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Autism, Neuroscience, Pediatrics, Research, Stanford News

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

A Stanford brain-imaging study has just shown that the brains of children with autism are less able to switch from rest to taking on a new task than the brains of typically developing children.

According to the study, which appears this week in the scientific journal Cerebral Cortex, instead of changing to accommodate a job, connectivity in key brain networks of autistic children looks similar to connectivity in the resting brain. The degree of inflexibility was linked to the intensity of children’s autism symptoms: those with less flexibility had more severe restrictive and repetitive behaviors, one of the hallmarks of the developmental disorder.

From our press release on the research:

“We wanted to test the idea that a flexible brain is necessary for flexible behaviors,” said Lucina Uddin, PhD, a lead author of the study. “What we found was that across a set of brain connections known to be important for switching between different tasks, children with autism showed reduced ‘brain flexibility’ compared with typically developing peers.” Uddin, who is now an assistant professor of psychology at the University of Miami, was a postdoctoral scholar at Stanford when the research was conducted.

“The fact that we can tie this neurophysiological brain-state inflexibility to behavioral inflexibility is an important finding because it gives us clues about what kinds of processes go awry in autism,” said Vinod Menon, PhD, the Rachel L. and Walter F. Nichols, MD, professor of psychiatry and behavioral sciences at Stanford and the senior author of the study.

The study is the first to examine unusual patterns of connectivity in the brains of children with autism while they are performing tasks; Menon’s team has previously published research on connectivity between different regions of the autistic brain at rest. Some regions of the autistic brain are over-connected to each other, that work has shown, and the degree of over-connection is linked to children’s social deficits, perhaps in part because it interferes with their ability to derive pleasure from human voices. Menon’s lab has also explored how differences in the organization of the autistic brain may contribute to better math performance in some people with autism.

“We’re making progress in identifying a brain basis of autism, and we’re starting to get traction in pinpointing systems and signaling mechanisms that are not functioning properly,” Menon told me. “This is giving us a better handle both in thinking about treatment and in looking at change or plasticity in the brain.”

Previously: Greater hyperconnectivity in the autistic brain contributes to greater social deficits, Unusual brain organization found in autistic kids who best peers at math and Stanford study reveals why human voices are less rewarding for kids with autism

Research, Science, Stanford News

They said “Yes”: The attitude that defines Stanford Bio-X

They said "Yes": The attitude that defines Stanford Bio-X

bio-X peopleI write a lot about interdisciplinary research (it’s my job), but it was just recently that I heard the best description of what it is that makes interdisciplinary collaborations possible. It came from Carla Shatz, PhD, who directs Stanford Bio-X — an interdisciplinary institute founded in 1998 that brings together faculty from the schools of medicine, humanities & sciences and engineering. She told me:

You have to be able to walk into someone’s lab and say, “You know, I have this problem in my lab. Would you like to have a cup of coffee and talk about it?” And then that person needs to say, “Yes.”

We were talking about a recent report by the National Research Council of the National Academies. They had put together a workshop and then published a report giving advice and best practices for supporting interdisciplinary research. The report used Bio-X as a success story for the type of innovation that can come out of programs that cross disciplines.

Nowhere in the report is there a subhead reading, “Faculty have to say yes,” but a lot of the other advice is straight out of the Bio-X playbook. The institute needs to be located at the cross section of several schools or departments (check). The institute needs a building that brings people together (check). The institute needs to support students (check). The institute needs to be a financial value add rather than taxing participating departments (check).

This isn’t specifically called out in the report, but Shatz added that a good interdisciplinary institute also needs good food. She pointed out that people come from all over campus to eat at Nexus, located in the middle of the Clark Center that houses Bio-X and serves as a focus for its activities. It turns out scientists are just like the rest of us: offer good food and they will come. And then they will chat, and the next thing you know they’ll be collaborating.

I wrote a Q&A with Shatz based on our conversation. From now on, when I hear the phrase “She said yes” I’ll think of her, and her great description of the attitude that underlies collaboration.

