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Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Autoimmune Disease, Bioengineering, Immunology, Research, Stanford News

Adult humans harbor lots of risky autoreactive immune cells, study finds

Adult humans harbor lots of risky autoreactive immune cells, study finds

dangerIf a new study published in Immunity is on the mark, the question immunologists may start asking themselves will be not “Why do some people get autoimmune disease?” but “Why doesn’t everybody get it?”

The study, by pioneering Stanford immunologist Mark Davis, PhD, and colleagues, found that vast numbers of self-reactive immune cells remain in circulation well into adulthood, upending a long-established consensus among immunologist that these self-reactive immune cells are weeded out early in life in an organ called the thymus.

A particular type of immune cell, called “killer T cells,” is particularly adept at attacking cells showing signs of harboring viruses or of becoming cancerous. As I wrote in my news release about Davis’s study:

[The human immune system generates] a formidable repertoire of such cells, collectively capable of recognizing and distinguishing between a vast array of different antigens – the biochemical bits that mark pathogens or cancerous cells (as well as healthy cells) for immune detection. For this reason, pathogenic invaders and cancerous cells seldom get away with their nefarious plans.

Trouble is, I wrote:

[This repertoire includes] not only immune cells that can become appropriately aroused by any of the billions of different antigens characteristic of pathogens or tumors, but also immune cells whose activation could be triggered by myriad antigens in the body’s healthy tissues. This does happen on occasion, giving rise to autoimmune disease. But it happens among few enough people and, mostly, late enough in life that it seems obvious that something is keeping it from happening to the rest of us from day one.

It’s been previously thought that the human body solves this problem by eliminating all the self-reactive T cells during our early years via a mysterious select-and-delete operation performed in a mysterious gland called the thymus that’s nestled between your heart and your breastbone. Sometime in or near your early teens, the thymus mysteriously begins to shrink, eventually withering and largely turning to useless fat. (Is that mysterious enough for you? It sure creeps me out.)

But Davis and his team used some sophisticated technology – some of it originally invented by Davis, some of it by Stanford bioengineering professor and fellow study co-author Stephen Quake, PhD – to show that, contrary to prevailing dogma, tons of self-reactive killer T-cells remain in circulation well into adulthood. Then the scientists proceeded to explore possible reasons why the immune system keeps these risky cells around (it boils down to: just in case a pathogen from Mars comes along and we need to throw the kitchen sink at it) and why (at least most of the time) they leave our healthy tissues alone: A still-to-be-fully-elucidated set of molecular mechanisms keeps these self-reactive cells locked in the biochemical equivalent of parking gear, shifting out of which requires unambiguous signs of an actual pathogen’s presence: bits of debris from a bacterial cell wall, or stretches of characteristically viral DNA.

That’s our immune system, folks. Complicated, mysterious, and yet somehow incredibly efficient. You really don’t want to leave home – or even the womb – without it.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, In men, a high testosterone count can mean a low immune response and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Frederic Bisson

Biomed Bites, Immunology, Research, Science, Technology, Videos

Not immune from the charms of the immune system

Not immune from the charms of the immune system

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

Once upon a time, a researcher named Holden Maecker, PhD, met flow cytometry, a technique used to examine cells by suspending them in fluid and then passing them by an electronic detector.

A match that could only be made in a science lab, Maecker was hooked. Maecker tells the tale in the video above:

Flow cytometry is a great technique for looking at the immune system and it’s also a little bit of an art, which also attracted me. It’s something that not everybody can do perfectly well and I got a little bit good at it and decided it was a fun thing to do and a good way to look at the immune system.

Maecker and flow cytometry haven’t parted, yet he’s broadened his mastery of a variety of other techniques to study the immune system as the director of Stanford’s Human Immune Monitoring Center.

“It’s a very interesting position because it allows me to collaberate with a lot of different peopel doing projects that have to do wiht human immune responses — everything from sleep apnea and wound healing to flu vaccines and HIV infections,” Maecker said. “It’s amazing the breadth we have here [at Stanford].”

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, Immunology meets infotech and Stanford Medicine magazine traverses the immune system

Global Health, Immunology, Infectious Disease, Pediatrics, Stanford News

Researchers tackle unusual challenge in polio eradication

Researchers tackle unusual challenge in polio eradication

poliovaccinationPolio is a tricky foe. One of the biggest hurdles in the World Health Organization’s polio eradication campaign is that the virus causes no symptoms in 90 percent of people who contract it. But these silently infected individuals can still spread the virus to others by coughing, sneezing or shedding it in their feces. And those they infect may become permanently paralyzed by or die.

