Someone posted a study on another list regarding flouride and the increased risk of DS. I decided to look at it a little further, since I thought it'd b interesting. It looks like there may be an association between flouride and an increased risk of DS, but there may also not be a significant link. So, basically they don't really know ;). But it's rather interesting.
Snip from the study, "Association of Down's syndrome and water fluoride level: a systematic review of the evidence."
Full text at:
"Four of the six studies provided a measure of the significance of the association of water fluoride level with Down's syndrome.[18, 14, 17, 16] Two of these studies found no significant difference in Down's syndrome incidence between high and lower water fluoride areas. [18, 14] The other two studies, by the same author, found an increased incidence of Down's syndrome in areas with higher water fluoride levels (p 16, 17] One of the other studies did not find any association between water fluoride level and Down's syndrome incidence,  depending on the control area selected, the crude relative risk ranged from 0.84 to 1.48. The remaining study  suggested a positive association between water fluoride level and Down's syndrome incidence (increased incidence with increased water fluoride concentration) when only the crude incidence rates were compared. To achieve some control for maternal age the analysis was limited to the 30 towns that initiated fluoridation. The rate of Down's syndrome among births in fluoridated areas was compared to the combined rate among births occurring before fluoridation and, for towns that stopped fluoridation, after fluoridation. Limiting the analysis in this way produced two groups comparable in maternal age, and produced similar estimates of the incidence of Down's syndrome in the two groups. Another factor thought to be confounding the association of Down's syndrome with water fluoride exposure was time. Time trend was controlled for and produced a maximum likelihood estimate for the relative risk was 0.95 (95% CI: 0.8, 1.2), suggesting no significant association between Down's syndrome and water fluoride level."
FLUORIDE-LINKED DOWN SYNDROME BIRTHSAND THEIR ESTIMATED OCCURRENCEDUE TO WATER FLUORIDATION
Fluoride 31 (2), 1998, pp 61-73
SUMMARY: Down syndrome (DS) birth rates (BR) as a function of maternal age exhibit a relatively flat linear regression line for younger mothers and a fairly steep one for older mothers with the second line intersecting the first line a little above maternal age 30. Consequently, overall DS-BR for all maternal ages are not a very reliable parameter for detecting environmental influences, since they may be strongly affected by the ratio of the number of younger to older mothers. For this reason, data for mothers under age 30 were selected to detect an association between water fluoridation and DS for which the lower maternal age regression would be a much smaller contributing factor.
"The early research of I Rapaport indicating a link between fluoride in drinking water and Down syndrome was followed by studies claiming there was no such association. Application of sound methodology to the data in those later investigations shows that none of the criticisms against Rapaport's work are valid. For example, in the data of J D Erickson on maternal age-specific DS births in Metropolitan Atlanta, Georgia, when the three youngest maternal age subgroups are reasonably combined into single groups for areas with and without water fluoridation, a highly significant association (P < color="#660000">Full text for the above article can be seen at:
Monday, February 26, 2007
Someone posted a study on another list regarding flouride and the increased risk of DS. I decided to look at it a little further, since I thought it'd b interesting. It looks like there may be an association between flouride and an increased risk of DS, but there may also not be a significant link. So, basically they don't really know ;). But it's rather interesting.
Posted by Qadoshyah at 1:56 PM
Friday, February 23, 2007
I was reading through the latest DSRF newsletter that I got (Feb. 2007) and it mentioned a new research area that is being undertaken in many areas. It's called Epigenetics. Epigenetics is when you can turn genes on and off by the environment, nutrition, diet, etc. It's a term used to describe modifications in the DNA by various ways - one such is methylation. We know methylation is a problem in DS. This is really fascinating and exciting research. This could have so many positive effects for Down Syndrome. This could all play into how TNI works - hoping to alter things that are caused by genes which are overexpressed. Of course TNI does not turn on or off a gene, but down the road this may be something that can be done. This does not change the genetic disease or abnormality, but it may change certain things which cause certain problems in a certain disease or abnormality.
Here are the two pages from the DSRF newsletter that talk about the Epigenetics - #1 & #2
Below is a lengthy article from Discover magazine, some other links, and abstracts regarding Epigenetics.
geneimprint - http://www.geneimprint.com/
epigenomics - www.epigenomics.com/
Human Epigenome Project - www.epigenome.org/
DNA Is Not Destiny
The new science of epigenetics rewrites the rules of disease, heredity, and identity.
By Ethan Watters
Back in 2000, Randy Jirtle, a professor of radiation oncology at Duke University, and his postdoctoral student Robert Waterland designed a groundbreaking genetic experiment that was simplicity itself. They started with pairs of fat yellow mice known to scientists as agouti mice, so called because they carry a particular gene—the agouti gene—that in addition to making the rodents ravenous and yellow renders them prone to cancer and diabetes. Jirtle and Waterland set about to see if they could change the unfortunate genetic legacy of these little creatures.
Typically, when agouti mice breed, most of the offspring are identical to the parents: just as yellow, fat as pincushions, and susceptible to life-shortening disease. The parent mice in Jirtle and Waterland's experiment, however, produced a majority of offspring that looked altogether different. These young mice were slender and mousy brown. Moreover, they did not display their parents' susceptibility to cancer and diabetes and lived to a spry old age. The effects of the agouti gene had been virtually erased.
Remarkably, the researchers effected this transformation without altering a single letter of the mouse's DNA. Their approach instead was radically straightforward—they changed the moms' diet. Starting just before conception, Jirtle and Waterland fed a test group of mother mice a diet rich in methyl donors, small chemical clusters that can attach to a gene and turn it off. These molecules are common in the environment and are found in many foods, including onions, garlic, beets, and in the food supplements often given to pregnant women. After being consumed by the mothers, the methyl donors worked their way into the developing embryos' chromosomes and onto the critical agouti gene. The mothers passed along the agouti gene to their children intact, but thanks to their methyl-rich pregnancy diet, they had added to the gene a chemical switch that dimmed the gene's deleterious effects.
With no more than a change in diet, laboratory agouti mice (left) were prompted to give birth to young (right) that differed markedly in appearance and disease susceptibility. "It was a little eerie and a little scary to see how something as subtle as a nutritional change in the pregnant mother rat could have such a dramatic impact on the gene expression of the baby," Jirtle says. "The results showed how important epigenetic changes could be."
Our DNA—specifically the 25,000 genes identified by the Human Genome Project—is now widely regarded as the instruction book for the human body. But genes themselves need instructions for what to do, and where and when to do it. A human liver cell contains the same DNA as a brain cell, yet somehow it knows to code only those proteins needed for the functioning of the liver. Those instructions are found not in the letters of the DNA itself but on it, in an array of chemical markers and switches, known collectively as the epigenome, that lie along the length of the double helix. These epigenetic switches and markers in turn help switch on or off the expression of particular genes. Think of the epigenome as a complex software code, capable of inducing the DNA hardware to manufacture an impressive variety of proteins, cell types, and individuals.
