|Unlikely genetic suspect implicated in common brain defect
A genetic search that wound its way from patients to mouse models and back to patients has uncovered an unlikely gene critically involved in a common birth defect which causes mental retardation, motor delays and sometimes autism, providing a new mechanism and potentially improving treatment for the disorder.
Researchers from the University of Chicago, University of Alberta and other institutions announce in the September issue of Nature Genetics--available online August 10--that the FOXC1 gene contributes to Dandy-Walker malformation (DWM), a brain defect that occurs in 1 of every 5,000 births.
The role of the gene in Dandy-Walker malformation dispels the fog surrounding what goes awry in the brains of children born with the disorder. DWM is characterized by an improperly formed cerebellum, the region at the back of the brain involved in movement and coordination. As a result children with this disorder require considerable medical care, and in some cases surgery to treat the build up of fluid around the brain, a condition called hydrocephalus.
Researchers were surprised to discover that the FOXC1 gene mediated development of the cerebellum and contributed to DWM, as the gene is never actually expressed in the brain itself. Instead, the FOXC1 gene is expressed in fetal tissue called mesenchyme, which forms the skull and other layers that surround and protect the brain. That mechanism suggests an exciting new element of embryonic brain development, said study co-author Kathleen Millen, Ph.D., assistant professor of human genetics at the University of Chicago.
This image shows MRI scans of normal patients (a, b) and patients with missing or affected FOXC1 genes or larger gene deletions. William Dobyns, M.D. Kathleen Millen, Ph.D
"The developing skull and all the stuff around the brain actually are as important for brain development as the brain itself," Millen said.
In the developing fetus, FOXC1 acts as a "master regulator," directing the expression of other genes that, in turn, give instructions necessary for the adjacent embryonic brain to properly form.
"It's controlling downstream genes, and some of those downstream genes we know are signaling molecules and growth factors that apparently are required for brain development," Millen said. "When you don't have them the brain gets screwed up; not because the causative gene is expressed in the brain but because it's in the surrounding tissue."
The new discovery follows research from the same group, published in 2004, that found the first genes associated with DWM. "The first gene didn't give us a huge clue, but this one gives us a major clue to the underlying cause," said study co-author William Dobyns, M.D., professor of Human Genetics, Neurology and Pediatrics at the University of Chicago.
The path to the unlikely FOXC1 gene began with a Dandy-Walker patient referred to Dobyns in 2004, shortly after the researchers had published on the first two genes associated with the disorder. While those genes were located on chromosome 3, this patient exhibited an abnormal chromosome 6, implicating a second hotspot for DWM.
The researchers narrowed their search to a region of eight genes on chromosome 6. Patients with severe DWM were missing as many as seven genes in the target region, while patients missing just one gene showed mild abnormalities detectable only by MRI brain scans.
To determine which of the eight genes were most critical in development of the disorder, researchers turned to mouse models. One mouse, selectively lacking the FOXC1 gene, was created to study eye, heart and muscle defects, but no one had studied its brain.
Millen herself said she was skeptical that the mouse lacking the FOXC1 gene would be relevant to their study, and said she bet Kimberly Aldinger, the University of Chicago neurobiology graduate student who is first author on the study, a free lunch that the gene would not be the one they were seeking. It was a bet she happily lost. "The moment we looked at the very first brain, it was so obvious they had a very messed up cerebellum and it had been completely overlooked," Millen said.
Now confident that FOXC1 was important for cerebellar development in mice, the researchers then searched for humans lacking all or part of the gene. Fortunately, they found 11 such subjects through Ordan Lehmann, associate professor of ophthalmology and medical genetics at the University of Alberta, who was studying patients with pediatric-onset glaucoma caused by FOXC1.
When the glaucoma patients were given MRI scans, the researchers observed cerebellar abnormalities that proved the involvement of FOXC1 in Dandy-Walker malformation.
"These patients were essential for blaming the brain malformation on the FOXC1 gene," Millen said. "Based on the mouse mutants we had a huge suspicion it had to be FOXC1, and the patients confirmed it."
