Posts tagged with "National Institutes of Health"

Into the light: Babies in the womb may see more than we thought

November 26, 2019

The transitions that mark the beginning and end of human life are marked by the same phenomenon: light. In fact, a new study conducted at the University of California-Berkeley has found that, eve by the second trimester—long before a baby’s eyes can see images—they can detect light.

Previously, the light-sensitive cells in the developing retina— the thin sheet of brain-like tissue at the back of the eye— were assumed to be simple” on-off switches,” presumably there to set up the 24-hour, day-night rhythms parents hope their baby will follow.

Now, with funding from the National Institutes of Health, researchers have discovered evidence that these simple cells actually talk to one another as part of an interconnected network that gives the retina more light sensitivity than once thought, and that may enhance the influence of light on behavior and brain development in unsuspected ways.

In the developing eye, perhaps 3% of ganglion cell—the cells in the retina that send messages through the optic nerve into the brain—are sensitive to light and, to date, researchers have found about six different subtypes that communicate with various places in the brain. Some talk to the suprachiasmatic nucleus to tune our internal clock to the day-night cycle. Others send signals to the area that makes our pupils constrict in bright light.

But others connect to surprising areas: the perihabenula, which regulates mood, and the amygdala, which deals with emotions.

In mice and monkeys, recent evidence suggests that these ganglion cells also talk with one another through electrical connections called gap junctions, implying much more complexity in immature rodent and primate eyes than imagined.

“Given the variety of these ganglion cells and that they project to many different parts of the brain, it makes me wonder whether they play a role in how the retina connects up to the brain,” said Marla Feller, a UC Berkeley professor of molecular and cell biology and senior author of a paper that appeared this month in the journal Current Biology. “Maybe not for visual circuits, but for non-vision behaviors. Not only the pupillary light reflex and circadian rhythms, but possibly explaining problems like light-induced migraines, or why light therapy works for depression.”

The cells, called intrinsically photosensitive retinal ganglion cells (ipRGCs), were discovered only ten years ago, surprising those such as Feller, who had been studying the developing retina for nearly 20 years. She played a major role, along with her mentor, Carla Shatz of Stanford University, in showing that spontaneous electrical activity in the eye during development— so-called retinal waves —is critical for setting up the correct brain networks to process images later on.

“We thought they (mouse pups and the human fetus) were blind at this point in development,” said Feller. “We thought that the ganglion cells were there in the developing eye, that they are connected to the brain, but that they were not really connected to much of the rest of the retina, at that point. Now, it turns out they are connected to each other, which was a surprising thing.”

UC Berkeley graduate student Franklin Caval-Holme combined two-photon calcium imaging, whole-cell electrical recording, pharmacology, and anatomical techniques to show that the six types of ipRGCs in the newborn mouse retina link up electrically, via gap junctions, to form a retinal network that the researchers found not only detects light, but responds to the intensity of the light, which can vary nearly a billionfold.

Gap junction circuits were critical for light sensitivity in some ipRGC subtypes, but not others, providing a potential avenue to determine which ipRGC subtypes provide the signal for specific non-visual behaviors that light evokes.

“Aversion to light, which pups develop very early, is intensity-dependent,” suggesting that these neural circuits could be involved in light-aversion behavior, Caval-Holme said. “We don’t know which of these ipRGC subtypes in the neonatal retina actually contributes to the behavior, so it will be very interesting to see what role all these different subtypes have.”

The researchers also found evidence that the circuit tunes itself in a way that could adapt to the intensity of light, which probably has an important role in development, Feller said.

“In the past, people demonstrated that these light-sensitive cells are important for things like the development of the blood vessels in the retina and light entrainment of circadian rhythms, but those were kind of a light on/light off response, where you need some light or no light,” she said. “This seems to argue that they are actually trying to code for many different intensities of light, encoding much more information than people had previously thought.”

Research contact: @EurekaAlert

Wanted: 10,000 dogs for the largest-ever study on canine aging

November 18, 2019

Every dog has his day—but they simply don’t get enough of them as far as we’re concerned. Most of our beloved pooches only live for about 11 years, according to the American Kennel Club.

But now, a group of researchers is hoping to lengthen the life expectancy of canines, as well as their overall quality of life, CNN reports.

Teams from the University of Washington School of Medicine and the Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVM), are being funded by the National Institute of Aging, a division the National Institutes of Health.

The study promises to be the largest-ever study on aging in dogs, according to the cable news outlet—and it may have implications for humans, too. .

“Dogs truly are science’s best friends,” the research team told CNN in a joint statement. “Though they age more rapidly than humans, they get the same diseases of aging, have a rich genetic makeup, and share our environment.”

“By studying aging in dogs,” they said, “we can more quickly expand our knowledge of aging not just in dogs but also in humans.” They added that the team is optimistic that its findings could lead to better

Dogs from all 50 states—and of all ages, sizes, and breeds—may apply with the help of their owners. The researchers will even consider dogs with chronic illnesses, because they are hoping to include as much genetic diversity as possible.