Previously: Bio-X Kids Science Day inspires young scientists, Dinners spark neuroscience conversation, collaboration, Stanford’s Clark Center, home to Bio-X, turns 10 and Pioneers in science
Photo from Bio-X

Research, Science, Stanford News, Stem Cells

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cells, also called iPS cells, made from easily accessible skin or other adult cells, are ideal for disease modeling, drug discovery and, possibly, cell therapy. That’s because they can be generated in large numbers and grown indefinitely in the laboratory. They also reflect the genetic background of the person from whom they were generated. However, some fundamental questions still remain before they’re ready for the full glare of the clinical limelight. Does it matter what type of starting cells scientists use to create the pluripotent stem cells? And what’s the best control to use when studying the effect of a particular, patient-specific mutation?

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have addressed and answered these questions. Their work was published yesterday in two back-to-back papers in the Journal of the American College of Cardiology. (Each paper is also accompanied by an editorial.) As Wu explained in an e-mail to me:

If your goal is to generate healthy iPS cell derivatives for regenerative therapy, it’s important to know whether the starting material makes a difference. For example, if I’m treating Alzheimer’s disease, is there a benefit to using iPS cell-derived brain cells made from brain cells? Likewise, if I’m treating a skin disorder, is there a benefit to using iPS cell-derived skin cells made from skin cells? As cardiologists, we are asked this quite often and each time, I had to say “I don’t know.” So we decided to do a study comparing the differentiation and functional ability of iPS cell-derived cardiomyocytes generated from two different sources: skin and heart. We also wanted to devise more efficient ways for researchers to quickly and easily create their own “designer” iPS cell lines to study particular mutations.

To answer the first question, the researchers created iPS cells from two types of starter cells: human fetal skin cells and cardiac progenitor cells. Not surprisingly, only the cardiac progenitor cells expressed genes known to be expressed in heart tissue. Wu and his colleagues then exposed the newly created pluripotent stem cells to growing conditions that favor the development of heart muscle cells called cardiomyocytes. They found that, although iPS cells derived from cardiac progenitor cells were more efficient at becoming cardiomyocytes, both types of starting material produced heart muscle cells that functioned similarly after a period of growth in the laboratory. As Wu explained:

These two populations of cells are essentially no different from one another over time. It appears that they lost the memory of their starting material (this memory is stored in the form of chemical tags on the cells’ DNA in a phenomena known as epigenetic marking). This suggests that I could take my own skin cells, make iPS cells and then create specialized brain, heart, liver or kidney cells for cell therapy. This is much easier than biopsying each tissue, and could be a good way to create universal iPS cell lines for research or cell therapy.

In the second paper, Wu and his colleagues devised a way to introduce specific mutations into iPS cells before transforming them into particular tissues. The approach relies on the use of what’s known as “dominant negative” mutations that exert their disruptive effect even when the unmutated gene is still present. This is important because it’s much easier and quicker than previous similar efforts, which required a complicated, time-consuming procedure to snip out and then replace individual genes. The technique also allows researchers to generate two cell lines that are identical except for the mutation under study. That way researchers can be confident that differences between the cell lines are due only to that mutation, which is particularly important when the lines are used to test the effect of therapeutic drugs. Again, from Wu:

Investigators can make their own designer iPS cell lines to study particular mutations with genetically identical controls to use in their experiments. We won’t have to make new iPS cells from each patient, which is laborious and time consuming. Instead we can create standardized lines to study many different mutations alone and in combination. This has the potential to revolutionize the field of disease modeling and drug discovery.

The two papers describe ongoing research in the Wu lab designed to optimize iPS cells for a variety of applications. The group, including graduate student Arun Sharma, recently published research using human iPS cell-derived cardiomyocytes to investigate the effect of various antiviral drugs againse coxsackievirus, a leading cause of an infection of the middle layer of the heart wall in children and the elderly. The research is the first time that iPS cell-derived heart muscle has been used to investigate the mechanisms behind an acquired viral disease.