In recent years, epigenetics researchers have made great strides in understanding the many molecular sequences and patterns that determine which genes can be turned on and off. Their work has made it increasingly clear that for all the popular attention devoted to genome-sequencing projects, the epigenome is just as critical as DNA to the healthy development of organisms, humans included. Jirtle and Waterland's experiment was a benchmark demonstration that the epigenome is sensitive to cues from the environment. More and more, researchers are finding that an extra bit of a vitamin, a brief exposure to a toxin, even an added dose of mothering can tweak the epigenome—and thereby alter the software of our genes—in ways that affect an individual's body and brain for life.
The even greater surprise is the recent discovery that epigenetic signals from the environment can be passed on from one generation to the next, sometimes for several generations, without changing a single gene sequence. It's well established, of course, that environmental effects like radiation, which alter the genetic sequences in a sex cell's DNA, can leave a mark on subsequent generations. Likewise, it's known that the environment in a mother's womb can alter the development of a fetus. What's eye-opening is a growing body of evidence suggesting that the epigenetic changes wrought by one's diet, behavior, or surroundings can work their way into the germ line and echo far into the future. Put simply, and as bizarre as it may sound, what you eat or smoke today could affect the health and behavior of your great-grandchildren.
All of these discoveries are shaking the modern biological and social certainties about genetics and identity. We commonly accept the notion that through our DNA we are destined to have particular body shapes, personalities, and diseases. Some scholars even contend that the genetic code predetermines intelligence and is the root cause of many social ills, including poverty, crime, and violence. "Gene as fate" has become conventional wisdom. Through the study of epigenetics, that notion at last may be proved outdated. Suddenly, for better or worse, we appear to have a measure of control over our genetic legacy.
"Epigenetics is proving we have some responsibility for the integrity of our genome," Jirtle says. "Before, genes predetermined outcomes. Now everything we do—everything we eat or smoke—can affect our gene expression and that of future generations. Epigenetics introduces the concept of free will into our idea of genetics."
Scientists are still coming to understand the many ways that epigenetic changes unfold at the biochemical level. One form of epigenetic change physically blocks access to the genes by altering what is called the histone code. The DNA in every cell is tightly wound around proteins known as histones and must be unwound to be transcribed. Alterations to this packaging cause certain genes to be more or less available to the cell's chemical machinery and so determine whether those genes are expressed or silenced. A second, well-understood form of epigenetic signaling, called DNA methylation, involves the addition of a methyl group—a carbon atom plus three hydrogen atoms—to particular bases in the DNA sequence. This interferes with the chemical signals that would put the gene into action and thus effectively silences the gene.
Until recently, the pattern of an individual's epigenome was thought to be firmly established during early fetal development. Although that is still seen as a critical period, scientists have lately discovered that the epigenome can change in response to the environment throughout an individual's lifetime.
"People used to think that once your epigenetic code was laid down in early development, that was it for life," says Moshe Szyf, a pharmacologist with a bustling lab at McGill University in Montreal. "But life is changing all the time, and the epigenetic code that controls your DNA is turning out to be the mechanism through which we change along with it. Epigenetics tells us that little things in life can have an effect of great magnitude."
Szyf has been a pioneer in linking epigenetic changes to the development of diseases. He long ago championed the idea that epigenetic patterns can shift through life and that those changes are important in the establishment and spread of cancer. For 15 years, however, he had little luck convincing his colleagues. One of his papers was dismissed by a reviewer as a "misguided attempt at scientific humor." On another occasion, a prominent scientist took him aside and told him bluntly, "Let me be clear: Cancer is genetic in origin, not epigenetic."
Despite such opposition, Szyf and other researchers have persevered. Through numerous studies, Szyf has found that common signaling pathways known to lead to cancerous tumors also activate the DNA-methylation machinery; knocking out one of the enzymes in that pathway prevents the tumors from developing. When genes that typically act to suppress tumors are methylated, the tumors metastasize. Likewise, when genes that typically promote tumor growth are demethylated—that is, the dimmer switches that are normally present are removed—those genes kick into action and cause tumors to grow.
Szyf is now far from alone in the field. Other researchers have identified dozens of genes, all related to the growth and spread of cancer, that become over- or undermethylated when the disease gets under way. The bacteria Helicobacter, believed to be a cause of stomach cancer, has been shown to trigger potentially cancer-inducing epigenetic changes in gut cells. Abnormal methylation patterns have been found in many cancers of the colon, stomach, cervix, prostate, thyroid, and breast.
Szyf views the link between epigenetics and cancer with a hopeful eye. Unlike genetic mutations, epigenetic changes are potentially reversible. A mutated gene is unlikely to mutate back to normal; the only recourse is to kill or cut out all the cells carrying the defective code. But a gene with a defective methylation pattern might very well be encouraged to reestablish a healthy pattern and continue to function. Already one epigenetic drug, 5-azacytidine, has been approved by the Food and Drug Administration for use against myelodysplastic syndrome, also known as preleukemia or smoldering leukemia. At least eight other epigenetic drugs are currently in different stages of development or human trials.
To the surprise of scientists, many environmentally induced changes turn out to be heritable. When exposed to predators, Daphnia water fleas grow defensive spines (right). The effect can last for several generations. Methylation patterns also hold promise as diagnostic tools, potentially yielding critical information about the odds that a cancer will respond to treatment. A Berlin-based company called Epigenomics, in partnership with Roche Pharmaceuticals, expects to bring an epigenetic screening test for colon cancer to market by 2008. They are working on similar diagnostic tools for breast cancer and prostate cancer. Szyf has cofounded a company, MethylGene, that so far has developed two epigenetic cancer drugs with promising results in human trials. Others have published data on animal subjects suggesting an epigenetic component to inflammatory diseases like rheumatoid arthritis, neurodegenerative diseases, and diabetes.
Other researchers are focusing on how people might maintain the integrity of their epigenomes through diet. Baylor College of Medicine obstetrician and geneticist Ignatia Van den Veyver suggests that once we understand the connection between our epigenome and diseases like cancer, lifelong "methylation diets" may be the trick to staying healthy. Such diets, she says, could be tailored to an individual's genetic makeup, as well as to their exposure to toxins or cancer-causing agents.
In 2003 biologist Ming Zhu Fang and her colleagues at Rutgers University published a paper in the journal Cancer Research on the epigenetic effects of green tea. In animal studies, green tea prevented the growth of cancers in several organs. Fang found that epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can prevent deleterious methylation dimmer switches from landing on (and shutting down) certain cancer-fighting genes. The researchers described the study as the first to demonstrate that a consumer product can inhibit DNA methylation. Fang and her colleagues have since gone on to show that genistein and other compounds in soy show similar epigenetic effects.
