This Issue Vaccine for Alzheimer's Disease, eating problems, cytokines and DS and in depression Next Issue Cardiac Issues in DS

The December Issue will be your last one of the year, so expect "Time to Reorder" notices in your next issue.

Have you ever wanted to learn to read EKGs? They make a few books to help that are extremely easy to read. The classic is by Dubin and is titled Rapid Interprtation of EKC. The other is named Flipchart ECG by Cohn. Both start at the very beginning ("this is the atrium of the heart") and can give those who are interested a basic lesson in the physiology of the cardiac system.

People with DS can suffer from mental illnesses
There is a case report of a male with DS who also suffered from major clinical depression, anorexia nervosa and obsessive compulsive disorder. The authors suggested the depression resulted from lack of control over his own life, and the other problems followed the depression.

Raitasuo, S. et al, 1998. Anorexia, major depression and anorexia nervosa in Downs syndrome patient. Int-J-Eat-Disord. 43(3), 107-9

Jill James is looking for kids with DS who are not on vitamins to test. She is comparing those who get leukemia vs. those who do not. Please email me or send me a note if you are interested, and I will pass it on to her. A blood draw is all that is needed.

Eating problems in DS
This research looked at feeding differences in 14 children with DS under the age of 5. They noted that the mental age in these kids was higher than what their feeding abilities were. Some things that they found were incoordination in moving the food from the lips to the phanyx. There was a tendancy for food to be "stored" in the cheeks without being swallowed, even if other mouthfuls had been taken. Food was often either removed, expelled or "lost".
The researcher predicted that parents would be more "controlling" towards these kids than normal during feeding, but this was not the case. Also, the time spent at each meal was similar to normal. One thing the researchers thought was interesting was that for all the problems they saw in the feedings, many parents denied that their kids had problems at mealtime. Perhaps the parents were able to adapt to these problems adequately, and felt no need to discuss them. Of the parents who did report problems, including picky eating, many felt it was a behavior or stubbornness issue, but changed their view after watching the video of their child eating and having specific difficulties pointed out. Perhaps a child avoids a certain texture because it is difficult for them to handle, not because they are trying to be naughty.
Finally, contrary to current stereotypes, the children taped were NOT viewed as happier than normal. In fact, they and their parents looked less happy than the normal group during feeding. (The researchers did not attribute that to an inaccurate stereotype, but to a lack of smiling due to poor oral abilities).

Spender, (1996) An exploration of feeding difficulties in children with Down syndrome. Devel-Med-and-Child-Neurol. 38, 681-694.

The vaccine for Alzheimer's
There was fascinating news that hit the press a few weeks ago regarding advances in Alzheimer's.
AD is characterized by the presence of large amount of amyloid beta peptides (AB) that is made from amyloid precursor protein (APP). The peptides in turn form plaques that clog up the function of the brain. There is still debate as to whether the plaques and its components are what causes the disease, or the result of another process.
Researchers took mice that were genetically engineered to enter early Alzheimer's because they overproduce APP. They injected those mice with human AB. That showed clearing and prevention of plaques.
Why would injecting more AB help if that is the component of plaques? It seems that if you infect enough AB, the body responds by producing antibodies to the AB and begins to clear out the plaques. At least that is what happened to theses mice.
There are a number of questions that need to be answered before anyone can call this a viable human treatment or prevention.
First of all, the only problem these mice have is the over expression of APP. There are most likely other processes of Alzheimer's that we do not know about. These mice only show subtle changes in behavior and learning, so researchers cant tell if the clearing of the plaques actually affected the disease.
Another issue, which is a big issue, is can this work in humans in a safe and effective manner?

St George Hyslop, P. & Westway, D. (1999) Antibodies clear senile plaques. Nature. 400. 116-117.

Cytokines
Cutokines are the chemical mediators of the immune system. There is a huge variety of them, and probably many that have not yet been discovered. Certainly the ones that have been identified have functions that medicine has not yet uncovered.
Generally what happens is a part of the immune system sees something foreign. Virus, for example, tune on one part of the immune system while extracellular bacteria turn on another part. Cytokines are produced by various cells in the body. Those cytokines turn on (or off) the production of other cytokines, and also have direct function in targeting foreign bodies and destroying them.
The following is a very incomplete list of cytokines and some very basic duties that each of them have.

Tumor Necorosis Factor (TNF) - causes the cells inside the vessel to secrete adhesive molecules so that leukocytes will stick. It also stimulates the production of IL6 (see below), more TNK and bone marrow. In an attempt to get rid of a cancer or an intruder, TNF causes direct tissue damage to its own host.
Interleukins - there are a ton of Interleukins
IL1 - IL1 stimulates IL6, and bone marrow like TNF does, but IL1 will not cause direct damage to the person. It is also considered the mediator of the inflammatory response.
IL2 - stimulates Natural Killer (NK) cells, Interferon gamma (IFN gamma), and gets T-cells ready to divide.
IL4 - blocks macrophage activation and turns DOWN allergic reactions. Stimulates thymus cells to produce thymocytes???
IL5 - stimulates eosinophils (which are increased in parasitic infections)
IL6 - helps B cells to grow up
IFN gamma - Increases the number of multihisotcompatability complexes, stimulate neutrophils and increase inflammation.
NK cells - can lyse either virus or cancer cells.