Applications to the project are officially open. Owners can visit the Dog Aging Project’s website to nominate their pooches. The submission process takes less than ten minutes, and generally consists of questions about your pet that will help the researchers to determine whether he or she is the right fit.

Have more questions? Here’s a helpful FAQs.

Research contact: @CNN

UW team devises first smartphone app that can ‘hear’ ear infections in children

May 17, 2019

Ear infections send more children to the pediatrician than any other ailment, according to the National Institutes of Health.

Even the youngest child may pull or tug at his or her ear when pressure and pain start to build up inside. This condition, usually caused by a bacterial infection, occurs when fluid gets trapped in the middle ear behind the eardrum. The same type of problem also is common in another condition called otitis media with effusion—where the infection is gone, but the fluid has not drained.

Any kind of fluid buildup in the ears can hurt and make it hard for children to hear, which is especially detrimental when they are learning to talk.

But now, researchers at the University of Washington have created a new smartphone app that can detect fluid behind the eardrum, when used along with three easily available aids: a piece of paper and the smartphone’s microphone and speaker.

The smartphone makes a series of soft audible chirps into the ear through a small paper funnel and—depending on the way the chirps rebound to the phone—the app determines the likelihood of fluid present with a probability of detection of 85% (similar to the results achieved with more sophisticated processes used currently, including acoustics and puffs of air).

When there is no fluid behind the eardrum, the eardrum vibrates and sends a variety of sound waves back. These sound waves mildly interfere with the original chirp, creating a broad, shallow dip in the overall signal. But when the eardrum has fluid behind it, it doesn’t vibrate as well and reflects the original sound waves back. They interfere more strongly with the original chirp and create a narrow, deep dip in the signal.

 “Designing an accurate screening tool on something as ubiquitous as a smartphone can be game-changing for parents as well as healthcare providers in resource-limited regions,” said co-author Shyam Gollakota, an associate professor in the UW’s Paul G. Allen School of Computer Science & Engineering. “A key advantage of our technology is that it does not require any additional hardware other than a piece of paper and a software app running on the smartphone.”

A quick screening at home could help parents decide whether or not they need to take their child to the doctor.

“It’s like tapping a wine glass,” said co-first author Justin Chan, a doctoral student at the Allen School. “Depending on how much liquid is in [the ear], you get different sounds. Using machine learning on these sounds, we can detect the presence of liquid.”

To train an algorithm that detects changes in the signal and classifies ears as having fluid or not, the team tested 53 children between the ages of 18 months and 17 years at Seattle Children’s Hospital. About half of the children were scheduled to undergo surgery for ear tube placement, a common surgery for patients with chronic or recurrent incidents of ear fluid. The other half were scheduled to undergo a different surgery unrelated to their ears, such as a tonsillectomy.

Among the children getting their ear tubes placed, surgery revealed that 24 ears had fluid behind the eardrum, while 24 ears did not. For children scheduled for other surgeries, two ears had bulging eardrums characteristic of an ear infection, while the other 48 ears were fine. The algorithm correctly identified the likelihood of fluid 85% of the time, which is comparable to current methods that specialized doctors use to diagnose fluid in the middle ear.

Then the team tested the algorithm on 15 ears belonging to younger children between 9 and 18 months of age. It correctly classified all five ears that were positive for fluid—as well as nine out of the ten ears, or 90%, that did not have fluid.

“Even though our algorithm was trained on older kids, it still works well for this age group,” said co-author Dr. Randall Bly, an assistant professor of otolaryngology at the UW School of Medicine who practices at Seattle Children’s Hospital. “This is critical because this group has a high incidence of ear infections.”

Because the researchers want parents to be able to use this technology at home, the team trained parents how to use the system on their own children. Parents and doctors folded paper funnels, tested 25 ears and compared the results. Both parents and doctors successfully detected the six fluid-filled ears. Parents and doctors also agreed on 18 out of the 19 ears with no fluid. In addition, the sound wave curves generated by both parent and doctor tests looked similar.

Rajalakshmi Nandakumar, a doctoral student in the Allen School, is also a co-author on this paper. This research was funded by the National Science Foundation, the National Institutes of Health and the Seattle Children’s Sie-Hatsukami Research Endowment.

The team published its results on May 15 in the journal, Science Translational Medicine.

Research contact: earhealth@uw.edu.

What’s wrong with you? Network of doctors diagnoses 100 previously unsolved cases

October 25, 2018

Not every doctor is an adroit diagnostician—and even those who are will admit to being stumped occasionally by a patient’s symptoms. Now, there is help, even for the hardest cases, from the Undiagnosed Diseases Network—a program created by the National Institutes of Health in 2012.