Meanwhile, epigenetic researchers around the globe are rallying behind the idea of a human epigenome project, which would aim to map our entire epigenome. The Human Genome Project, which sequenced the 3 billion pairs of nucleotide bases in human DNA, was a piece of cake in comparison: Epigenetic markers and patterns are different in every tissue type in the human body and also change over time. "The epigenome project is much more difficult than the Human Genome Project," Jirtle says. "A single individual doesn't have one epigenome but a multitude of them."
Research centers in Japan, Europe, and the United States have all begun individual pilot studies to assess the difficulty of such a project. The early signs are encouraging. In June, the European Human Epigenome Project released its data on epigenetic patterns of three human chromosomes. A recent flurry of conferences have forwarded the idea of creating an international epigenome project that could centralize the data, set goals for different groups, and standardize the technology for decoding epigenetic patterns.
Until recently, the idea that your environment might change your heredity without changing a gene sequence was scientific heresy. Everyday influences—the weights Dad lifts to make himself muscle-bound, the diet regimen Mom follows to lose pounds—don't produce stronger or slimmer progeny, because those changes don't affect the germ cells involved in making children. Even after the principles of epigenetics came to light, it was believed that methylation marks and other epigenetic changes to a parent's DNA were lost during the process of cell division that generates eggs and sperm and that only the gene sequence remained. In effect, it was thought, germ cells wiped the slate clean for the next generation.
That turns out not to be the case. In 1999 biologist Emma Whitelaw, now at the Queensland Institute of Medical Research in Australia, demonstrated that epigenetic marks could be passed from one generation of mammals to the next. (The phenomenon had already been demonstrated in plants and yeast.) Like Jirtle and Waterland in 2003, Whitelaw focused on the agouti gene in mice, but the implications of her experiment span the animal kingdoms.
"It changes the way we think about information transfer across generations," Whitelaw says. "The mind-set at the moment is that the information we inherit from our parents is in the form of DNA. Our experiment demonstrates that it's more than just DNA you inherit. In a sense that's obvious, because what we inherit from our parents are chromosomes, and chromosomes are only 50 percent DNA. The other 50 percent is made up of protein molecules, and these proteins carry the epigenetic marks and information."
Michael Meaney, a biologist at McGill University and a frequent collaborator with Szyf, has pursued an equally provocative notion: that some epigenetic changes can be induced after birth, through a mother's physical behavior toward her newborn. For years, Meaney sought to explain some curious results he had observed involving the nurturing behavior of rats. Working with graduate student Ian Weaver, Meaney compared two types of mother rats: those that patiently licked their offspring after birth and those that neglected their newborns. The licked newborns grew up to be relatively brave and calm (for rats). The neglected newborns grew into the sort of rodents that nervously skitter into the darkest corner when placed in a new environment.
Traditionally, researchers might have offered an explanation on one side or the other of the nature-versus-nurture divide. Either the newborns inherited a genetic propensity to be skittish or brave (nature), or they were learning the behavior from their mothers (nurture). Meaney and Weaver's results didn't fall neatly into either camp. After analyzing the brain tissue of both licked and nonlicked rats, the researchers found distinct differences in the DNA methylation patterns in the hippocampus cells of each group. Remarkably, the mother's licking activity had the effect of removing dimmer switches on a gene that shapes stress receptors in the pup's growing brain. The well-licked rats had better-developed hippocampi and released less of the stress hormone cortisol, making them calmer when startled. In contrast, the neglected pups released much more cortisol, had less-developed hippocampi, and reacted nervously when startled or in new surroundings. Through a simple maternal behavior, these mother rats were literally shaping the brains of their offspring.
How exactly does the mother's behavior cause the epigenetic change in her pup? Licking and grooming release serotonin in the pup's brain, which activates serotonin receptors in the hippocampus. These receptors send proteins called transcription factors to turn on the gene that inhibits stress responses. Meaney, Weaver, and Szyf think that the transcription factors, which normally regulate genes in passing, also carry methylation machinery that can alter gene expression permanently. In two subsequent studies, Meaney and his colleagues were even able to reverse the epigenetic signals by injecting the drug trichostatin A into the brains of adult rats. In effect, they were able to simulate the effect of good (and bad) parenting with a pharmaceutical intervention. Trichostatin, interestingly, is chemically similar to the drug valproate, which is used clinically in people as a mood stabilizer.
Meaney says the link between nurturing and brain development is more than just a curious cause and effect. He suggests that making postnatal changes to an offspring's epigenome offers an adaptive advantage. Through such tweaking, mother rats have a last chance to mold their progeny to suit the environment they were born into. "These experiments emphasize the importance of context on the development of a creature," Meaney says. "They challenge the overriding theories of both biology and psychology. Rudimentary adaptive responses are not innate or passively emerging from the genome but are molded by the environment."
The hippocampus in a sheep's brain. Meany's research showed that, in rats, hippocampus size is influenced by maternal nurturing behavior such as licking after birth. Well-licked rats had more developed hippocampi and produced less of the stress hormone corstisol. (Courtesy of the University of Pennsylvania School of Veterinary Medicine)Meaney now aims to see whether similar epigenetic changes occur when human mothers caress and hold their infants. He notes that the genetic sequence silenced by attentive mother rats has a close parallel in the human genome, so he expects to find a similar epigenetic influence. "It's just not going to make any sense if we don't find this in humans as well. The story is going to be more complex than with the rats because we'll have to take into account more social influences, but I'm convinced we're going to find a connection."
In an early study, which provided circumstantial evidence, Meaney examined magnetic resonance imaging brain scans of adults who began life as low-birth-weight babies. Those adults who reported in a questionnaire that they had a poor relationship with their mother were found to have hippocampi that were significantly smaller than average. Those adults who reported having had a close relationship with their mother, however, showed perfectly normal size hippocampi. Meaney acknowledges the unreliability of subjects reporting on their own parental relationships; nonetheless, he strongly suspects that the quality of parenting was responsible for the different shapes of the brains of these two groups.
In an effort to solidify the connection, he and other researchers have launched an ambitious five-year multimillion-dollar study to examine the effects of early nurturing on hundreds of human babies. As a test group, he's using severely depressed mothers who often have difficulty bonding and caring for their newborns and, as a result, tend to caress their babies less than mothers who don't experience depression or anxiety. The question is whether the babies of depressed mothers show the distinct brain shapes and patterns indicative of epigenetic differences.
The science of epigenetics opens a window onto the inner workings of many human diseases. It also raises some provocative new questions. Even as we consider manipulating the human epigenome to benefit our health, some researchers are concerned that we may already be altering our epigenomes unintentionally, and perhaps not for the better. Jirtle notes that the prenatal vitamins that physicians commonly encourage pregnant women to take to reduce the incidence of birth defects in their infants include some of the same chemicals that Jirtle fed to his agouti mice. In effect, Jirtle wonders whether his mouse experiment is being carried out wholesale on American women.
"On top of the prenatal vitamins, every bit of grain product that we eat in the country is now fortified with folic acid," Jirtle notes, and folic acid is a known methyl donor. "In addition, some women take multivitamins that also have these compounds. They're getting a triple hit."