The dramatic changes in the brains of these patients offers new insight into mechanisms contributing to glaucoma, a common disorder previously considered to be just a disease of the optic nerve – the nerve connecting the eye to the brain. Further studies of how the FOXC1 gene directs development of the cerebellum and other brain structures could also lead to new research avenues and treatments for hydrocephalous, autism and other diseases.
"Now that we understand what's going on, we can look at all the other loci and see if there are any other genes that fit this framework," Millen said. "From now on gene finding should be a lot faster because we understand the basic biology."
"This finding makes us rethink the basis of this disease," said Joseph Gleeson, M.D., an investigator with the Howard Hughes Medical Institute at the University of California, San Diego, who was not involved with the study. "It's going to be a shift from the way we were thinking about it to a new paradigm where there are a whole bunch of new ideas about how we understand Dandy-Walker malformation."
The National Institutes of Health, Autism Speaks, the Alberta Heritage for Medical Research, the Canadian Institute for Health Research, and the March of Dimes Birth Defects Foundation supported the research. Additional authors include, Victor Chizhikov of the University of Chicago, Louanne Hudgins of Stanford University Alexander Bassuk of the University of Iowa, Lesley Ades of the Children's Hospital at Westmead and the University of Sydney, and Ian Krantz of the Children's Hospital of Pennsylvania.
An HIV-blocking gel for women
New 'molecular condom' meant to prevent AIDS
SALT LAKE CITY University of Utah scientists developed a new kind of "molecular condom" to protect women from AIDS in Africa and other impoverished areas. Before sex, women would insert a vaginal gel that turns semisolid in the presence of semen, trapping AIDS virus particles in a microscopic mesh so they can't infect vaginal cells.
"The first step in the complicated process of HIV (human immunodeficiency virus) infection in a woman is the virus diffusing from semen to vaginal tissue. We want to stop that first step," says Patrick Kiser, an associate professor of bioengineering at the University of Utah's College of Engineering. "We have created the first vaginal gel designed to prevent movement of the AIDS virus. This is unique. There's nothing like it."
"We did it to develop technologies that can enable women to protect themselves against HIV without approval of their partner," he adds. "This is important – particularly in resource-poor areas of the world like sub-Sahara Africa and south Asia where, in some age groups, as many as 60 percent of women already are infected with HIV. In these places, women often are not empowered to force their partners to wear a condom."
A study testing the behavior of the new gel and showing how it traps AIDS-causing HIV particles will be published online later this week in the journal Advanced Functional Materials. Kiser is the senior author.
"Due to cultural and socioeconomic factors, women often are unable to negotiate the use of protection with their partner," says Julie Jay, the study's first author and a University of Utah doctoral candidate in pharmaceutics and pharmaceutical chemistry.
So the researchers developed a vaginal gel that a woman could insert a few hours before sex and "could detect the presence of semen and provide a protective barrier between the vaginal tissue and HIV," Jay says. "We wanted to build a gel that would stop HIV from interacting with vaginal tissue."
Kiser estimates that if all goes well, human tests of the gel would start in three to five years, and the gel would reach the market in several more years. He and Jay want to incorporate an antiviral drug into the gel so it both blocks HIV movement and prevents the virus from replicating.
A Rocky Road to Microbicides against AIDS
The effort to develop microbicides – intravaginal gels, rings and films – to prevent transmission of the AIDS virus has been halting. The few that have reached human clinical trials in Africa failed to prevent HIV transmission – either because they carried antiviral drugs that were not long-lived or strong enough, or because patients failed to use them. Some experimental microbicides increased the risk, possibly by irritating vaginal tissue and attracting immune cells that are targeted by the virus.
In 2006, Kiser and colleagues published a study on their development of another "molecular condom" to be applied vaginally as a liquid, turn into a gel coating at body temperature, then, in the presence of semen, turn liquid and release an anti-HIV drug.
Unfortunately, few antiviral drugs bind to and attack HIV in semen. And in Africa, high air temperatures prevent the gel from turning liquid so it could coat the vagina evenly, Kiser says.
The new "molecular condom" gel in the current study works in the opposite way. Like the old version, it changes in response to changes in pH – acidity or alkalinity – in the vagina caused by the introduction of semen during sex. But unlike the old gel, which became liquid at the higher (less acidic) pH of semen, the new "molecular condom" becomes a semisolid at the pH of semen, forming a mesh of "crosslinked" molecules.