Polio’s evasiveness has also led to a big speed bump on the road to eliminate the disease. As I report in the current issue of Inside Stanford Medicine, scientists are trying to figure out how to stop a form of poliovirus that is derived from one type of  polio vaccine. Oral vaccines, which consist of live poliovirus that has been inactivated, can occasionally mutate in someone’s intestines to regain infectiousness. And, in rare instances, these viruses escape to the environment in feces, spreading to other people via sewage-contaminated water.

These “circulating vaccine-derived viruses” are threatening to overtake naturally occurring, “wild” poliovirus as the main source of paralysis in the communities where polio persists. The CDC’s most recent report on polio infections in Nigeria says that during the first nine months of 2014, the vaccine-derived viruses caused 22 cases of paralyzing poliomyletis, whereas wild virus caused six cases, for instance.

To tackle the problem, researchers are investigating how the injected polio vaccine, which is made with killed virus, might be substituted for the oral vaccine. The injected vaccine has some potential disadvantages for use in developing countries, so it’s not necessarily an easy substitution. In my story, Stanford’s Yvonne Maldonado, MD, who is studying the problem with a grant from the Bill & Melinda Gates Foundation, explains:

“We don’t really understand how well the killed vaccine is going to work in kids in developing countries, where there is lots of exposure to sewage, and malnutrition leaves children with weakened immune systems,” Maldonado said.

Her Gates Foundation grant examines semi-rural communities in Mexico where children now receive routine doses of the killed vaccine, followed by twice-a-year doses of the live vaccine.

“It’s an opportunity for us to study a natural experiment,” Maldonado said. Her team wants to know if the primary immune response to the killed vaccine will reduce shedding and transmission of later doses of live vaccine. They hope that starting with one or more doses of the injected vaccine will give kids the best of both worlds: from the shot, protection against circulating vaccine-derived viruses; from the oral vaccine, intestinal immunity.

Previously: TED talk discusses the movement to eradicate polio and New dollar-a-dose vaccine cuts life-threatening rotavirus complications by half
Photo of children in South Sudan receiving oral polio vaccine by United Nations Photo

Aging, Immunology, Infectious Disease, Research, Stanford News

Frenemies: Chronic cytomegalovirus infection boosts flu vaccination efficacy (IF you’re young)

Frenemies: Chronic cytomegalovirus infection boosts flu vaccination efficacy (IF you're young)

cheapo boost“The enemy of my enemy is my friend.” This phrase, or at least the thinking it embodies, is at least 2,400 years old. So, there must be something to it, right?

Of course, it’s arguably a vast oversimplification. The more nuanced and much newer term “frenemy,” dating back merely to the early 1950s, is more apt in the case of infection by the microbe known as cytomegalovirus (CMV, for short). If the name is unfamiliar, brace yourself: You’ve probably already been introduced. It’s ubiquitous.

“Between 50 percent and 80 percent of adults in the United States have had a CMV infection by age 40,” states a page on the National Institutes of Health’s website. (Worldwide, the proportion of people infection exceeds 90 percent.) Once CMV is in a person’s body, it stays there for life,” the page soberly adds.

For the most part in healthy people, CMV pretty much sits there inside of cells (particularly in the salivary glands), pretty much biding its time and getting slapped down by the immune system if it tries to act up.

On the other hand, the virus can cause serious trouble if you’re immune-compromised: say, getting a bunch of immune-suppressing drugs pending or after a transplantation operation, or carrying another virus, the infamous immune-deficiency-causing HIV (which as far as we know is nothing but an enemy, plain and simple.)

But in a new study published in Science Translational Medicine, Stanford immunology expert Mark Davis, PhD, and his colleagues show that carriers of CMV mount a more robust immune response to seasonal influenza vaccinations, increasing the chances that the annual vaccine will be more effective in those people.

That’s the good news. The not-so-great news is that this only holds for young people (20-30 years old), not the older ones (age 60 and up) who could really use a boost: The older you get, it’s well known, the less effective the standard seasonal flu vaccine is in helping you fight off an influenza infection.

Experimenting with mice, Davis and his associates went a step farther. They actually infected the animals with influenza itself. Sure enough, young mice who were carrying CMV fought off the bug better than the non-infected mice did.

That’s the good news. The not-so-great news is that the old mice didn’t.

And although the study didn’t say so, one wonders whether in young people whose immune systems are going strong, that extra rocket fuel CMV seems to provide may have a dark side, for example a tendency to autoimmunity. Women’s immune systems tend to be more robust than those of men (very possibly due to the effects of testosterone, as Davis and his crew found a little over a year ago. And they have several times the rate of many autoimmune diseases that men do.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Why do flu shots work in some but not others? Stanford researchers are trying to find out, In men, a high testosterone count can mean a low immune response and Mice to men: Immunological research vaults into the 21st century
Photo by Joe Lillibridge

Immunology, Microbiology, Research, Stanford News

Drugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes

Drugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes

bacterial cytoplasmMy first encounter with microbiologist Justin Sonnenburg, PhD, came when I was researching “Caution: Do Not Debug,” an article I wrote five years ago for Stanford Medicine about the astonishing microbiotic superorganism that beats within the human gut.