While the prenatal supplements have an undisputed positive effect, Jirtle says, no one knows where else in the fetal genome those gene-silencing methyl donors might be landing. A methyl tag that has a positive effect on one gene might have a deleterious effect if it happens to fall somewhere else. "It's the American way to think, 'If a little is good, a lot is great.' But that is not necessarily the case here. You might be overmethylating certain genes, which could potentially cause other things like autism and other negative outcomes."
Szyf shares the concern. "Fueling the methylation machinery through dietary supplements is a dangerous experiment, because there is likely to be a plethora of effects throughout a lifetime." In the future, he believes, epidemiologists will have their hands full looking for possible epigenetic consequences of these public-health choices. "Did this change in diet increase cancer risk? Did it increase depression? Did it increase schizophrenia? Did it increase dementia or Alzheimer's? We don't know yet. And it will take some time to sort it out."
The implications of the epigenetic revolution are even more profound in light of recent evidence that epigenetic changes made in the parent generation can turn up not just one but several generations down the line, long after the original trigger for change has been removed. In 2004 Michael Skinner, a geneticist at Washington State University, accidentally discovered an epigenetic effect in rats that lasts at least four generations. Skinner was studying how a commonly used agricultural fungicide, when introduced to pregnant mother rats, affected the development of the testes of fetal rats. He was not surprised to discover that male rats exposed to high doses of the chemical while in utero had lower sperm counts later in life. The surprise came when he tested the male rats in subsequent generations—the grandsons of the exposed mothers. Although the pesticide had not changed one letter of their DNA, these second-generation offspring also had low sperm counts. The same was true of the next generation (the great-grandsons) and the next.
Such results hint at a seemingly anti-Darwinian aspect of heredity. Through epigenetic alterations, our genomes retain something like a memory of the environmental signals received during the lifetimes of our parents, grandparents, great-grandparents, and perhaps even more distant ancestors. So far, the definitive studies have involved only rodents. But researchers are turning up evidence suggesting that epigenetic inheritance may be at work in humans as well.
In November 2005, Marcus Pembrey, a clinical geneticist at the Institute of Child Health in London, attended a conference at Duke University to present intriguing data drawn from two centuries of records on crop yields and food prices in an isolated town in northern Sweden. Pembrey and Swedish researcher Lars Olov Bygren noted that fluctuations in the towns' food supply may have health effects spanning at least two generations. Grandfathers who lived their preteen years during times of plenty were more likely to have grandsons with diabetes—an ailment that doubled the grandsons' risk of early death. Equally notable was that the effects were sex specific. A grandfather's access to a plentiful food supply affected the mortality rates of his grandsons only, not those of his granddaughters, and a paternal grandmother's experience of feast affected the mortality rates of her granddaughters, not her grandsons.
This led Pembrey to suspect that genes on the sex-specific X and Y chromosomes were being affected by epigenetic signals. Further analysis supported his hunch and offered insight into the signaling process. It turned out that timing—the ages at which grandmothers and grandfathers experienced a food surplus—was critical to the intergenerational impact. The granddaughters most affected were those whose grandmothers experienced times of plenty while in utero or as infants, precisely the time when the grandmothers' eggs were forming. The grandsons most affected were those whose grandfathers experienced plenitude during the so-called slow growth period, just before adolescence, which is a key stage for the development of sperm.
The studies by Pembrey and other epigenetics researchers suggest that our diet, behavior, and environmental surroundings today could have a far greater impact than imagined on the health of our distant descendants. "Our study has shown a new area of research that could potentially make a major contribution to public health and have a big impact on the way we view our responsibilities toward future generations," Pembrey says.
The logic applies backward as well as forward: Some of the disease patterns prevalent today may have deep epigenetic roots. Pembrey and several other researchers, for instance, have wondered whether the current epidemic of obesity, commonly blamed on the excesses of the current generation, may partially reflect lifestyles adopted by our forebears two or more generations back.
Michael Meaney, who studies the impact of nurturing, likewise wonders what the implications of epigenetics are for social policy. He notes that early child-parent bonding is made more difficult by the effects of poverty, dislocation, and social strife. Those factors can certainly affect the cognitive development of the children directly involved. Might they also affect the development of future generations through epigenetic signaling?
"These ideas are likely to have profound consequences when you start to talk about how the structure of society influences cognitive development," Meaney says. "We're beginning to draw cause-and-effect arrows between social and economic macrovariables down to the level of the child's brain. That connection is potentially quite powerful."
Lawrence Harper, a psychologist at the University of California at Davis, suggests that a wide array of personality traits, including temperament and intelligence, may be affected by epigenetic inheritance. "If you have a generation of poor people who suffer from bad nutrition, it may take two or three generations for that population to recover from that hardship and reach its full potential," Harper says. "Because of epigenetic inheritance, it may take several generations to turn around the impact of poverty or war or dislocation on a population."
Historically, genetics has not meshed well with discussions of social policy; it's all too easy to view disadvantaged groups—criminals, the poor, the ethnically marginalized—as somehow fated by DNA to their condition. The advent of epigenetics offers a new twist and perhaps an opportunity to understand with more nuance how nature and nurture combine to shape the society we live in today and hope to live in tomorrow.
"Epigenetics will have a dramatic impact on how we understand history, sociology, and political science," says Szyf. "If environment has a role to play in changing your genome, then we've bridged the gap between social processes and biological processes. That will change the way we look at everything."
Abstracts regarding Epigenetics:
LOTS of Epigenetic studies at PubMed: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=17304537
Full text for abstract below at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16460559
Epigenetics and airways disease.
ABSTRACT: Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.
PMID: 16460559 [PubMed - as supplied by publisher]
The cancer epigenome--components and functional correlates.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
It is increasingly apparent that cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes, which convey heritable gene expression patterns critical for neoplastic initiation and progression. These aberrant epigenetic mechanisms are manifest in both global changes in chromatin packaging and in localized gene promoter changes that influence the transcription of genes important to the cancer process. An exciting emerging theme is that an understanding of stem cell chromatin control of gene expression, including relationships between histone modifications and DNA methylation, may hold a key to understanding the origins of cancer epigenetic changes. This possibility, coupled with the reversible nature of epigenetics, has enormous significance for the prevention and control of cancer.
PMID: 17158741 [PubMed - indexed for MEDLINE]
Epigenetics, disease, and therapeutic interventions.
Department of Dermatology and Epigenetic Research Center, Second Xiangya Hospital, Central South University, Hunan 410011, PR China.
Heritable changes in gene expression that do not involve coding sequence modifications are referred to as "epigenetic". Epigenetic mechanisms principally include DNA methylation and a variety of histone modifications, of which the best characterized is acetylation. DNA hypermethylation and histone hypoacetylation are hallmarks of gene silencing, while DNA hypomethylation and acetylated histones promote active transcription. Aberrant DNA methylation and histone acetylation have been linked to a number of age related disorders including cancer, autoimmune disorders and others. Since epigenetic alterations are reversible, modifying epigenetic marks contributing to disease development may provide an approach to designing new therapies. Herein we review the role of epigenetic changes in disease development, and recent advances in the therapeutic modification of epigenetic marks.
