the genetic material is the same in all cells, the fate of the cells is necessarily determined by factors outside of the genome itself; they are epigenetic. For example, it is possible to perform somatic cell nuclear transfer into an oocyte and thus reprogram the mature somatic nucleus to an undifferentiated state. This is the procedure at the basis of animal cloning. Until now, the factors that perform the reprogramming function were unknown, so the only way to derive true pluripotent stem cell lines was to take them from an early human embryo. A revolution may be under way. In the December 21 issue of Science, a report from the laboratory of James A. Thomson, the ES cells pioneer, describes the recipe for turning mature somatic cells into cell lines indistinguishable form ES cells [4]. The authors started from the known fact that human ES cells can reprogram myeloid precursor cells through cell fusion. They compiled a list of genes with enriched expression in human ES cells relative to that in myeloid precursors and prioritized the list based on known involvement in the establishment and maintenance of pluripotency. Then they sought to identify the minimal set of genes that will do the job. The researchers cloned the genes into a lentiviral vector (lentiviruses are related to HIV, they can insert themselves into the genome). They started with 14 genes and systematically tested subsets. Ultimately, a core set of 4 genes emerged: OCT4, SOX2, NANOG, and LIN28. These were able to reprogram somatic cells with a mesenchymal phenotype back to an undifferentiated state. Then the authors tried the same combination on fully differentiated fibroblasts. These also dedifferentiated into colonies (iPS) that were indistinguishable from ES cells. These iPS cell lines expressed normal human ES cell–specific surface antigens and normal telomerase activity, and were morphologically identical to ES cells. The fibroblasts were initially fetal cells, but postnatal human newborn foreskin fibroblasts responded similarly.

These are early data, but the achievement is already huge. For example, patient-specific stem cell lines are now a realistic possibility. A tremendous amount of work remains before any clinical application, but the new cells lines can also be used for drug testing and research in embryology. This is a Nobel prize–level research.