According to the Human Microbiome Project, the typical healthy person is inhabited with trillions of intestinal microbes. A person typically hosts 160 or so species of gut bacteria. This bug collection carries its own “shadow genome” consisting of hundreds of times as many genes, in all, than our own measly 20,000 or so human ones.

In exchange for the three square meals a day we provide them, our microbial moochers do lots of good things: From my article:

[O]ur commensal microbes work hard for their living. They synthesize biomolecules that manipulate us in ways that are helpful to both them and us. They produce vitamins, repel pathogens, trigger key aspects of our physiological development, educate our immune system, help us digest our food and for the most part get along so well with us and with one other that we forget they’re there.

Since I wrote that piece, the list of microbial good deeds has continued to grow. As Sonnenburg pointed out recently in a review article in CELL Metabolism, “Starving our Microbial Self,” our resident microbes are producing hundreds or thousands of little drug-like compounds. For example: Short-chain fatty acids, generated by our gut bacteria from starches and fiber in our diet, downregulate inflammation.

Quoted in a just-published feature in Nature Biotechnology, “Drugging the Microbiome,” Sonnenburg elaborates:

Might a lack of dietary fiber lead directly to autoimmune and inflammatory diseases? That’s the view of Justin Sonnenburg, a Stanford microbiologist. “A reduction in short-chain fatty acid production… is what happens when you get rid of dietary fiber, and [leads to] increasing inflammatory responses of the host immune system,” he says. “And it’s this simmering state of inflammation that the Western immune system exists in that’s really the cause of all the diseases that we’ve been talking about. … You can just imagine that if you get rid of these important regulatory molecules, and the immune system becomes a little bit pro-inflammatory across a large population, you’re going to see increases in things like cancer, heart disease, allergies, asthma and inflammatory bowel disease.”

While they’re indispensable, our gut microbes can do bad things, too. Research has implicated them in the production of certain metabolites implicated in deleterious effects, with potential involvement in conditions ranging from heart disease to autism to Parkinson’s to colon and liver cancer, according to the Nature Biotechnology feature.

Either way, it’s going to be well worth our while to learn everything we can about the details of the ecosystem of one-celled creatures who call us “home.”

Previously: Civilization and its dietary (dis) contents: Do modern diets starve out our gut-microbial community?, The future of probiotics and Researchers manipulate microbes in the gut
Photo by Duncan Hull

Chronic Disease, Immunology, Infectious Disease, Neuroscience, Research, Stanford News

ME/CFS/SEID: It goes by many aliases, but its blood-chemistry signature is a giveaway

ME/CFS/SEID: It goes by many aliases, but its blood-chemistry signature is a giveaway

signature

It’s the disease that dare not speak its name without tripping over one of its other names. Call it what you will – chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) or its latest, Institute of Medicine-sanctioned designation, systemic exertion intolerance disease (SEID). It’s very real, affecting between 1 million and 4 million people in the United States alone, according to Stanford infectious-disease sleuth Jose Montoya, MD, who has closely followed more than 200 SEID patients for several years and done extensive testing on these patients in an effort to find out what’s causing their condition.

Different authorities have quoted different numbers regarding those with SEID. The name-calling and number-assigning squishiness stems from the fact that beyond its chief defining symptom – overwhelming, unremitting exhaustion lasting for six months or longer – it’s tough to pin down. Additional symptoms can range from joint and muscle pain, incapacitating headaches or food intolerance to sore throat, lymph-node enlargement, gastrointestinal problems, abnormal blood-pressure or hypersensitivity to light, noise or other sensations.

Research into the hows and whys of SEID has been plagued by the inability to establish any characteristic biochemical or neuroanatomical underpinnings of the disorder. Although many viral suspects have been interrogated, no accused microbial culprit has been indicted. To this day, there are no valid laboratory tests for diagnosing SEID.

But a burst of insight into SEID’s physiological substrate came only months ago when Stanford neuroradiologist Mike Zeineh, MD, PhD, working with patients from Montoya’s registry, found that they shared a pattern of white-matter loss in specific parts of the brain. The discovery drew a great deal of attention in the press as well as the CFS community. (See our news release about that study for details.)

Now a high-profile, multi-institution team including Montoya has published a study in Science Advances showing yet another physiological basis for a diagnosis of SEID: a characteristic pattern, or “signature,” consisting of elevated levels of various circulating immune-signaling substances in the blood.

Continue Reading »

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Immunology, In the News, Nutrition, Pediatrics, Research

Peanut products and babies: Now okay?