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells, “Clinical trail in a dish” may make common medicines safer, say Stanford scientists and Lab-made heart cells mimic common cardiac disease in Stanford study

Cancer, Dermatology, In the News, Public Safety, Research, Stanford News

A closer look at new research showing disproportionate rates of melanoma in Marin County

Last week, Cancer Prevention Institute of California/Stanford Cancer Institute researcher Christine Clarke, PhD, shared results of a new report (.pdf) showing that a county in California has higher numbers of melanoma skin cancer than the rest of the state. On this morning’s Forum Clarke joined two other guests, including Stanford dermatologist Susan Swetter, MD, director of the Pigmented Lesion and Melanoma Program at the Stanford Cancer Institute, to discuss the research and to offer skin safety and screening tips for the summer.

It’s worth a listen – especially if you live in the county just north of San Francisco.

Previously: Melanoma rates exceed rates of lung cancer in some areasWorking to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma, New research shows aspirin may cut melanoma risk and Working to prevent melanoma

Cardiovascular Medicine, Research, Videos

Researchers capture detailed three-dimensional images of cardiac dynamics in zebrafish

Researchers capture detailed three-dimensional images of cardiac dynamics in zebrafish

The stunning video above depicts a reconstructed beating heart of a zebrafish embryo with the muscle layer shown in red and the endothelium highlighted in blue. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Germany created the video using a new three-dimensional imaging technique, which holds the promise of leading to a better “understanding of congenital heart defects as well in future experiments on cardiac function and development”. As explained in a release:

[Researchers] developed a high-speed, selective plane illumination microscope that manages to do just that. By gently illuminating the fish heart with a thin light sheet and observing the emitted fluorescence with a fast and sensitive camera the researchers have achieved fast, non-invasive imaging of labelled heart tissue. The process involves taking multiple movies, each covering individual planes of the heart (movie stacks), then using the correlations between the individual planes to generate a synchronised, dynamic 3D image of the beating heart.

“These renderings allow us to further follow characteristic structures of the heart throughout the cardiac cycle,” says Michaela Mickoleit, PhD student who performed the experiments in [Jan Huisken's] lab.

Via Medgadget
Previously: An advancement in optogenetics: Switching off cells with light now as easy as switching them on and New York Times profiles Stanford’s Karl Deisseroth and his work in optogenetics

Cancer, Genetics, Research, Stanford News

Stanford partnering with Google [x] and Duke to better understand the human body

Stanford partnering with Google [x] and Duke to better understand the human body

Most biomedical research is focused on disease and specific treatments for illness, rather than on understanding what it means to be healthy. Now researchers at Stanford, in collaboration with Duke University and Google [x], are planning a comprehensive initiative to understand the molecular markers that are key to health and the changes in those biomarkers that may lead to disease. The project was featured in a Wall Street Journal article today.

The study is at the very early stages, with researchers planning to enroll 175 healthy participants in a pilot trial later this year. The participants will undergo a physical exam and provide samples of blood, saliva and other body fluids that can be examined using new molecular testing tools, such as genome sequencing.  The pilot study will help the researchers design and conduct a much larger trial in the future.

“We continue as a global community to think about health primarily only after becoming ill,” Sanjiv Sam Gambhir, MD, PhD, professor and chair of radiology, told me. “To understand health and illness effectively, we have to have a better understanding of what ‘normal’ or ‘healthy’ really means at the biochemical level.”

“The study being planned will allow us to better understand the variation of many biomarkers in the normal population and what parameters are predictive of illness and may eventually change as a given individual transitions from a healthy to a diseased state. This will be a critical study that will likely help the field of health care for decades to come,” said Gambhir, who also directs the Canary Center at Stanford for Cancer Early Detection.

The researchers hope the work will provide insights on a variety of medical conditions, such as cancer and heart disease, and point to new methods for early detection of illness. Their studies will focus on the genetic basis of disease, as well as the complex interplay between genes and environment.

These kinds of studies haven’t been done before because of the cost and complexity of molecular measurement tools, the scientists say. However, the cost of some technologies, such as DNA sequencing, has been steadily declining, while some new tools and new ways of analyzing large quantities of data have just recently become available. So a first step in the study is to determine how best to use these technologies and determine what questions need to explored on a larger scale.

The work is sponsored by Google [x] and will be led by Andrew Conrad, PhD, a cell biologist and project manager at the company.

Cancer, Dermatology, Public Health, Research, Stanford News

Melanoma rates exceed rates of lung cancer in some areas

Melanoma rates exceed rates of lung cancer in some areas

stinson_beach

Californians, step away from the beach and grab a hat and sunscreen. Our team of researchers from the Cancer Prevention Institute of California/Stanford Cancer Institute released a new report (.pdf) this week documenting the rapidly growing burden of melanoma in Marin County, California. This small, homogenous (and wealthy) county just over the Golden Gate Bridge from San Francisco has been the focus of cancer studies before, as high rates of breast cancer were first reported there in the late 1990’s (rates declined there as in the rest of the country in 2003 when women stopped taking hormone therapy).

Our most recent cancer registry data show that rates of malignant melanomas in Marin County are 43 percent higher than the rest of the San Francisco Bay Area and 60 percent higher than other parts of California among non-Hispanic whites, who because of their fairer skin tones are diagnosed with melanoma at 20-30 times the rate of other ethnic groups. Also of concern is that the death rate due to melanoma is 18 percent higher in Marin whites than whites in other regions, a significant difference not seen before. Most of the elevated rates are limited to persons over age 65, especially men.

The Bay Area news media reported our findings as front-page news. Most coverage centered on the question of why the rates are so much higher in Marin County. Our best guess is that the higher average socioeconomic status of its residents corresponds to a higher proportion of people with the known risk factors for melanoma: fair complexion (pale skin, blonde or red hair, blue or green eyes) and a history of “intense intermittent” sun exposure over their lifetimes (exposure in big doses like you might get on a beach vacation in the winter).

However, it is also likely that better access to health care and skin screening has resulted in earlier diagnosis, a notion confirmed by the higher proportion of melanomas in Marin County caught when thin and more curable. Local dermatologists reacted to the statistics with some surprise, but didn’t change their standing advice regarding skin cancer prevention: talk to your doctor about skin screening and stay sun safe by wearing hats, long-sleeves and broad-spectrum sunscreen during outdoor activities.

One statistic mostly overlooked by the media was our finding that melanoma is now the second most common cancer diagnosed in men living in Marin County, as rates have surpassed those for lung cancer. This pattern is very different than that observed for whites in the US and world, for whom prostate or lung are first, and melanoma is ranked much lower. With one of the most successful public tobacco control efforts in the world, most populations in California have seen rapid declines in the incidence of smoking-related cancers of the lung and respiratory system.

Unfortunately, it seems for older white persons in Marin County (as well as parts of Utah and Hawaii, where smoking rates have also declined), melanoma and skin cancers represent a major—and relentlessly growing—cancer threat. Perhaps putting down the cigarettes was accompanied by more time at the pool or beach without adequate sun protection. Although California was the first state to ban tanning bed use by minors, we should look to Australia and other countries also battling rising skin cancer rates for innovative new policies and strategies for encouraging safe sun exposure in our at-risk communities.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: Beat the heat – and protect your skin from the sun, Working to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma and How ultraviolet radiation changes the protective functions of human skin
Photo by stefan klocek

In the News, Nutrition, Research

How much caffeine is really in one cup of coffee?

How much caffeine is really in one cup of coffee?

coffee_beansPrevious research has shown that regularly drinking coffee could offer a number of health benefits, including reducing prostate cancer risk, improving symptoms related to Parkinson’s disease, staving off the development of Alzheimer’s, decreasing diabetes risk and providing antioxidants.

But too much caffeine can make you jittery, disrupt your sleep and, potentially, shorten your life span. So it’s often recommended that you drink coffee in moderation, which is defined as two or three eight-ounce cups of brewed or drip coffee.

The problem with recommending a certain number of cups, reports Scientific American, is that new research shows the caffeine and caffeoylquinic acid (CQA) content can vary greatly depending on the type and preparation of the coffee. From the piece:

Results showed that the caffeine-to-CQA ratio in espressos ranged from 0.7–11, depending on the preparation conditions. With serving volumes from 13–104ml, it’s no wonder that Crozier says ‘cup of coffee is an exceedingly variable unit. To estimate health benefits using cups may be very difficult,’ – and inadvisable in epidemiological studies.

