SIDS.Words

--Common cardiac gene linked to sudden infant death in African Americans--

(Shorter version appearing on ScienceNOW, Wednesday, February 1)

Infants with 2 copies of a common variant in a gene associated with irregular heartbeat are 24 times more likely to experience sudden death, a new study shows.

The variant, considered common because it is present in over 10% of African Americans, does not cause sudden infant death syndrome (SIDS) on its own, nor is it a problem when present in one copy. However, a double dose of the defect seems to make infants more vulnerable to environmental stresses that are typically associated with SIDS and that healthy children can easily tolerate.

"The common polymorphism alone does not cause SIDS," said Steven Goldstein, M.D., Ph.D., professor and chairman of pediatrics at the University of Chicago and director of the study. "Our findings suggest, however, that it renders infants vulnerable to environmental challenges -- such as a long pause in respiration -- that are tolerated by children without the mutation."

"The hope," he added, "is that findings like this may one day allow us to intervene. We might screen to identify children at high risk and teach parents how to lessen the likelihood of secondary challenges. We have already begun to evaluate drugs that may mitigate the risk."

SIDS is the sudden and unexpected death of a child with no detectable lethal disorder. It is the leading cause of infant mortality in the United States among infants between one month and one year of age. While research suggests that environmental factors – like sleeping on the stomach or exposure to second-hand smoke – are partly to blame, the fact that African Americans are three times more likely than Caucasians, and six times more likely than Hispanics or Asians to experience sudden death, suggests an important role for genetics, too.

Particular genetic variation tends to run in ethnic groups. Yet no previous work has specifcally examined a group of African American SIDS victims to understand how genetic variation might contribute to SIDS in this cohort. “That’s what is different about this study,” said Alfred George, M.D., chief of the Division of Genetic Medicine at Vanderbilt University School of Medicine.

Goldstein and colleagues at the University of Chicago studied genes in the heart tissue of 133 African American infants diagnosed, after autopsy, with SIDS. Goldstein’s search focused on abnormalities in one gene in particular: SCN5A, which codes for a sodium ion channel in the heart and in which rare SIDS-related mutations had previously been found. His team indentified genetic variants in SCN5A, observing that one variant in particular, Y1103, was 24 times more frequent in two alleles in SIDS victims than it was in healthy individuals. Goldstein had no idea how a double dose of Y1103 increased risk of SIDS, however, since it did not appear to hinder ion channel operation – or interrupt heartbeat -- under normal conditions.

SIDS is not purely genetic, though, and Goldstein decided to consider environmental triggers, too. It is known that sudden death occurs in settings of interrupted breathing, common in infants who sleep on their stomachs. Interrupted breathing deprives cells of oxygen and causes a slight increase in acid levels in the blood.

Goldstein simulated this acidic environment in culture, and then compared cells with the Y1103 mutation against normal cells. The cells with the abnormal channels misbehaved in acidic conditions; they could not regulate sodium ion levels, a difficulty which leads to changes known to increase the risk for abnormal heart rhythms and sudden death. The Chicago team speculates online February in the Journal of Clinical Investigation that, in the setting of impaired breathing, SIDS occurs more readily when an individual carries two copies of Y1103.

“This study doesn’t imply that Y1103 is the only genetic factor in SIDS,” George explained. “However, it supports the idea that genetic variation coupled with a specific environmental stressor, like acidosis, may trigger sudden death. The study emphasizes the need to determine the true incidence of genetic causes of sudden death in infants. Once that’s done, a decision can be made as to the rationale and cost effectiveness of general population screening for these genetic factors.”

According to Debra E. Weese-Mayer, M.D, professor of pediatrics at Rush University's Center for SIDS Research in Chicago, “the study is a major step forward in terms of the sophisticated kind of analsyis that should be expected as additional cardiac rhythm genes are considered in SIDS.”

.MGW.

NewSiteWords

A new site has been made! It contains links to the articles I publish at Science Magazine's website.

If interested, you can also type the following into your browser!

http://www.kalin-bg.com/meagan-white/


.MGW.

CD8+T-cellWords

-- Mouse study suggests a risk of serious side effects with peptide
vaccines --

(To be published on ScienceNOW, "Science" magazine's website, on Thursday, January 19th)

T-cells – crucial players in the body's defense against viruses -- have good memories, but that could mean bad luck for vaccine recipients. According to a new study, vaccinating mice with peptides that mimic viruses to which the mice have already been exposed can be harmful. That’s because peptides trick the mouse’s T cells into making toxic antiviral compounds that – when present in large numbers – not only kill viruses, but also cause host symptome ranging from mild harm to death. These negative effects, say researchers at The Scripps Research Institute, are due to activation of too many T cells at one time. The study has implications for improving design of peptide vaccines for humans.