Peanut products and babies: Now okay?

peanut butter2 - big

Updated 2-25-15: Allergy expert Sharon Chinthrajah, MD, discussed the study and its implications on KQED’s Forum today:

***

2-24-15: Any parent of young children is likely familiar with the warnings: It’s not okay to give your baby peanut butter, or any other peanut product, before he or she turns one. Don’t do it! These instructions are so imprinted on my brain that I practically did a double-take when I came across headlines about new research suggesting that infants should, indeed, be fed peanut products – in order to prevent the development of peanut allergies.

This isn’t the first time that the benefits of giving allergenic foods to babies have been outlined, but the language surrounding this study has been particularly strong. As the writer of a New York Times blog entry explained, the authors of the study and accompanying editorial “called the results ‘so compelling’ and the rise of peanut allergies ‘so alarming’ that guidelines for how to feed infants at risk of peanut allergies should be revised soon.” He went on to outline the study findings:

In the study, conducted in London, infants 4 to 11 months old who were deemed at high risk of developing a peanut allergy were randomly assigned either to be regularly fed food that contained peanuts or to be denied such food. These feeding patterns continued until the children were 5 years old. Those who consumed the foods that had peanuts in them were far less likely to be allergic to peanuts when they turned 5.

After hearing the news, I reached out to the folks at the Sean N. Parker Center for Allergy Research at Stanford to get their take on the findings. Sharon Chinthrajah, MD, a clinical assistant professor of medicine, explained that this work is the first randomized controlled study to look at how to prevent peanut allergies. She told me:

We’ve all been waiting for the results of this landmark study to confirm the shift in the paradigm of when to introduce foods into the diet. Early introduction of peanut in the right infants can prevent peanut allergy. Dr. [Gideon Lack, the leader of the study] and colleagues were able to show an 80 percent reduction in peanut allergy in children who started eating peanut early and incorporated it into their regular diet.

Chinthrajah believes the guidelines on babies and peanut products should be revised, “because peanut allergies affect 2 percent of our population in the U.S. and most people do not outgrow this allergy.” But, as other experts have done, she cautions that not everyone should introduce peanuts and other foods into their diet early. “Those who are ‘high-risk’ – who have other allergic conditions such as eczema or other food allergies – should consult with their allergist to see if it would be safe to introduce peanut into their child’s diet,” she advised.

Previously: Taking a bite out of food allergies: Stanford doctors exploring new way to help sufferers, Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows, Researchers show how DNA-based test could keep peanut allergy at bay, A mom’s perspective on a food allergy trial and Searching for a cure for pediatric food allergies
Photo by Anna

Autoimmune Disease, Chronic Disease, Immunology, Stanford News, Videos

Chronic fatigue syndrome gets more respect (and a new name)

Chronic fatigue syndrome gets more respect (and a new name)

As has been widely reported, an Institute of Medicine (IOM) report released yesterday acknowledged that chronic fatigue syndrome is a real and serious disease and renamed the disorder “systemic exertion intolerance disease” to better reflect its key symptoms.

Stanford professor José Montoya, MD, who served as a reviewer on the IOM report, is featured in the video above, which accompanied Washington Post coverage of the development. The Post article goes on to say:

“We just needed to put to rest, once and for all, the idea that this is just psychosomatic or that people were making this up, or that they were just lazy,” said Ellen Wright Clayton, a professor of pediatrics and law at Vanderbilt University, who chaired the committee of the Institute of Medicine, the health arm of the National Academy of Sciences.

Although the cause of the disorder is still unknown, the panel established three critical symptoms for the condition (also known as myalgic encephalomyelitis):

  • A sharp reduction in the ability to engage in pre-illness activity levels that lasts for more than six months and is accompanied by deep fatigue that only recently developed.
  • Worsening of symptoms after any type of exertion, including “physical, cognitive or emotional stress.”
  • Sleep that doesn’t refresh the sufferer.

The panel also requires that a patient have one of two other disease manifestations, either cognitive impairment or orthostatic intolerance. Orthostatic intolerance is an autonomic nervous system disorder that is caused by an abnormal increase in heart rate and low blood pressure, believed to be triggered by the disease.

Susan Kruetzer, an SEID patient interviewed by Erin Allday in this San Francisico Chronicle article, expressed guarded optimism about the report’s ability to generate more research funding and patient support, saying “What I want to see is someone in Congress get pretty riled up by this report — have them see how many people are affected, how these people are really ill, how they’ve been mistreated,” Kreutzer said. “I’d just like to light a fire. I don’t know if this report will do that, but I suppose it gives us some ammunition.”

Previously: Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed, Unbroken: A chronic fatigue syndrome patient’s long road to recovery and Deciphering the puzzle of chronic fatigue syndrome

Stanford Medicine Resources: