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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.

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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

Immunology, In the News, Medicine and Society, Pediatrics, Public Health, Stanford News

A discussion of vaccines, “the single most life-saving innovation ever in the history of medicine”

A discussion of vaccines, "the single most life-saving innovation ever in the history of medicine”

vaccine and syringeIn a recent, in-depth interview with KCBS Radio, now available online, Stanford immunologist Mark Davis, PhD, called vaccines “the single most life-saving medical innovation ever in the history of medicine” and called not vaccinating children a real danger.

Davis was interviewed on air for 30 minutes following the announcement that he’ll direct a new, $50-million initiative at Stanford, funded by the Bill & Melinda Gates Foundation, which aims to speed discovery of vaccines for some of the world’s deadliest infectious diseases, such as malaria, tuberculosis and HIV.

Davis, who directs the Stanford Institute for Immunity, Transplantation and Infection, harked back to the time when cemeteries were filled with the graves of young children who fell victim to diseases such as measles and mumps that were virtually wiped out with the advent of vaccines. In the pre-vaccine era, about half of all children died of infectious diseases that are readily preventable today, he noted.

“One day I wandered through Union Cemetery in Redwood City, which started around 1850,” he said. “What was telling about the earlier graves is how many graves you have where they are two large headstones for the mother and father and a lot of little headstones for the children who died in infancy from measles and mumps and all these diseases that had also vanished with childhood vaccination but that are now coming back because people say, ‘I’ve heard something bad about these vaccines. So we are not going to give them to our kid.’”

Parents who chose not to vaccinate their children “are putting your kid at risk and also putting other young children at risk, as children don’t get vaccinated for measles until they are one year old. So kids die. Older people – a population we study here at Stanford – don’t respond very well. Their immune system often deteriorates with age… So even if they had a measles shot in their youth, they might still be vulnerable. So if you don’t vaccinate your child, you are putting your kid at risk, anyone with an immune deficiency at risk, little babies at risk, old people at risk. It just shouldn’t be permitted.”

Measles, he noted, is a “very ambitious” virus that spreads through the air, surviving on droplets of water vapor, so coughing can readily spread the disease. As a matter of public health, the disease can be controlled through the principle of “herd immunity” – the idea that if most people are vaccinated, a disease will be less likely to move through the population, he said.

“So it’s not just about you and your child. It’s about society… If more and more people are not vaccinated, it gives a virus, like the measles virus, an opportunity to run through the population very quickly, which it does, and endanger many more people,” he told listeners.

As to whether California should require parents to vaccinate their children, Davis was adamant on the subject:

I wouldn’t want unvaccinated kids in a classroom with my kids. I think it’s a danger. These are decisions made by parents that could affect the health of their children for the rest of their lives… The government is totally correct to say you should not kill your child, you should not starve your child, you should not beat your child, and you should not deprive your child of vaccines.

Previously: With a Gates Foundation grant, Stanford launches major effort to expedite vaccine discovery, Infectious disease expert discusses concerns about undervaccination and California’s measles outbreak and Side effects of childhood vaccines are extremely rare, new study finds
Photo by NIH

Aging, Immunology, Neuroscience, Research, Stanford News, Stroke

Can immune cells’ anomalous presence in brain explain delayed post-stroke dementia?

Can immune cells' anomalous presence in brain explain delayed post-stroke dementia?

bees in the bonnetAbout every 40 seconds, someone in the United States has a stroke. About one in three of those people will eventually suffer from dementia if they live long enough, even if there’s been no initial damage to brain structures involved in memory and cognition. That’s a mystery.

In a recent study in The Journal of Neuroscience, Stanford neurologist and stroke expert Marion Buckwalter, MD, PhD, points a bony scientific finger at a major likely reason why having a stroke doubles a person’s risk of incurring dementia within the next decade.

The culprit, surprisingly, seems to be a type of normally very beneficial immune cells that under ordinary circumstances have no business being in the brain. These trespassers, called B cells, are best known for generating antibodies that fight off invading pathogens. As I wrote in my release on the new study:

The antibodies that B cells produce are normally of great value to us. They circulate throughout blood and lymph, and bind to microbial invaders, gumming up the pathogens’ nefarious schemes and marking them for destruction by other immune cells. Occasionally, B cells wrongly begin generating antibodies that bind to the body’s own healthy tissues, causing certain forms of autoimmune disease, such as rheumatoid arthritis. Rituxan, a drug approved by the Food and Drug Administration for this condition, is actually an antibody itself: Its target is a protein found on the surface of every B cell. Use of this drug depletes B cells in the body, relieving the symptoms of rheumatoid arthritis and other B-cell-mediated disorders.

The blood-brain barrier, which tightly controls what enters and what leaves the brain, can be disrupted by a stroke, permitting the anomalous appearance of B cells there. Buckwalter and her colleagues showed that in mice experiencing strokes, the affected brain region – immune-cell-free at least one week later – started filling up with B cells until, at seven and twelve weeks post-stroke, there were “tons” of them, she told me. Around the same time, these mice started showing signs of dementia that hadn’t been at all evident a mere week after the stroke.