Cytokines and depression
The fact that there is a connection between the immune system and the central nervous system has been known forever. However, it was previously believed that stress decreases the immune system. Part of that equation is still true. Steroids are released during stress that can suppress parts of the immune system. People are known to have a higher incidence of cancer following a stressful time in their lives.
What researchers are just starting to discover is the effect the immune system has on the brain, emotions and mental illness. It is a two way connection.
The following was taken from a very long review of the literature regarding this topic. The high points will be discussed.
Stress and depression seem to exhibit an increase in IL1, IL6 and IFN gamma. Depressed patients have an increase in CD4, T memory and activated T cells. They also have higher serotonin antibody titters (measures), and higher antibodies to part of the serotonin receptor. This would greatly diminish the ability of serotonin to perform, and serotonin deficiency has long been implicated as being a major cause of depression. Most antidepressants work by keeping serotonin near its receptor longer before it is taken back up (so less is needed to have an effect).
A large number of previously psychiatrically healthy adults were treated with high doses of cytokines such as IL2 and IFN gamma. They developed depression or depressive-like symptoms. The symptoms appeared quickly after the cytokines were given, and went away quickly when the cytokines are no longer given.
Childbirth can cause a huge swing in cytokine levels, which may be the start of post partum depression.
Antidepressants also have an effect on cytokines. One in particular, imiprine, decreased IL2, IL6, IFN gamma and TNK. It also acts as an IL1 receptor blocker.
While there are cytokine made in the brain and receptors for them, there is a question as to whether cytokines in the rest of the body could get into the brain. The Blood Brain Barrier (BBB) tends to keep out items as big as a cytokine. One study found in that the permeability of the BBB increases in mice exposed to stress. They hypothesized that cytokines from the body maybe able to get into the brain during times of stress, allowing in more cytokines than the brain could produce.
The large volume of research that is occuring in the area of cytoline affects on the brain are just beginning. IT is not only interesting but relevant to those with DS. If the immune imbalances that are found in DS create much of the brain problems that are seen, this is a different game. Cytokines can be somewhat controlled to prevent some of the brain damage. I have heard that one researcher believes that the IFN gamma antibody (that was given to the mouse with trisomy 16) could help in significantly decreasing the problems seen in DS, at least if given early enough.

Connel, T & Leonard, B. (1998) Minireview: Depression, stress and immunological activation. Life Science. 62 (7) 583-606.
Holliday, J. et al (1995) Cerebellar granule neurons develop elevated calcium response when treated with IL6 in culture. Brain-Res. 673(1), 141-8.
Kalman, J. (1997) Serum IL6 levels correlate with severity of dementia in Down syndrome and in Alzheimer's disease. Acta-Neurol-Scand. 96(4), 236-40.
Maroun, LE. (1995) Anti-interferon immunoglobulins can improve the trisomy 16 mouse phenotype. Teratology. 51(5), 329-35.
Murphy, M. et al (1992) TNF-alpha and IFN-gamma expression in human thymus. I-Immunol. 149(7), 2506-12.
Murphy, M. et al (1992) A role for TNF-alpha and IFN-gamma in the regulation of IL4-induced human thymocyte proliferation in vito. Pediatr-Res. 32(3), 269-76.

Eating problems in DS
This research looked at feeding differences in 14 children with DS under the age of 5. They noted that the mental age in these kids was higher than what their feeding abilities were. Some things that they found were incoordination in moving the food from the lips to the phanyx. There was also a tendency for food to be "stored" in the cheeks without being swallowed, even if other mouthfuls had been taken. Food was often removed, expelled or "lost".
While they looked at different textures like puree, semi-solid and solids, kids with DS have the most problems with solids.
The researcher predicted that parents would be more "directing" towards these kids than normal during feeding, but this was not the case. However, self-feeding was less in the kids with DS than normal. Also, the time spent at each meal was similar to normal. One thing the researchers thought was interesting was that for all the problems they saw in the feedings, many parents denied that their kids had problems at mealtime. Perhaps the parents were able to adapt to these problems adequately, and felt no need to discuss them.
Of the parents who did report problems, including picky eating, many felt it was a behavior or stubbornness issue, but changed their view after watching the video of their child eating and having specific difficulties pointed out. Perhaps a child avoids a certain texture because it is difficult for them to handle, not because they are trying to be naughty.
Finally, contrary to current stereotypes, the children taped were NOT viewed as happier than normal. In fact, they and their parents looked less happy than the normal group during feeding. (The researchers did not attribute that to an inaccurate stereotype, but to a lack of smiling due to poor oral abilities).

Spender, Q. (1996) An exploration of feeding difficulties in children with Down syndrome. Devel-Med-and-Child-Neurol. 38, 681-694.

How maternal factor effect a baby with DS
219 babies with DS born between 1968 and 1980 were tracked and information regarding their gestation computed. 50 had cardiac defects, which seems to correlate more with being black than white. Also, maternal alcohol use was associated specifically ventricular septal defects (VSDs).
Nine babies had GI atresia, which seemed to coincide with a first trimester fever. Younger mothers tended to have more babies with oral clefts (none were born to moms over 34 year old).

Khoury, MJ & Erickson, JD (1992) Am-J-Med-Genet, 43(6) 1016-22

Disclaimer 3.21 is not associated with any organization. The information provided is not intended as medical advice. Please consult your physician.

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