Published by
Stanford Medicine


Chronic Disease, Clinical Trials, Mental Health, Research, Stanford News

Treating insulin resistance may speed recovery from major depression

Treating insulin resistance may speed recovery from major depression

depressionIn a randomized, placebo-controlled clinical trial detailed in this study in Psychiatry Research, pioglitazone – a generically available drug that’s approved for type 2 diabetes – helped to relieve symptoms of major depression in patients whose blues had withstood an assault by standard therapeutic regimens for six months or longer.

But this beneficial effect was seen only in depressed patients who were also insulin-resistant.

Depression is remarkably common. Stanford psychiatric researcher Natalie Rasgon, MD, PhD, the study’s senior author, told me that close to one in five Americans are diagnosed with depressive illness at some point in their lives.

Insulin resistance, a stepping stone on the path to type 2 diabetes (not to mention cardiovascular disease and probably Alzheimer’s), is even more common: About one in three otherwise healthy Americans – and an even greater share of people with depression – are insulin-resistant. Especially prevalent among overweight people, insulin resistance also occurs more often than one might expect even among thinner folks, a lot of whom don’t have the faintest idea that’s the case.

Insulin, released by the pancreas in response to food intake, alerts cells throughout the body to the presence of glucose, the body’s primary energy source, in the blood. Insulin-resistant people’s cells fail to take up glucose adequately, leaving high residual blood levels of the sugar to wreak havoc on the body’s tissues. Because the brain is a glucose glutton – it soaks up about 20 percent of all glucose consumption in a healthy, active person – it’s easy to imagine that lousy glucose uptake in the brain would have all kinds of deleterious effects, including effects on mood. Food for thought, anyway.

Here’s how my news release described the study:

[R]esearchers were blinded as to which patients were receiving pioglitazone versus a placebo. The patients didn’t know which they were getting, either. … All the patients had been experiencing episodes of depression lasting, on average, more than one year. Their symptoms had failed to remit under standard treatment regimens. They remained on these regimens for the duration of the Stanford study and, in addition, were given either pioglitazone or a placebo. … The patients were tested for depression severity and insulin resistance at the study’s outset and then roughly every two weeks from the beginning of the trial to the end.

A total of 37 patients – 29 women and eight men – completed the 12-week study. The insulin-sensitive subjects did about as well on the drug as they did on placebo. But among the insulin-resistant group, those given pioglitazone showed a much greater improvement than those who got a placebo. They also showed more improvement than insulin-sensitive patients did.

The more insulin-resistant a participant was at the beginning of the study, the better the drug’s antidepressant effect. Possible, but not proven, explanation: It could be that for some patients standard antidepressant therapies can kick into gear only once these patients’ insulin resistance is reduced. Hungry brains gotta eat.

Previously: Survey shows nearly a quarter of U.S. workers have been diagnosed with depression in their lifetime, Revealed: the brain’s molecular mechanism behind why we get the blues, and International led by Stanford researchers identifies gene linked to insulin resistance
Photo by S.Hart Photography

Clinical Trials, Pain, Research, Stanford News

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

shoulderHundreds of millions of people worldwide (115 million in the United States alone) suffer from chronic pain. Stanford diagnostic radiologist Sandip Biswal, MD, calls this group “one of the largest populations in the world for medical need of any kind.” But current treatments either aren’t all that great or – in the case of opioids, which are highly effective – put patients at risk for addiction.

A pair of randomized, double-blinded clinical trials, described in a study co-authored by Biswal, former Stanford visiting scholar Charlie Koo, PhD, and several colleagues and published in Nature Scientific Reports, may point to a potential path toward more pain-free lives. In the trials, patients with chronic neck or shoulder pain were treated with three to six 90-minute sessions of either standard physical therapy – so-called transcutaneous electrical nerve stimulation,  or TENS, along with exercise and both manual and heat treatments – or a protocol designed by Koo, who now runs a facility called the Pain Cure Center in Palo Alto, California.

The new method, which Koo calls Noxipoint therapy, also employs electrical stimulation of painful areas, but in a carefully defined way: electrodes are placed precisely at both of the two attachment points for each muscle in pain, and the electrical-current jolt is brief and just enough to cause local soreness and dull, but not sharp, pain. Patients receiving the novel therapy are also told to take it easy for several days after each treatment.