Peptide vaccines are new members in today’s arsenal of vaccination tools. The peptides – or proteins -- used in these vaccines bolster the immune system because they are identical to short sequences of virus proteins called epitopes. T cells learn to recognize epitopes, in different viruses, so that when next exposed to them, the T cells activate, attacking the epitopes and preventing infection in the host. Epitope injection in peptide vaccines also poses a risk, however; unlike DNA-based vaccines, for example, where proteins have to be processed before epitopes are in the proper form to activate T cells, peptide vaccines can activate T cells immediately. In naïve mice – those not previously exposed to a certain virus – immediate activation is necessary to prevent infection. But what happens if a recipient of a peptide vaccine already has a large number of T cells specific for the viral epitope being injected? That would make for quite a lot of T’s, both the old epitope-specific ones and the newly recruited ones, responding to peptide injection. And while tons of T cells tackling the trouble sounds like it would be beneficial, it’s not.

Researchers at Scripps Research Institute have determined how particular T cells, known as CD8+ cells, respond to peptide vaccines. At the Department of Neuropharmacology, J. Lindsay Whitton and colleagues, whose results will be published next month in The Journal of Clinical Investigation, infected mice with lymphocytic choriomeningitis virus, or LCMV. Eight days later, Whitton vaccinated these mice either with a peptide representing the LCMV epitope, or with saline alone. The saline-injected mice displayed no negative side effects, but the peptide-injected mice developed several shocklike symptoms, including hypothermia, and died within 24 hours of injection. (Whitton and his colleagues identified TNF – tumor necrosis factor – as the molecule responsible for the temperature drop and the lethal effects in these mice. The TNF, they discovered, was produced by the CD8+ T cells in response to the LCMV peptide.) Thus, peptide injection in a naive individual does not activate large numbers of T cells, since the T cells present have not yet seen the virus, nor had a chance to congregate in epitope-specific pools. However, this same peptide injection activats numerous T cells – thereby harming the host -- in an individual who has been previously exposed to the virus. Whitton was careful to explain that “this study is a cautionary flag for peptide vaccines, and not an indication to abandon ship.”

Matthias von Herrath, head of the Immune Regulation Lab at La Jolla’s Institute for Allergy and Immunology agrees, saying that peptide vaccines are useful, “as long as we ensure that they cannot cause synchronous activation of pre-existing T cells.”

Mark Larche, Ph. D. and Senior Research Fellow at the Imperial College of London’s Department of Clinical Immunology, also corroborates on the potential for peptide vaccines. He attributes their negative side effects to dosage issues. “The message of this study is that yes, you will have problems with the wrong -- too high -- dose of peptides, but that does not mean peptides will not be good vaccine components. Peptide vaccines offer the ultimate in specificity. It’s just that great attention must be paid to defining doses so as not to cause activation of huge numbers of T cells.”

Larche has done work similar to Whitton’s in asthma patients, administering synthetic peptides that elicit T cell responses. “We have spent a lot of time working out the dose relationships,” he explained, “and you can avoid negative side effects with peptide vaccines while still achieving immunological tolerance, by delivering low doses. The correct dose-finding studies in humans should make this effect less of an issue. Essentially, you want to induce an immune response with these vaccines, but you don't want to induce a response so great that the antiviral effects, like TNF, end up killing the subject. Everything in moderation...just like everything else in life.”

.MGW.

UpdateWords

Hark! A blog update?!

Great Scott... nearly a month has passed since the last.

And an update is most assuredly due. Yes-- this is true. (Thank you to those who've acknowledged. I appreciate your interest!)

I admit I've been remiss in updating my blog. But it's not been bare of new beef for no reason. Nooo. Rather, I've not been writing science here because I've been thinking science, elsewhere, for this semester. (Although... you can look for an article at the end of next week on a new mouse study, done at Scripps Research Institute, that suggests risk of serious side effects associated with peptide vaccines. MmmmmT cells.)

But, I've not been blogging science for the past month because I'm:

1) reading lots of it.

I'm preparing to do my Master's thesis this semester, and that will entail some good background work. Some interviews at the Medical School. Some serious time with the books. *Topic to be disclosed at a later date!

2) Teaching an interdisciplinary intersession course at Hopkins: "Digital Storytelling: Narrating your Personal History."

This course requires students to write narratives -- which will be turned into documentaries -- about influential familiy members. I am working with the students to develop narratives that convey a theme, or a point, if you will, for a broader audience. Narratives that leave the reader with a better understanding of some difficult life tenet.

The digital media department is working with the students, too. The science writing link? I will learn the art of podcastin'. And as a communicator of science, any new means of media that I can grasp especially well will position me better.

Bring on the podcasts!

* * *

This semester, I'll be interning at NPR in DC, working with Anna Vigran at Science Desk. Radio broadcast. Another form of communication.

My blog should still be changing though; I'll be taking psychopharmacology and Rise of Modern Science here at Hopkins, both of which will provide good fodder for my inquiring mind. For articles!

I'll also intern with David Grimm, writing 350-400 word pieces for Science Magazine's online site, ScienceNOW. These should come out bi-monthly. And be onnnnn the blog.

Lastly, thesis work will give me lots to think about~ to write! And really truly, I aspire to just research & write science as it strikes me -- the science of everything around me.

Thank you again, for stopping to glimpse. Happy 2006! May biology, physics...chemistry, nanotechnology... space and the sea!... stars, vessels, and memes... provide us with new excitement -- new discovery -- each and every day.


Best,

MGW