But in mice of a strain that is genetically incapable of producing B cells, no such cognitive loss occurred. Not only that, but giving plain old ordinary mice Rituxan five days after a stroke prevented this post-stroke dementia.

Then Buckwalter and her team looked at preserved, autopsied brain-tissue samples from people who had had stroke and dementia. Once again, they observed inordinate numbers of B cells in the majority of these brains, suggesting that humans, too, can experience late but lasting infiltration of rampaging B cells into our brains after a stroke.

So maybe giving a Rituxan-like B-cell-depleting compound to these people within that first week after their stroke could stave off dementia.

This wouldn’t by advisable for all stroke patients. You don’t want to wipe out somebody’s B cells (usually, they’re good guys) unless they are causing trouble. And, as seen in the autopsied tissue samples, not all stroke sufferers’ brains fall into that category.

But, Buckingham noted, Rituxan or something like it could work a double shift as both a therapeutic and a diagnostic. Rituxan pretty much binds only to B cells (a prelude to killing them), so tagging the drug with an imaging agent that could be picked up by, say, an MRI scan might tell clinicians which stroke patients have, or don’t have, B’s in their bonnets.

Previously: Targeted stimulation of specific brains cells boosts stroke recovery in mice, Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed and Brain sponge: Stroke treatment may extend time to prevent brain damage
Photo by _annamo

Global Health, Immunology, Research, Stanford News

With a Gates Foundation grant, Stanford launches major effort to expedite vaccine discovery

With a Gates Foundation grant, Stanford launches major effort to expedite vaccine discovery

Mark DavisThe vaccine field got a major boost today with the announcement that the Bill & Melinda Gates Foundation will invest $50 million in a new collaboration with Stanford’s School of Medicine to speed the development of vaccines for some of the world’s major scourges. The funds will support the new Stanford Human Systems Immunology Center, a multidisciplinary effort led by immunologist Mark Davis, PhD.

In recent decades, efforts to develop vaccines for major killers such as HIV and malaria have been stymied in part by the expense and time involved in conducting large-scale trials, which have often proved disappointing. Through the new initiative, scientists will use advanced immunological tools to better understand how vaccines provide protection and identify the most promising candidates to pursue in clinical trials.

What we need is a new generation of vaccines and new approaches to vaccination

“What we need is a new generation of vaccines and new approaches to vaccination,” said Davis, director of the Stanford Institute for Immunity, Transplantation and Infection. “This will require a better understanding of the human immune response and clearer predictions about vaccine efficacy for particular diseases.”

The 10-year initiative will involve multiple faculty from diverse fields, including medicine, engineering and computer science. It will capitalize on a range of technologies, some of which have been pioneered at Stanford, which can rapidly analyze individual cells and provide a detailed profile of the human immune response, with all of its various components.

“This grant will provide crucial support to Stanford’s world-class scientists as they collaborate with investigators around the globe to assess vaccines against some of the most formidable diseases of our time,” said Lloyd B. Minor, dean of Stanford’s medical school. “The Stanford Human Systems Immunology Center will help the most promising vaccine candidates to move quickly and efficiently from the lab to the front lines of treatment, impacting countless lives.”

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail
Photo of Mark Davis by Steve Fisch

Immunology, Infectious Disease, Public Health, Research

Is honey the new antibiotic?

Is honey the new antibiotic?

3535805377_807788e3e1_z…Well, not quite. But recent research shows that honey does have infection-fighting properties surprisingly similar to the common antibiotic ampicillin. And even more importantly, honey worked just as well against bacteria that had developed a resistance to ampicillin, which is good news as the medical community raises awareness about antibiotic resistance.

The study, which was recently published in PLOS ONE, compared the effects of Canadian honey and ampicillin on E. coli bacteria. The most common kind of antibiotics – beta-lactams, which includes ampicillin – work by destroying the cell wall of a bacterium. This prohibits the bacterium from surviving, growing, and reproducing. In the experiment, the researchers used scanning electron microscopy to visualize the changes in the bacterial cultures’ cell structures. They saw that honey and ampicillin had similar effects on the shapes of the E. coli, that they affected it to a similar degree, and that honey had equal effects on normal and antibiotic-resistant E. coli.

As reported on the PLOS blog:

While scientists have yet to confirm the exact compounds responsible, the results of the above study support the idea that honey and ampicillin may have similar antibacterial efficacies, with possibly different mechanisms of attack.

But before you start smothering your toast with gooey goodness each morning or adding heaping spoonfuls to your tea, keep in mind that more research is needed to better understand the potential for honey’s medicinal use.