In both trials, Noxipoint therapy proved superior to conventional physical therapy using TENS by close to an order of magnitude. Four weeks after their last treatment, patients given Noxipoint therapy reported substantial pain reduction, restoration of function (for example, regained range of motion) and improved quality of life, without significant side effects. Those given standard treatment reported no significant lasting improvement.

These trials are preliminary and call for confirmation in larger studies, Biswal told me. Given the pressing need for safe, lasting relief from chronic pain and the apparent success of this new method, it would be nice to see those expanded trials take place.

Previously: “People are looking for better answers”: A conversation about chronic painNational survey reveals extent of Americans living with pain and Stanford researchers address the complexities of chronic pain
Photo by Jason Trbovich

Chronic Disease, Infectious Disease, Microbiology, Research, Science, Stanford News

Bad actors: Viruses, pathogenic bacteria co-star in health-horrific biofilms

Bad actors: Viruses, pathogenic bacteria co-star in health-horrific biofilms

biofilmA group under the direction of Stanford infectious disease investigator Paul Bollyky, MD, PhD, has uncovered a criminal conspiracy between two microbial lowlifes that explains how some of medicine’s most recalcitrant bacterial infections resist being expunged.

In a study published today in Cell Host & Microbe, Bollyky and his associates reveal that bacterial pathogens responsible for a big chunk of chronic infections can team up with a type of virus that bacteria ordinarily consider their worst enemies to form biofilms, which, our news release on the study explains, are “slimy, antiobiotic-defying aggregates of bacteria and organic substances that stick to walls and inner linings of infected organs and to chronic wounds, making infections excruciatingly hard to eradicate.” More from that release:

Biofilms factor into 75 to 80 percent of hospital-acquired infections, such as those of the urinary tract, heart valves and knee-replacement prostheses, Bollyky said. “A familiar example of a biofilm is the plaque that forms on our teeth,” he said. “You can brush twice a day, but once that plaque’s in place you’re never going to get rid of it.”

The study first focused on Pseudamonas aeruginosa, which accounts for one in ten hospital-acquired infections, many chronic pneumonia cases and much of the air-passage obstruction afflicting cystic-fibrosis patients.

Cystic fibrosis is deadly mainly because of biofilms formed by P. aeruginosa, Bollyky told me. “These biofilms fill up all the air spaces, and antibiotics can’t seem to penetrate them,” he said.

But he and his colleagues found that P. aeruginosa forms biofilms only when it’s been infected itself.

Continue Reading »

Big data, Clinical Trials, Health Policy, Precision health, Research

Push-button personalized treatment guidance for patients not covered by clinical-trial results

green buttonA pediatrician, a cardiologist and a biomedical informaticist walk into a pharmacy. They all look as if they could use some strong medicine. “We want a Green Button,” they tell the pharmacist in unison.

“Green Button? Hmmm. I can’t say I know how to compound that prescription,” the puzzled pharmacist replies. “But if all three of you are ordering it, maybe I should. Can you tell me what, specifically, goes into a Green Button?”

“A lot of patients,” reply the three thirsty health experts.

“OK, I’ll play along,” says the pharmacist, beginning to lose his patience. “What comes out?”

“If we knew the answer to that, we wouldn’t need a Green Button.”

Actually, that punch line is no joke. The “Green Button” signifies a profound, potentially pervasive approach that could revolutionize medical practice. In a just-published feature in Inside Stanford Medicine, I report on a futuristic (but not too futuristic) vision of a “learning health-care system” outlined in a 2014 Health Affairs paper by three Stanford experts: pediatric specialist Chris Longhurst, MD, cardiologist Bob Harrington, MD, and biomedical informaticist Nigam Shah, MBBS, PhD.

As I noted in that feature:

The randomized clinical trial is considered the gold standard of medical research. In a randomized clinical trial… participants are randomly assigned to one of two – or sometimes more – groups. One group gets the drug or the procedure being tested; the other is given a placebo or undergoes a sham procedure. … Once the trial’s active phase ends, rigorous statistical analysis determines whether the hypothesis, spelled out in advance of the trial, was fulfilled.