The new gel is applied as a gel, and then becomes more solid and impenetrable as changes in pH alter the strength of the bond between the gel's two key components, both of which are polymers, or long, chain-like molecules made of many smaller, repeating units: PBA, or phenylboronic acid, and SHA, or salicylhydroxamic acid.
Slowing and Blocking the AIDS Virus
Kiser's team first published a study about the invention of the polymers and their behavior in 2007. A patent is pending on the invention.
The chemical bonds between the two polymers constantly attach and detach at normal, acidic vaginal pHs of about 4.8, allowing the gel to flow, Kiser says. But at a pH of 7.6 – the slightly alkaline condition when semen enters the vagina – the PBA and SHA polymers "crosslink" and stick tightly together, he adds.
Part of the new study characterized the flow of the gel.
"It flows at a vaginal pH, and the flow becomes slower and slower as pH increases, and it begins to act more solid at the pH of semen," Jay says. HIV moves slowly within the gel, even when the gel is at lower pHs (higher acidity) and still flowing, but the virus is blocked at higher pHs caused by the entry of semen into the vagina.
The crosslinked polymers form a mesh that is smaller than microscopic, and instead is nanoscopic – on the scale of atoms and molecules – with a mesh size of a mere 30 to 50 nanometers – or 30 to 50 billionths of a meter. (A meter is about 39 inches.) By comparison, an HIV particle is about 100 nanometers wide, sperm measure about 5 to 10 microns (5,000 to 10,000 nanometers) in cross section, and the width of a human hair is roughly 100 microns (100,000 nanometers).
Kiser says the gel should block other viruses and sperm, thus could work as a contraceptive and possibly prevent infection by herpes viruses and human papillomavirus (HPV), a major cause of cervical cancer.
The gel also could help prevent AIDS by blocking movement of immune system cells that try to combat infectious agents but instead get hijacked by the AIDS virus.
During the study, coauthors from Northwestern University in Chicago used a sophisticated microscope to track how fast HIV particles marked with fluorescent dye moved when they were caught in the gel, and how the speed varied with changes in pH.
The researchers compared movement of HIV particles with latex particles, which revealed that under somewhat acidic conditions, the HIV particles are slowed down in part because their surfaces react chemically with the polymers.
By adding an anti-AIDS drug such as tenofovir to the gel, "the virus would have two barriers to get through: the polymer barrier and then the drug barrier," Kiser says. Unlike an antiviral used with the old gel, tenofovir would not attack HIV directly, but protect immune cells in the vagina from infection.
Kiser says that after sex, the vagina gradually becomes acidic again, and any residual HIV particles would be inactivated both by acidity and an antiviral drug within the remaining gel, which still impedes HIV to some extent at normal vaginal acidity.
Kiser and Jay conducted the study with four other University of Utah researchers: bioengineering undergraduates Kristofer Langheinrich and Melissa Hanson, bioengineering graduate student Todd Johnson, and bioengineering researcher Meredith Clark. Other coauthors were from the Department of Cell and Molecular Biology at Northwestern University Medical School in Chicago: Thomas Hope, Shetha Shukair and Gianguido Cianci.
The study was funded by National Institutes of Health. Kiser's research team is continuing the effort to develop microbicides to prevent AIDS thanks to a $100,000 grant from the Bill and Melinda Gates Foundation.
Upcoming work includes assessing the HIV-prevention potential of other polymers, testing the safety of the new gel on vaginal cells, and studying how well the new gel blocks the transport of HIV into samples of human vaginal and penile tissue from hysterectomies and circumcisions, respectively.
Chinese acupuncture affects brain's ability to regulate pain, UM study shows
ANN ARBOR, Mich. – Acupuncture has been used in East-Asian medicine for thousands of years to treat pain, possibly by activating the body's natural painkillers. But how it works at the cellular level is largely unknown.
Using brain imaging, a University of Michigan study is the first to provide evidence that traditional Chinese acupuncture affects the brain's long-term ability to regulate pain.
The results appear online ahead of print in the September Journal of NeuroImage.