PMID: 16965942 [PubMed - indexed for MEDLINE]
Full text for abstract below at: http://www.cmaj.ca/cgi/content/full/174/3/341
Epigenetics and human disease: translating basic biology into clinical applications.
EpiGenWestern Research Group, Children's Health Research Institute, London, Ont. email@example.com
Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Research has shown that epigenetic mechanisms provide an "extra" layer of transcriptional control that regulates how genes are expressed. These mechanisms are critical components in the normal development and growth of cells. Epigenetic abnormalities have been found to be causative factors in cancer, genetic disorders and pediatric syndromes as well as contributing factors in autoimmune diseases and aging. In this review, we examine the basic principles of epigenetic mechanisms and their contribution to human health as well as the clinical consequences of epigenetic errors. In addition, we address the use of epigenetic pathways in new approaches to diagnosis and targeted treatments across the clinical spectrum.
PMID: 16446478 [PubMed - indexed for MEDLINE]
Targeting DNA methylation in cancer.
Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal PQ H3G 1Y6 Canada. firstname.lastname@example.org
Cancer growth and metastasis require the coordinate change in gene expression of different sets of genes. While genetic alterations can account for some of these changes, many of the changes in gene expression observed in cancer are caused by epigenetic modifications. The epigenome consists of the chromatin and its modifications, the "histone code" as well as the pattern of distribution of covalent modifications of cytosines residing in the dinucleotide sequence CG by methylation. The normal pattern of distribution of DNA methylation is altered in cancer. A number of genes are regionally hypermethylated but many parts of the genome are hypomethylated. Hypermethylation of tumor suppressor genes is involved in silencing of strategic genes. DNA hypermethylation has received much attention and a number of clinical trials are underway with different inhibitors of DNA methylating enzymes. It is now becoming clear however that hypomethylation also plays a role in cancer by activating genes required for invasion and metastasis. The potential therapeutic implications of targeting DNA methylation in cancer are discussed.
PMID: 16980240 [PubMed - indexed for MEDLINE]
Abstract below from: http://www.geneimprint.com/site/meetings/2005-durham
Epigenetics: Tying it All Together
Department of Medicine, Molecular Biology and Genetics, and Oncology; Johns Hopkins University School of Medicine
Although the human genome sequence has been complete for several years, few common diseases have been explained by common variants in the coding sequence of genes, suggesting that noncoding sequence and/or epigenetic variants are at least as important. Analysis of constrained sequence elements suggest that most is noncoding, and the challenge is to relate this information to phenotype and human disease. Another conundrum is the increasing incidence and severity of common disease with age, despite the fact rare highly penetrant Mendelian disorders generally appear congenitally or in early childhood. Epigenetic alterations represent an attractive potential mechanism for common disease as they involve noncoding sequence, increase with age, and are affected by diverse environmental agents including diet. An important role for somatically occurring epigenetic changes in cancer is now well established. I will discuss how epigenetic changes in apparently normal cells may also contribute to risk of cancer and other common diseases, and suggest how these epigenetic alterations may arise and act with genetic alterations to cause disease.
Posted by Qadoshyah at 12:04 PM
Thursday, February 22, 2007
Oral Motor issues are common to children with DS - mainly due to their low tone. There are many things which can be done to strengthen the oral motor muscles. The oral motor muscles are the cheeks, lips, tongue, mouth, etc. There are many areas that they need help with alot of the time - lip rounding, tongue retraction, lateral tongue movement, and the list goes ON and ON! There are a ton of different therapies you can do in this area. For anyone looking for more information on this, please see Sara Rosenfeld-Johnson's Oral Motor Therapy at TalkTools. She has a really good 6-hour DVD set on the DS Population.
But, one of SRJ's main therapy "tools" is teaching the child to learn to drink from a straw. This helps with muscles in their lips, cheeks and also helps tongue retraction. To help teach your child to learn to drink from a straw, TalkTools sells a honey bear with straw cup. This works so well to teach the child to learn to drink from a straw. My brother learned to drink from a straw, by using this honey bear, in TWO DAYS! We've seen a great improvement in my brother already in the several months he's been using Straw #1 in the straw hierarchy.
Anyways, onto the sippy cup which I was going to put up here. This sippy cup that is great for OMT is called Playtex QuickStraw Stage 4 Sippy Cup. It can be hard to find at times, but it can be found at Walmart, Raphs or on Ebay (the best deal). The cool thing about this sippy cup is that the straw is almost identical to a regular straw, with the same size etc, except of course it's a different texture. When you get these cups the straw that the child drinks out of is a couple inches long, so I can cut about 1/2 an inch or so off of the straw and my brother has a shorter straw that is almost the same exact length as his Straw #1 (we've cut it down alot, since he's progressed). So, you can use this sippy cup and cut down the length as you cut down the length on your Straw #1. The point of cutting down the length is so that the child learns to suck with his lips, instead of his tongue. He should only be sucking with a 1/4 ro 1/2 an inch of the straw in his mouth - not much at all. We've noticed a set-back with my brother if we get lax and don't make him only drink out of these certain sippy cups or his Straw #1. So, we've gotten rid of all other sippy cups and have only these in the house - so he won't ever use any other sippy cup that might be laying around. Here's a picture of what this sippy cup looks like:
Below is another picture of the cup and the red line across the straw is how short I cut the straw for my brother. It works GREAT!!
There are also a few other brands and kinds of sippy cups that have this same silicone straw. So, you can also get those other ones and cut the straw down the same way. All of these cups with this particular silicone straw are good, since they are like a regular straw and it helps the child's muscles. Here are links to a few of the other brands and kinds that have this same silicone straw:
Posted by Qadoshyah at 10:06 PM
Tuesday, February 20, 2007
On the Einstein-Syndrome listserv there was a discussion regarding the brains of children with DS and how they are when they are born and in pregnancy. These are the recent posts I did on it and I thought this would be good information for others as well:
Back in November of '06 there was some discussion regarding the brains of children with DS starting out normal and then start going downhill at 6 months of age. Regina sent me 4 articles that she was able to get from a doctor who had said that the brains of children with DS start out normal and then go awry at 6 mths old. I finally had a chance to look at the 4 studies she emailed to me. I read in-depth one of the studies (see below) and skim read the others. I also did a bit of research on PubMed too. All 4 of these studies talk about the Dendritic cells (regards neurons & the brain). To look to these 4 studies and say that the brain of children with DS starts out normal is incorrect. These 4 studies were done in the 70's & 80's, so there obviously has been much advance in the research since then and particularly in regards to the brain. I wouldn't go just on these 4 studies to try to show that the brains in DS are normal. These studies do show some good things in regards to dendritic cells and such. In the study that I will quote below, they have already seen changes at 4 months of age! But, you can look this stuff up on PubMed and find that there are changes in the dendritic area in brains of children with DS as early as 19 wks gestation. So, there is newer research and evidence that shows that there are abnormalities in the DS brain in this particular area before birth. Plus, you cannot just look at one particular area and say that the brain is normal up until a certain age. There are many other problems present in the DS brain when they are born (as I posted back in November some studies & I'll repost those again).
Dendritic Atrophy in Children with Down's Syndrome. Becker, 1986
"The results suggest that the dendritic tree atrophies in early childhood in DS."
This study is speaking of the dendritic tree atrophying. This does not mean that the brain of children with DS is normal at birth. This shows that the dendritic tree has not yet atrophied at birth, but appears to start atrophy at a later age. There are many, many complex systems in the Down syndrome body which do not function correctly. When all of these systems start to cause problems it is not completely known. There are certain things that are present at birth (such as oxidative stress and many other things). The gene overexpressions are all present at birth (present when the child is created with the 21st chromosome mutation), but when each one's influence starts, it is not completely known.
In the beginning of this study, it cites several different studies which have been done that are examining the basis for mental retardation in DS. They mention throughout some changes which have been seen in children over 4 months of age. Things are changing at a young age.
An interesting thing in this study is that there are changes in a child with down syndrome even as an infant. One paragraph of the study states, "Our analysis of dendritic branching development in brains of patients with Down's syndrome reveals that the pattern of branching is different from that of control brains."
So, in this study they acknowledge that the brains of children with DS are different from normal brains. They go onto say that there are changes even in the infants, "In the infantile period, the total number of intersections was greater in subjects with Down's syndrome than in controls. By the juvenile period, the number of intersections was significantly decreased. . ."
Another spot in the study says, "With early growth and development, the normal dendritic tree expands. This expansion is not seen in Down's syndrome. On each of the measures ( . . .), the Down's syndrome neurons showed decreased numbers with increasing age."
As I stated above, the brains of children with DS are different at birth, but they do not start to see atrophy until the child gets older.
Another statement in the study states that they see another interesting difference in DS, at a young age of only 4 months. They write, "The Down's syndrome neurons showed one other striking difference from controls -- a relatively expanded dendritic tree at 4 months of age. There are several plausible explanations for the excessive early outgrowth of dendritic branches followed by subsequent atrophy. The excessive dendrite branching may be an abortive attempt by the neuron to compensate for the decreased numbers of spines and synapses on its receptive surfaces."
They speculate why this may happen and say, "The extra chromosome 21 may produce excess RNA and protein that cannot be permanently incorporated into the dendritic membrane or cytoskeleton, so membrane turnover is decreased. This would prevent the dendritic tree from being maintained, which would cause the neurons to become "atrophic" relative to the control dendritic pattern."
They note at the end of the article, "Like other investigators, we have found quantitative differences between controls and patients. . . a quantitative change should be expected." This is something I wish some of those people who are not for TNI would realize. A change should be expected in DS compared to normal individuals. They don't seem to realize that all too often!
Looking up some information on PubMed regarding the dendritic cells and DS brings up this current information:
---- This below abstract states that they see abnormalities in the fetus with Down Syndrome. Thus, showing that dendritic abnormalities are present in the brain of a baby with DS. I'll paste another abstract below which says that dendritic abnormalities are known to be one of the reasons for MR in Down Syndrome.
J Neuropathol Exp Neurol. 2004 Jul;
Trisomy 21 and the brain.
Mrak RE, Griffin WS.
In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a "tree in winter" appearance. This developmental failure is thought to result in mental retardation. In adults with Down syndrome, neuronal loss is dramatic and neurofibrillary and neuritic Abeta plaque pathologies are consistent with Alzheimer disease. These pathological changes are thought to underlie the neuropsychological and physiological changes in older individuals with Down syndrome. Two chromosome 21-based gene products, beta-amyloid precursor protein (betaAPP) and S100B, have been implicated in these neuronal and interstitial changes. Although not necessary for mental retardation and other features, betaAPP gene triplication is necessary, although perhaps not sufficient, for development of Alzheimer pathology. S100B is overexpressed throughout life in Down patients, and mice with extra copies of the S100B gene have dendritic abnormalities. S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis. Interleukin-1 (IL-1) is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome. IL-1 upregulates betaAPP and S100B expression and drives numerous neurodegenerative and self-amplifying cascades that support a neuroinflammatory component in the pathogenesis of sporadic and Down syndrome-related Alzheimer disease.
PMID: 15290893 [PubMed - indexed for MEDLINE]
Prog Neurobiol. 2004 Oct
On dendrites in Down syndrome and DS murine models: a spiny way to learn.
de Lagran MM,
Cajal Institute, 28002 Madrid, Spain.
Since the discovery in the 1970s that dendritic abnormalities in cortical pyramidal neurons are the most consistent pathologic correlate of mental retardation, research has focused on how dendritic alterations are related to reduced intellectual ability. Due in part to obvious ethical problems and in part to the lack of fruitful methods to study neuronal circuitry in the human cortex, there is little data about the microanatomical contribution to mental retardation. The recent identification of the genetic bases of some mental retardation associated alterations, coupled with the technology to create transgenic animal models and the introduction of powerful sophisticated tools in the field of microanatomy, has led to a growth in the studies of the alterations of pyramidal cell morphology in these disorders. Studies of individuals with Down syndrome, the most frequent genetic disorder leading to mental retardation, allow the analysis of the relationships between cognition, genotype and brain microanatomy. In Down syndrome the crucial question is to define the mechanisms by which an excess of normal gene products, in interaction with the environment, directs and constrains neural maturation, and how this abnormal development translates into cognition and behaviour. In the present article we discuss mainly Down syndrome-associated dendritic abnormalities and plasticity and the role of animal models in these studies. We believe that through the further development of such approaches, the study of the microanatomical substrates of mental retardation will contribute significantly to our understanding of the mechanisms underlying human brain disorders associated with mental retardation.
PMID: 15518956 [PubMed - indexed for MEDLINE]
--- Another interesting study below done by Lubec states that there are significant abnormalities in babies with DS before birth. The babies they did these studies on were 19wks gestation.
J Neural Transm Suppl. 2001;
Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure.
Department of Pediatrics, University of Vienna, Austria.
Information on fetal brain in Down Syndrome (DS) is limited and there are only few histological, mainly anecdotal reports and no systematic study on the wiring of the brain in early prenatal life exists. Histological methods are also hampered by inherent problems of morphometry of neuronal structures. It was therefore the aim of the study to evaluate neuronal loss, synaptic structures and dendritic spines in the fetus with Down Syndrome as compared to controls by biochemical measurements. 2 dimensional electrophoresis with subsequent mass spectroscopical identification of spots and their quantification with specific software was selected. This technique identifies proteins unambiguously and concomitantly on the same gel. Fetal cortex samples were taken at autopsy with low post-mortem time, homogenized and neuron specific enolase (NSE) determined as a marker for neuronal density, the synaptosomal associated proteins alpha SNAP [soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein], beta SNAP, SNAP 25 and the channel associated protein of synapse 110 (chapsyn 110) as markers for synaptosomal structures and drebrin (DRB) as marker for dendritic spines. NSE, chapsyn 110 and beta SNAP were comparable in the control fetus panel and in Down Syndrome fetuses. Drebrin was significantly and remarkably reduced and not even detectable in several Down Syndrome brain samples. Quantification of SNAP 25 revealed significantly reduced values in DS cortex and alpha SNAP was only present in half of the DS individuals. We conclude that at the time point of about 19 weeks of gestation (early second trimester) no neuronal loss can be detected but drebrin, a marker for dendritic spines and synaptosomal associated proteins alpha SNAP and SNAP 25 were significantly reduced indicating impaired synaptogenesis. Early dendritic deterioration maybe leading to the degeneration of the dendritic tree and arborization, which is a hallmark of Down Syndrome from infancy.
PMID: 11771761 [PubMed - indexed for MEDLINE]
Here's the earlier post that has the abstracts regarding the differences in the DS brain:
Here's a really good abstract I found that talks about oxidative stress in DS. This abstract below is saying that there is oxidative stress in DS, but it is not due to the overexpression of SOD1, at this point. But, rather due to the low levels of antioxidant and reducing agents, which cannot deal with getting rid of hydrogen peroxide. This makes lots of sense, since so many with DS are born with congenital heart defects, which have been associated with low antioxidant levels and increased oxidative stress.
Antioxidant proteins in fetal brain: superoxide dismutase-1 (SOD-1) protein is not overexpressed in fetal Down syndrome.
Gulesserian T, Engidawork E, Fountoulakis M, Lubec G.
Department of Pediatrics, University of Vienna, Austria.
Exposure of living organisms to reactive oxygen species (ROS), notably oxygen free radicals and hydrogen peroxide is closely linked to the very fact of aerobic life. Oxidants, however, are not always detrimental for cell survival, indeed moderate concentrations of ROS serve as signaling molecules. To maintain this level, cells have evolved an antioxidant defense system. Disruption of this balance leads either to oxidative or reductive stress. Down syndrome (DS) is a genetic disorder associated with oxidative stress. Overexpression of superoxide dismutase-1 (SOD-1) as a result of gene loading is suggested to be responsible for this phenomenon. To examine this view, we investigated the expression of thirteen different proteins involved in the cellular antioxidant defense system in brains of control and DS fetuses by two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). No detectable change was found in expression of SOD-1, catalase, phospholipid hydroperoxide glutathione peroxidase, glutathione reductase, antioxidant enzyme AOE372, thioredoxin-like protein and selenium binding protein between control and DS fetuses. By contrast, a significant reduction was observed in levels of glutathione synthetase (P < color="#990000" size="4">Molecular changes in fetal Down syndrome brain
Ephrem Engidawork and Gert Lubec
Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegeneration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of developmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of biochemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation.
Full text @
Another follow-up post regarding this subject. I read through the study mentioned above by Gert Lubec and these are some notes from it:
I was reading through the study by Gert Lubec - Molecular changes in fetal Down syndrome brain - and thought I would note some points he makes regarding the differences that have been seen.
From the study:
"Stereological cell counting techniques, however, revealed that the second phase of cortical development and the emergence of lamination are both delayed and disorganized in fetal DS brain (Golden and Hyman 1994)"
" In addition, although the emergence and morphology of microglial cells appear not to differ from those in normal fetuses, microglial cells outnumber astroglial cells in fetal DS brain (Wierzba-Bobrowicz et al. 1999)."
"In addition, other studies have revealed relatively delayed myelination, fewer neurones, lower neuronal density and distribution, and abnormal synaptic density and length, caused probably by prenatal abnormal neuronal migration and retarded synaptogenesis (Wisniewski and Schmidt-Sidor 1989; Wisniewski 1990)."
"Consistent with the gene dosage effect, gene products that are over-expressed in fetal DS brain include Down syndrome critical region-1 (DSCR-1) (mRNA), intersectin (mRNA), S100β (mRNA and protein) and synaptojanin (protein) (Table 1). DSCR-1 is a developmentally regulated gene involved in neurogenesis and its over-expression may contribute to brain abnormalities through inhibition of calcineurin-dependent gene transcription (Fuentes et al. 2000). The intersectin gene is widely expressed in fetal as well as adult tissues, and codes for two isoforms, short and long, by alternative splicing. The long isoform is brain specific; it takes part in synaptic vesicle recycling activities and is over-expressed in brain of DS fetuses compared with controls (Pucharcós et al. 1999). S100β protein exhibits a lifelong over-expression in DS brain (Griffin et al. 1998). Its mRNA is also documented to be increased in fetal DS brain (Epstein 2001). S100β is synthesized and released by astrocytes in response to serotonin (5-HT)-mediated stimulation of 5-HT1A receptors and appears to be an important neurotrophic agent during normal fetal brain development, with effects on neuroblasts and glia (Azmitia et al. 1992). Early over-expression of S100β may therefore indicate a potential role of this protein in dendritic abnormalities and mental retardation. More importantly, it can provide an important clue to the link between 5-HT and DS (Whitaker-Azmitia 2001). Synaptojanin is a highly abundant polyphosphoinositide phosphatase over-expressed in fetal DS brain (Arai et al. 2002). It modulates synaptic transmission and plays a role in clathrin-mediated synaptic vesicle endocytosis and signalling. Over-expression may form the neurochemical basis for impaired synaptic functions in DS brain."
"In stark contrast to the products mentioned above, collagen (VI) α1 chain precursor protein is decreased in fetal DS brain (Engidawork et al. 2001a). "
"Reduced expression of collagen type (VI) α1 chain precursor complements the finding of deteriorated expression of axonal guidance proteins, including dihydropyrimidinase-related proteins in fetal DS brain (Weitzdoerfer et al. 2001b)."
"Human Ets-2 is a proto-oncogene and transcription factor that defines the distal limit of the Down syndrome critical region. It is coded by the ets-2 gene, which is a member of the ets-2 gene family identified on the basis of homology to the v-ets oncogene isolated from the E26 erythroblastosis virus (Raouf and Seth 2000). The ubiquitous distribution of Ets-2, including the brain (Bhat et al. 1987; Baffico et al. 1989), and its role in leukaemia and organogenesis together with the fact that its encoding gene is located on chromosome 21, would make Ets-2 a logical protein to provide evidence for the gene dosage hypothesis and its consequences. In this regard, the development of skeletal abnormalities resembling those of DS in transgenic mice over-expressing Ets-2 (Sumarsono et al. 1996) strengthened this view. However, neither Ets-2 message (Baffico et al. 1989) nor Ets-2 protein levels (Engidawork et al. 2001a) are significantly different between control and DS fetal brain, in contrast to what would be expected from a gene dosage effect. This discrepancy emphasizes that extra gene load is not always associated with gain of function."
