Research news and notes

1. More evidence for the benefit of folic acid 

Folic acid supplementation gets new support from a large Canadian study [2]. The authors identified all live births with neural tube defects, as well as still births and terminations of pregnancies due to those anomalies, in 7 Canadian provinces. They report a total of 2446 subjects with neural tube defects among 1.9 million births. In 1998, mandatory fortification of certain cereal products with folic acid was introduced. The prevalence of neural tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births. The decrease was greater for spina bifida than for anencephaly and encephalocele. Before fortification, the prevalence of neural tube defects was greater in the eastern provinces. After fortification began, geographical differences almost disappeared. This pattern would be expected if relative folic acid deficiency was increasing the risk for neural tube defects. An important aspect of this study is the apparent impressive improvement in public health from a limited intervention. A 46% reduction in neural tube defects, and in particular a 53% reduction in spina bifida, was achieved after supplementation of part of the food supply with folic acid. This improvement is similar to that expected from taking folic acid supplements. However, it is also possible that the use of folic acid supplements increased at the same time, so the supplementation may not be responsible for all of the benefit.

2. A simple way to treat Alzheimer disease? 

Few medications are available now that are effective in delaying the progression of Alzheimer disease (AD). The treatments are mainly directed at alleviating memory deficit by increasing the availability of acetylcholine. Such treatments do not prevent the neurodegeneration itself. A recent article by Fiala et al [3] from UCLA suggests a different treatment that may act to prevent and delay neuronal damage.

Patients with AD accumulate amyloid beta (Abeta) in their neurons. The authors noted that in most patients with AD, the macrophages do not clear Abeta from the brain, in contrast to effective clearance by normal macrophages. When sections from AD brains are exposed to normal macrophages, they clear Abeta well. Apparently, a deficiency in macrophage response to Abeta is an important factor in progression of AD. The mechanism is possibly related to inappropriate regulatory response in AD macrophages. Instead of up-regulating certain genes that are important in phagocytosis, AD macrophages down-regulate those genes in response to Abeta. When the authors tested mononuclear cells from some patients with AD, the curcuminoid compound bisdemethoxycurcumin enhanced previously defective phagocytosis of Abeta. It also increased the transcription of MGAT3 and toll-like receptor, an enzyme and a receptor that are important in phagocytosis. Curcuminoids are natural compounds found in the spice turmeric—an ingredient in curry spices. Thus, bisdemethoxycurcumin and maybe simply using more turmeric may correct immune defects of patients with AD. The authors suggest that their findings can “provide a previously uncharacterized approach to AD immunotherapy.” That would definitely be a major advance.

3. Pluripotent cells generated from mouse skin fibroblasts 

The inadequate availability of fetal and embryonic stem cells and the technical, ethical, and political difficulties associated with their procurement and maintenance limit research into stem cell–based therapies. Generation of stem cells from differentiated tissues will be immensely important. Patient's own tissues could then be used to generate stem cells and use those for tissue and organ repair—truly a dream worthy of a science fiction story.

Okita et al [5] from Kyoto University came one step closer to getting what appears to be real stem cells derived form mouse skin fibroblasts. They started with induction of pluripotent stem cells from mouse fibroblasts by induction of several genes associated with a more primitive state of differentiation. The induction was performed by introducing the genes within a retrovirus. The cells were similar to embryonic stem cells in morphology and proliferation. However, they were not fully reprogrammed—they differed from real stem cells in gene expression, DNA methylation patterns, and, importantly, they could not integrate and form functional cells in a variety of tissues. In the new study, the authors went a step further and selected among the transfected cells for those with Nanog (an important developmentally regulated gene) expression. This looked like a more successful marker gene that could identify completely reprogramed stem cells. When they implanted cells from some of the cloned lines into mouse embryos, they acted like stem cells and the embryos developed into adult mice carrying DNA from the inserted genes. In other words, they created successful adult chimeras. In the case of one of the clones, the inserted genes were found in the germ line and in the offspring of the experimental animals. This is the best evidence so far for complete reprogramming of a mature adult cell into a pluripotent stem cell, including germ cell line. It is quite amazing, but is very far from application in humans. This finding does not detract from the need to continue research into human embryonic stem cells. There is no reason to believe that the same type of intervention will work to reprogram human cells. The method of reprogramming included induction with a retrovirus—it is difficult to predict how this strategy would work in humans. About 20% of the mice in the study died of cancer brought on by activation of the dedifferentiation genes.

Clinical application is not in sight yet.

4. Repair of spinal disk—nucleus pulposus replacement 

The prevalent technologies for repair of severely degenerated lumbar disks call for arthrodesis or a total replacement of the disk with a prosthesis. Both procedures are complex and associate with short- and long-term complications. Replacement of the degenerated nucleus pulposus only may be an attractive option for many patients. In a recent issue of Spine, So et al [7] present a study of partial disk replacement in a rabbit model of disk degeneration. They damaged 60 disks from 30 rabbits by puncturing them with a 2-mm wire. One of the adjacent disks was then repaired with a rod-shaped polyvinyl hydrogel, and the other disk was left alone. The animals were divided into 3 groups by length of follow-up—1, 3, or 6 months after surgery. The analysis included radiologic assessment and hostologic examination. The levels with implants showed less height loss and delayed degeneration compared to the disks that were only injured.

This is interesting animal model evidence for the potential benefit of nucleus pulposus replacement, although the method may be somewhat crude. An implant made from a single piece of gel in a predetermined shape may not be the best option. There is a fairly extensive research effort into better materials for nucleus pulposus replacement and better delivery. Physical-mechanical properties like water uptake, biocompatibility, stiffness, and fatigue and creep behavior are studied [1], [4]. I particularly like the injectable polymers that solidify to a consistency that resembles nucleus pulposus [8]. A very promising idea is to combine an injectable polymer with autologous bone marrow. In an experiment in pigs, Revell et al [6] were able to reverse the damage resulting from a prior nucleotomy in pigs. The disks were reconstituted to an appearance similar to normal disks, and functional chondrocytes producing matrix were recovered from the treated disks. This is a system that appears relatively close to clinical application. All of us who do spine surgery should take notice.