But what are CQAs? Beans contain various (poly)phenols, including 3-, 4- and 5-O-caffeoylquinic acids, the main phenolic compounds in coffee. Epidemiological studies have suggested the link between the lower risk of type 2 diabetes, cardiovascular diseases, and endometrial and hepatocellular cancer in habitual coffee consumers might be due to the presence of CQAs in coffee. They sound like super-compounds, but that’s a big ‘might’, and research continues.

Whilst the biological effects of CQAs are uncertain, one thing we do know about them is they are more sensitive to roasting than caffeine. The bean or blend also affects the caffeine-to-CQA ratio. Arabica and Robusta are the most common bean types and the latter contains twice as much caffeine as the former.

The article highlights the need to better inform consumers about the actual amount of caffeine in coffee and the need for more research on the health benefits of coffee.

Previously: How the body’s natural defenses help protect cells from toxins in everyday foods and flavorings, What is coffee?, For new moms, coffee scores a point: Caffeine doesn’t seem to interfere with baby’s sleep in study and Does coffee lower the risk of prostate cancer?
Photo by Nina Matthews

Health Disparities, Men's Health, Public Health, Research, Stanford News, Women's Health

Why it’s critical to study the impact of gender differences on diseases and treatments

man_womanWhen it comes to diagnosing disease and choosing a course of treatment, gender is a significant factor. In a Stanford BeWell Q&A, Marcia Stefanick, PhD, a professor of medicine at the Stanford Prevention Research Center and co-director of the Stanford Women & Sex Differences in Medicine Center, discusses why gender medicine research benefits both sexes and why physicians need to do a better job of taking sex difference into consideration when make medical decisions.

Below Stefanick explains why a lack of understanding about the different clinical manifestations of prevalent diseases in women and men can lead to health disparities:

…Because we may have primarily studied a particular disease in only one of the sexes, usually males (and most basic research is done in male rodents), the resulting treatments are most often based on that one sex’s physiology. Such treatments in the other sex might not be appropriate. One example is sleep medication. Ambien is the prescription medicine recently featured on the TV show, 60 Minutes. Reporters found out that women were getting twice the dose they should because they had been given the men’s doses; consequently, the women were falling asleep at the wheel and having accidents. Physicians had not taken into account that women are smaller and their livers’ metabolize drugs differently than do men’s. Some women have responded by reducing their own medication dosages, and yet that practice of self-adjusting is not the safest way to proceed, either.

Previously: A call to advance research on women’s health issues, Exploring sex differences in the brain and Women underrepresented in heart studies
Photo by Mary Anne Enriquez

Aging, Chronic Disease, Public Health, Research

How multiple chronic conditions are affecting older Americans’ life expectancy

old_coupleOne in four adults in the United States has two or more chronic conditions, according to the latest data from the Centers for Disease Control and Prevention. And, findings published in the August issue of Medical Care show that the burden of multiple chronic diseases could explain why life expectancy increases among elderly Americans are slowing.

In the study (subscription required), researchers at Johns Hopkins Bloomberg School of Public Health analyzed a nationally representative sample of 1.4 million Medicare beneficiaries. According to a release:

The analysis found that, on average, a 75-year-old American woman with no chronic conditions will live 17.3 additional years (that’s to more than 92 years old). But a 75-year-old woman with five chronic conditions will only live, on average, to the age of 87, and a 75-year-old woman with 10 or more chronic conditions will only live to the age of 80. Women continue to live longer than men, while white people live longer than black people.

It’s not just how many diseases you have, but also what disease that matters. At 67, an individual with heart disease is estimated to live an additional 21.2 years on average, while someone diagnosed with Alzheimer’s disease is only expected to live 12 additional years.

On average, life expectancy is reduced by 1.8 years with each additional chronic condition, the researchers found. But while the first disease shaves off just a fraction of a year off life expectancy for older people, the impact grows as the diseases add up.

Previously: Americans are living longer, but are we healthier in our golden years?, Longevity gene tied to nerve stem cell regeneration, say Stanford researchers, Study shows regular physical activity, even modest amounts, can add years to your life and TED Talk with Laura Carstensen shows older adults have an edge on happiness
Photo by Marcel Oosterwijk

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