Previously: A look at our disappearing microbes
Photo by bionicgrrl

Events, Immunology, Infectious Disease, Microbiology, Public Health

A look at our disappearing microbes

A look at our disappearing microbes

8146322408_5312e9deb2_zCould obesity, asthma, allergies, diabetes, and certain forms of cancer all share a common epidemiological origin? NYU microbiologist Martin Blaser, MD, thinks so – he calls these “modern plagues” and traces them to a diminished microbial presence in our bodies, caused by the overuse of antibiotics and the increased incidence of caesarian sections.

I attended a recent public lecture sponsored by UC Santa Cruz’s Microbiology and Environmental Toxicology department, during which the charismatic Blaser cited statistics about antibiotic use in childhood. Alarmingly, American children receive on average seventeen courses of antibiotics before they are twenty years old, taking a progressively bigger toll on their internal microbial ecosystems. We also have an unprecedented rate of c-sections – at nearly 33 percent. Babies delivered this way are deprived of contact with their mothers’ vaginal microbes, which in vaginal deliveries initiates the infant’s intestinal, respiratory, and skin flora. Breastfeeding has implications for beneficial bacterial transfer, too.

It’s not news that antibiotics are being overused – Stanford Medicine hosts an Antimicrobial Stewardship Program dedicated to this cause, and the CDC has been hosting a campaign for awareness about appropriate antibiotic use for several years, including their use in farm animals. (Seventy to eighty percent of antibiotic use takes place on farms to promote growth – that is, not for veterinary reasons.)

Overuse leads to antibiotic resistance, a serious problem. Meanwhile, research by Blaser and others – notably Stanford microbiologist David Relman, MD – has shown that abundant bacterial and viral life is essential to healthy bodies, and that imbalances in the microbial ecosystems that inhabit our gut play an important role in the chronic diseases of the modern age. Blaser said he is concerned that we’re going down a path where each generation has fewer and fewer species of microbes; part of his research is to compare human gut biodiversity in different parts of the globe, and people in remote areas of New Guinea have far more variety than those in Western nations.

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Aging, Genetics, Immunology, Infectious Disease, Research, Stanford News

In human defenses against disease, environment beats heredity, study of twins shows

In human defenses against disease, environment beats heredity, study of twins shows

Pfc. Lane Higson and Pfc. Casey Higson, identical twins serving in Iraq with the Enhanced Combat Aviation Brigade, 1st Infantry Division. The twins, natives of Myrtle Beach, S.C., joined the Army together and have not separated since.I’m one of those people who’ve paid to have their genomes analyzed for the purpose of getting a handle on susceptibility to this or that disease as time goes by. So it was with great interest that I came across a new study of twins conducted by immunologist Mark Davis, PhD, and fellow Stanford investigators. The study, published in CELL, shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body’s primary defense against disease. This is especially true as we age.

Improving gene-sequencing technologies have focused attention on the role of genes in diseases. But the finding that the environment is an even greater factor in shaping our immune response should give pause to anyone who thinks a whole-genome test is going to predict the course of their health status over a lifetime.

“The idea in some circles has been that if you sequence someone’s genome, you can tell what diseases they’re going to have 50 years later,” Davis told me when I interviewed him for a news release I wrote on the study. But, he noted, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation.

Davis, who heads Stanford’s Institute for Immunity, Transplantation and Infection, is worth taking seriously. He’s made a number of major contributions to the field of immunology over the last 30 years or so.  (Not long ago, I wrote an article about one of those exploits for Stanford Medicine.)

To find out whether the tremendous differences observed between different people’s immune systems reflec tunderlying genetic differences or something else, Davis and his colleagues compared members of twin pairs to one another. Identical twins inherit the same genome, while fraternal twin pairs are no more alike genetically than regular siblings, on average sharing 50 percent of their genes. (Little-known fun factoid: The percentage can vary from 0 to 100, in principle, depending on the roll of the chromosomal dice. But it typically hovers pretty close to 50 percent, just as rolling real dice gives you a preponderance of 6s, 7s, and 8s. Think of a Bell curve.)

Because both types of twins share the same in utero environment and, usually, pretty close to the same childhood environment as well, they make great subjects for contrasting hereditary versus environmental influence. (If members of identical-twin pairs are found to be no more alike than members of fraternal-twin pairs with respect to the presence of some trait, that trait is considered to lack any genetic influence.)

In all, the researchers recruited 78 identical-twin pairs and 27 pairs of fraternal twins and drew blood from both members of each twin pair. That blood was hustled over to Stanford’s Human Monitoring Center, which houses the latest immune-sleuthing technology under a single roof. There, the Stanford team applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system cell types, substances and activities.

Said Davis: “We found that in most cases – including your reaction to a standard influenza vaccine and other types of immune responsiveness – there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver.”

It makes sense. A healthy human immune system has to continually adapt to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more.

“The immune system has to think on its feet,” Davis said.

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Immunology escapes from the mouse trap
Photo by DVIDSHUB

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