In the study, researchers at the U-M Chronic Pain and Fatigue Research Center showed acupuncture increased the binding availability of mu-opoid receptors (MOR) in regions of the brain that process and dampen pain signals – specifically the cingulate, insula, caudate, thalamus and amygdala.
Opioid painkillers, such as morphine, codeine and other medications, are thought to work by binding to these opioid receptors in the brain and spinal cord.
"The increased binding availability of these receptors was associated with reductions in pain," says Richard E. Harris, Ph.D., researcher at the U-M Chronic Pain and Fatigue Research Center and a research assistant professor of anesthesiology at the U-M Medical School.
One implication of this research is that patients with chronic pain treated with acupuncture might be more responsive to opioid medications since the receptors seem to have more binding availability, Harris says.
These findings could spur a new direction in the field of acupuncture research following recent controversy over large studies showing that sham acupuncture is as effective as real acupuncture in reducing chronic pain.
"Interestingly both acupuncture and sham acupuncture groups had similar reductions in clinical pain," Harris says. "But the mechanisms leading to pain relief are distinctly different."
The study participants included 20 women who had been diagnosed with fibromyalgia, a chronic pain condition, for at least a year, and experienced pain at least 50 percent of the time. During the study they agreed not to take any new medications for their fibromyalgia pain.
Patients had position emission tomography, or PET, scans of the brain during the first treatment and then repeated a month later after the eighth treatment.
Additional authors: Jon-Kar Zubieta, M.D., Ph.D., David J. Scott, Vitaly Napadow, Richard H. Gracely, Ph.D, Daniel J. Clauw, M.D.
Funding: Department of Army, National Institutes of Health Reference: Journal of NeuroImage, Vol. 5, No. 83, 2009
Ditching binary will make quantum computers more powerful
* 16:42 10 August 2009 by Paul Marks
Unlike most pieces of computer hardware, this quantum bit handles data using five basic states instead of the conventional two (Image:
Unlike most pieces of computer hardware, this quantum bit handles data using five basic states instead of the conventional two (Image:
Memo to the developers of superfast quantum computers: give up on the familiar 1s-and-0s binary system used in conventional computers. By switching to a novel five-state system, you will find it easier to build the staggeringly powerful machines.
So claim Matthew Neeley and colleagues at the University of California, Santa Barbara (UCSB).
So far, the development of quantum computers has followed the traditional binary computing model. This encodes all information using components that can be in two states, either 1 or 0.
But other possibilities exist, Neeley explains. "We could use a 'trinary' system with three digits – 0, 1 and 2 – and then the fundamental units would be trinary digits, or trits, that would essentially be three-position switches." A single "trit" would contain more information a conventional "bit".
Neeley's team have now built a quantum computer whose building blocks have five basic states.
Until now, quantum computers' basic components have been binary quantum bits – qubits – which encode two states in the quantum spin of atoms, electrons or photons. The ability of such particles to defy everyday logic, and exist in multiple quantum states at once, should one day enable quantum computers to perform vast numbers of calculations simultaneously.
Neeley's group used a superconducting aluminium and silicon circuit on a sapphire wafer to make five-state qubits, or "qudits", that operate at 0.025 kelvin.
"There's more information stored in a qudit than a qubit, so a given computation can be done with fewer qudits," Neeley told New Scientist.
By firing microwave photons of five different frequencies into the circuit, they were able to encourage it to jump between five discrete energy levels. "We also developed a quantum measuring technique that can distinguish between all of these levels," says Neeley.
Because, in probabilistic terms, the qudit's five quantum states are able to exist simultaneously, the team had a working qudit on their hands.
One qudit alone is of little use, however.
Jonathan Home at the US National Institute of Standards and Technology in Boulder, Colorado, says Neeley's team needs to extend its basic system in such a way that two or more qudits can transport information between them, which would allow more complex computational operations to be undertaken.
"Designing the sort of system where two qudits interact, but still retain the interesting properties of a five-level system, will be a major challenge," Home says.
The potential power of quantum computers means has attracted the interest of the US Intelligence Advanced Research Projects Agency (IARPA), which hopes to use them to break codes.
Home's team has received funding from the agency to work on a room-temperature quantum computer that allows binary qubits to interact and swap information.