The program, which first was conceived back in 2008, now depends on a network of collaborative healthcare institutions nationwide—and cross-disciplinary physicians at those institutions—including Baylor College of Medicine, Brigham and Women’s Hospital, Boston Children’s Hospital, Massachusetts General Hospital, Children’s Hospital at Philadelphia and University of Pennsylvania, Duke University and Columbia University, Harvard Medical School and University of Alabama at Birmingham, Mayo Clinic, Stanford Medicine, UCLA, University of Miami School of Medicine, University of Utah, University of Washington School of Medicine and Seattle Children’s Hospital, Vanderbilt University Medical Center, and Washington University in St. Louis.

Through the efforts of the network, more than 100 patients afflicted by mysterious illnesses have been diagnosed to date—and 31 new diseases have been identified.

“Our goal is to take on the hardest cases in medicine — to find patients and families with conditions that no one has been able to solve,” explained Euan Ashley, M.D., a professor of Medicine (Cardiology) at Stanford University, in a news release from the school. “We wanted to provide a place that these people could come, so the Undiagnosed Diseases Network came together to try to answer that need.”

The group, which comprises hundred of doctors, has so far sleuthed out 132 of 382 previously unknown ailments —or roughly 35%.

Some of these patients had been waiting decades to put a name to their illness. They tell us how much of a relief it is simply to know what they were up against,” Ashley said. But what’s most exciting, he said, was that for 80% of the network’s diagnoses, they distilled actionable information, such as changes to patient therapy, adjustments to future diagnostic testing and recommendations for family screening.

“Our findings underscore the impact that establishing a clear diagnosis can have on clinical decision-making for previously undiagnosed patients,” said Kimberly Splinter, associate director Research Operations for the network’s Coordinating Center and a genetic counselor at Harvard Medical School. “We hope that the results of this analysis will provide a compelling case for adopting some of the network’s diagnostic approaches more broadly in an attempt to clarify diagnoses and refine treatment for patients with rare conditions.”

Splinter is the lead author (and Ashley is the senior author) of a paper describing the study that was published online on October 11 in The New England Journal of Medicine.

Of the 1,519 applications from patients that the network received when it was formed, 601 were accepted based on the likelihood that the network would be able to help them, given their past medical records and available data. Now, Ashley and the team of physicians have seen more than half of those patients, combining traditional medicine with increasingly cutting-edge diagnostic tests. The network continues to accept applications.

 “We do this Sherlock Holmes-like detective work-up by carefully observing, gathering information and asking pointed questions, but we’re also pairing that with the most advanced genomic technologies to try to solve their case,” Ashley said.

Every patient had their genome sequenced, even those whose genomes had been previously sequenced. The field of genetic and genomic testing moves so quickly, Ashley explained, that even patients who’ve had their genome sequenced six months ago benefit from another look. In coordination with genome sequencing, the physicians looked at patients’ RNA profiles, analyzing precursor molecules to the proteins found in their bodies. They also broke down a collection of molecules called metabolites, which form as a product of metabolism and can hint at where metabolic processes go wrong.

“Some cases are solved simply because we know more today than we did a year ago,” Ashley said.

Among those diagnosed, most exhibited rare versions of known diseases, broadening the symptomatic information doctors can look for when evaluating patients for those particular diseases in the future. But in 31 patients, the network identified previously unknown syndromes.

A particularly interesting case study is provided by co-author Matthew Wheeler, M.D., assistant professor of Medicine at Stanford and executive director of the Stanford Center for Undiagnosed Diseases.  The case involved a patient whom the network followed for multiple years. The patient had mysterious and life-threatening episodes of something called lactic acidosis, a dangerous buildup of lactic acid in the body.

“It’s sort of like an extreme version of when you exercise intensely, and you feel that burn from the lactate buildup — only it’s your whole body that feels that way,” Wheeler said. “Lactic acidosis can also cause your acid-base balance to be out of whack, and when people have severe acid-base disturbances, they’re at high risk for arrhythmia or death.”

It wasn’t clear why the patient was experiencing these symptoms, which seemed to be prompted by a cold or flu. After giving the patient the full gamut of tests and analyzing sequencing information, a team of Stanford scientists found the culprit: a single mutation in the gene ATP5F1D, which is involved in the function of mitochondria, the cell’s powerhouse.

The genetic oddity and symptoms had never been classified together officially, but from connections within the network and in some instances word of mouth, the scientists found that other doctors around the world had patients plagued by this syndrome. In verifying that the mutation causes the syndrome—called mitochondrial complex V deficiency, nuclear type 5 — network collaborators on the study developed animal models to show causality.

“This is a new type of scientific odyssey,” Ashley said. “We’re learning about biology in a way that could help not just one family, but potentially dozens, even hundreds, of families who suffer that same rare condition. That’s the biggest benefit of this network effect — the impact of identifying one patient’s disease could end up being global.”

Even the patients who did not receive a diagnosis benefit from knowing that a team continues to investigate their conditions and that the future may hold an answer even if the present does not.

“We’ve had patients tell us that just knowing that there is a team looking into their condition, that there is someone in the world who has not given up on them, scientists continuing to keep an eye on the literature — that provides hope,” Ashley said.

Research contact: euan@stanford.edu