"Indeed, although levels of β-amyloid precursor protein (APP) (Epstein 2001) and superoxide dismutase [Cu–Zn] (SOD)-1 (de Haan et al. 1997) mRNA are increased in fetal DS brain, levels of the corresponding proteins are comparable to those in controls (Arai et al. 1996; Griffin et al. 1998; Engidawork et al. 2001a; Gulesserian et al. 2001)."
"In keeping with the lack of an adaptive response in DS, expression of catalase is unaltered in fetal DS brain (Gulesserian et al. 2001), but it is SOD-1 activity (Brooksbank and Balazs 1984) rather than expression (Gulesserian et al. 2001) that was increased. "
"Accordingly, increased SOD-1 activity might be a consequence rather than an antecedent of oxidative stress. However, SOD-1 activity can later have a positive reinforcing effect. This line of thinking hints that there are other possible primary causes of oxidative stress in fetal DS. The possible candidates are peroxiredoxins and Aβ. Peroxiredoxins, a family of enzymes that detoxify hydrogen peroxide, are decreased in fetal DS brain (Gulesserian et al. 2001) and Aβ can cause increased production of hydrogen peroxide and lipid peroxides (Behl et al. 1994). Although the exact mechanism by which Aβ causes accumulation of hydrogen peroxide is not known, three possible sources can be envisaged. The first is iron release from aconitase (Longo et al. 2000), shown to be increased in fetal DS brain (Bajo et al. 2002). The second is binding to advanced glycation end products receptor (Yan et al. 1997), which is also increased in fetal DS brain (Odetti et al. 1998). The third mechanism involves Aβ-mediated generation of hydrogen peroxide through its interaction with copper (Huang et al. 1999)."
"Among these molecular switches, synaptic proteins appear to sustain major alterations in prenatal DS brain. Synaptic proteins involved in activities ranging from neurotransmitter release to synaptic maturation during cortical development, including Aβ precursor-like protein-1, synaptosome-associated protein (SNAP)-25, αSNAP and septins, are significantly reduced (Cheon et al. 2001; Weitzdoerfer et al. 2001a; Lubec G. unpublished data). Altered expression of these synaptic markers can provide at least a partial explanation for retarded synaptogenesis. Cholinergic and catecholaminergic markers are unaffected, whereas glutamatergic and serotonergic markers have been reported to be increased by some, if not all, authors (Brooksbank et al. 1989; Bar-Peled et al. 1991; Arai et al. 1996; Oka and Takashima 1999; Lubec et al. 2001b)."
"A host of proteins involved in signalling processes downstream of chemical transmission or other signal transduction pathways is also decreased in fetal DS brain (Fig. 2). This includes 14-3-3 protein γ isoform, nucleoside diphosphate kinase (NDK)-B, Rab GDP-dissociation inhibitor (GDI)-β, signalling adapter proteins, such as receptor for activated C kinase (RACK)-1, Crk, Crk-like protein and Nck adapter protein 2 (Freidl et al. 2001; Weitzdoerfer et al. 2001c; Peyril et al. 2002; Lubec G. unpublished data). "
"Thus, transcription factors play a pivotal role in modelling and wiring the brain. Altered expression of several transcription factors has been reported in fetal DS brain, which tentatively explains the abnormal neurogenesis (Table 2). At the mRNA level, repressor element-silencing transcription factor (REST) (also called neurone restrictive silencer factor), a transcription factor that plays an important role in brain development, neuronal plasticity and synapse formation, is down-regulated in neurospheres derived from fetal DS (Bahn et al. 2002). "
" Not unlike REST, the junD component of the AP-1 transcription factors implicated in neurogenesis and nuclear factor-kappa B, a transcriptional regulator of a multitude of genes involved in immune and inflammatory responses, is decreased in fetal DS brain (Labudova et al. 1999). On the other hand, scleraxis, a basic helix–loop–helix type transcription factor that regulates growth and differentiation of numerous cells, is up-regulated (Labudova et al. 1999)."
"Aberrant expression of splicing, RNA stabilizing and translation factors has been noted in fetal DS brain (Freidl et al. 2001; Engidawork E. et al., unpublished data) (Table 2). Collectively, these findings suggest that failure of the transcription and translation machinery early in life may be responsible for, or may reflect, impaired brain development and deficient wiring of the brain in DS."
"An increasing body of evidence indicates that cytoskeletal abnormalities are apparent in prenatal life and may be largely responsible for the cortical dysgenesis in DS"
"Components of the dynactin complex, such as centractin α and F-actin capping protein subunits, are significantly reduced in fetal DS brain (Gulesserian et al. 2002), indicating disruption of a supply line that provides structural and functional materials required for normal growth to intraneuronal sites. "
"A number of actin-binding proteins have been shown to be decreased in fetal DS brain, underpinning that loss of actin function indeed accounts for dendritic and migration abnormalities. Drebrin, an actin-binding and -bundling protein that forms dendritic spines, has been noted to be missing (Weitzdoerfer et al. 2001a). "
"Because cytoskeletal regulation is important for synapse development, its deregulation seems to be a major determinant for migration and synaptic abnormalities associated with DS (Fig. 3)."
"Conspicuous morphological abnormalities start to be apparent in brains of newborns and older infants with DS. They have shortened basilar dendrites, a decreased number of spines with altered morphology and defective cortical layering (Marin-Padilla 1976; Takashima et al. 1981; Becker et al. 1986; Schmidt-Sidor et al. 1990)."
Back to me:
There are SO many different abnormalities in the DS brain before birth or at birth and later on. It is amazing! It is so complex, they do not understand it all. All this seems like so much evidence for the use of TNI. And people try to say that they don't need anything different for their child than they do a regular child - do they not realize there are so many different abnormalities????? No, I don't think they do sometimes!
Lubec closes with this conclusion:
"It should be borne in mind that DS is a complex disorder because it is caused by an extra copy of a whole set of genes. The impact of gene over-dosage on the transcription level may vary because some genes are highly regulated. Thus, the presence of three copies of many genes may result either in over-expression or repression of transcripts. The effects of three copies of a gene may be even more complex at the protein level, as additional regulatory points are introduced, for example post-translational modifications that can alter the function or stability of the protein. The cumulative observations presented in this article suggest that the presence of an extra gene does not necessarily lead to a gain of function. Instead, the mere presence of a chromosomal imbalance appears to affect the coordinated regulation of expression and interaction of genes/proteins that have relevance to normal brain development and functions. Misexpression of genes/proteins that play crucial roles in neuromorphogenesis and neurogenic cascades appears to be the biological mechanism responsible for the pathogenesis of mental retardation in DS. Such aberration results in developmental abnormalities in neural patterning and signal transduction pathways, eventually leading to formation of suboptimal functioning neuronal circuitry (Fig. 4)."
Posted by Qadoshyah at 9:46 PM