Their latest results show that magnesium ions can be used to stop the qubits destabilising one another by transferring heat as well as their quantum states.
The trick, reported in this week's Science (DOI: 10.1126/science.1177077) is to use serried ranks of trapped beryllium ions as the qubits, while using neighbouring magnesium ions to absorb any heat. The heat would normally destroy quantum information as it is transported between them.
"This will pave the way to large-scale quantum computing, because it addresses the major task: information transport," says Home. Journal reference: Science, DOI: 10.1126/science.1173440
Doctors' opinions not always welcome in life support decisions
Some caregivers of critical care patients prefer doctors to keep their opinions on life support decisions to themselves, according to new research that challenges long-held beliefs in the critical care community.
The research, an article to be published in the August 15 issue of the American Journal of Respiratory and Critical Care Medicine, found that surrogates are virtually split when it comes to how much guidance they want to receive from physicians in making end-of-life medical choices on behalf of critically ill patients, according to lead author of the paper, Douglas B. White, of the University of Pittsburgh Medical Center.
"In fact, what we found was that, while a slight majority did prefer doctors to help them make those difficult decisions, many felt that it was a decision they wanted to make without guiding input from doctors other than an explanation of the options," said Dr. White.
At the end of life, critically ill patients frequently require surrogates to make their medical decisions for them, who, in the absence of advance directives from the patient, must rely on what they believe would have been the patients' desires. "This puts an enormous emotional burden on surrogates; not only are they losing a loved one, they also may feel burdened by guilt about allowing the patient to die." said Dr. White. "It was therefore assumed by some in the medical community that a doctor's dispassionate advice could reduce some of that burden and help surrogates make a good decision with less second-guessing themselves. However, there was little or no research to support this assumption."
Dr. White and colleagues set out to test that assumption, recently formalized as a recommendation by a number of critical care societies, by asking surrogates of critical care patients to watch and respond to two videos. The videos depicted a hypothetical ICU "family conference" in which surrogates must decide whether to continue or withdraw life support from a loved one who has a small chance of survival with continued intervention, but a high likelihood of severe functional impairment in the long-term, including dependence on a ventilator. Both videos were identical in all ways except one: in one version, the doctor says that the most important thing is for the surrogate to "make the choice that's consistent with [the patient's] values," but states that only the surrogate could make that decision; in the alternate version, the doctor offers his opinion that the patient would likely not have wanted to continue aggressive treatment given the likely outcome.
A total of 169 surrogates who were recruited from four ICUs at the University of California San Francisco Medical Center to watch the films in randomized order and respond to it. The researchers used a multi-method analysis to code the responses and validated their analyses with the surrogates themselves to ensure an accurate and complete qualitative assessment of the data.
To their surprise, Dr. White and colleagues found that only a slight majority, 56 percent, of surrogates expressed a preference for the version in which the physician offered an opinion to limit life support. A slight minority, 42 percent, preferred no recommendation, and the final two percent had no preference.
"This is an important article that has changed my clinical practice," said J. Randall Curtis, M.PH., M.D., president of the American Thoracic Society and Professor of Medicine Pulmonary and Critical Care Medicine Section Head, Harborview Medical Center in Seattle, WA"I had previously assumed that almost all families would want physicians' recommendations, but these findings indicate that there is no such consensus among surrogates. I suspect that physicians can do more harm by withholding a recommendation that is desired than by providing a recommendation that is not desired, but this study suggests we should ask rather than assume."
Just over half (51 percent) of the surrogates expressing a preference for receiving their doctors' advice believed that it was the doctor's role to provide that opinion, whereas nearly four of five (79 percent) who preferred not to receive the advice saw it as overstepping.
"A very important part of American bioethics is respecting patient's choices," said Dr. White. "The family's most important job when acting as a surrogate decision maker is to give voice to the patient's values. I think our research highlights that the physician's job is to be flexible enough and insightful enough to respond to the surrogate's individual needs for guidance.
"It is rare that a research paper changes clinical practice, and I think this one will," said Dr. Curtis.
Link to original article: http://www.thoracic.org/sections/publications/press-releases/resources/081509white.pdf