There’s one problem: Clinical trials select only a small, artificial subset of the real population. The rest of us are kind of out of luck.

“Clinical trials are designed to prove one thing,” Shah told me. “And you’re testing it on people with just one thing: type 2 diabetes, eczema, whatever. But most real-life people don’t have just one thing. They have three or four or five things.”

Enter the Green Button. Suppose you’re a clinician facing a patient for whom no clear clinical guidelines exist. Instead, according to the scheme depicted by Longhurst, Harrington and Shah, you press a virtual “green button” on a computer screen displaying your patient’s electronic medical record. This triggers a real-time search of millions, or tens or millions, of other electronic records. In a matter of minutes, up pops a succinct composite summary of the outcomes of 25 or 100 or perhaps 1,000 patients very similar to the one in front of you – same race, same height, same age, same symptoms, similar medical histories, lookalike lab-test results – who were given various medications or procedures for the condition you’re hoping to treat. Those “lookalikes,” it turns out, respond much better to one treatment than to the others – something you’d have been hard put to guess on your own.

That’s all very nice, you say. Now I get your “artisanal faux-joke” lead. But, you ask, why does the button have to be green? And I answer: It doesn’t. But the other good colors were already taken.

Previously: Widely prescribed heartburn drugs may heighten heart-attack risk, New research scrutinizes off-label drug use and A new view of patient data: Using electronic medical records to guide treatment
Photo by Green Mamba :)–<

Dermatology, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

bank heistStaphylococcus aureus is a bacterium that colonizes the skin (and, often, the noses) of about one in three people, mostly just hanging out without causing symptoms. But when it breaches the skin barrier, it becomes a formidable pathogen.

S. aureus not only accounts for the majority of skin and soft-tissue infections in the U.S. and Europe, but can spread to deeper tissues leading to dangerous invasive infections in virtually every organ including the lungs, heart valves, and bones. These complications cause an estimated 11,000 deaths in the U.S. annually.

Making matters worse, antibiotic-resistant strains of S. aureus are becoming increasingly prevalent and even more difficult and costly to treat. All of which makes it crucial to understand the factors that control the bug’s virulence: What turns a common colonizer into a pathogen?

The answers that typically spring to mind involve molecules the pathogen produces that enable damage to cells of the host organism. Certainly S. aureus is no slouch in that arena. Prominent among the many virulence factors it produces, one called α-toxin aggregates on host cell surfaces to form pores that injure the cells’ outer membranes, often killing the cells.

But it turns out that forming pores appears not to be enough, by itself, for lethal host-cell injury. In a study published in Proceedings of the National Academy of Sciences, a team directed by Stanford microbe sleuths Manuel Amieva, MD, PhD, and Jan Carette, PhD, identified several hitherto-unsuspected molecules produced within host cells themselves that determine whether the cells live or die after α-toxin-induced pore formation.

Continue Reading »

Behavioral Science, Neuroscience, Research, Stanford News

Step by step: Study pinpoints brain connection required for performing serial tasks

Step by step: Study pinpoints brain connection required for performing serial tasks

one step at a timeA journey of a thousand miles begins with the first step, as the Chinese philosopher Lao-Tse is reported to have said 2,600 years ago. People have been saying it ever since. But you never hear much about the second step.

Think about it: That second step is taken by your other leg and requires the coordinated contracting of a completely different set of muscle groups, each of them on the opposite side of your body from the ones you used on the first step. There has to be some kind of switch in your brain that unconsciously transitions your exertions from one set of muscle groups to the other set. (Caution: Do not think about this while you’re walking. You’ll trip.)

It’s not just walking that involves such “serially ordered” actions: You’d certainly want to precede that long journey by putting your pants on, a performance best executed one leg at a time. In fact, pretty much everything we do is actually a sequence of seamlessly switched component actions, carried out under the command of brain circuitry about which we know next to nothing.

And that’s fine, until some aspect of said circuitry isn’t working right, as occurs in various movement disorders. That’s when we want to look under the hood, so to speak, at the brain’s immensely complicated mesh of interwoven nerve-cell circuits, in the hopes of ferreting out and fixing the wiring that’s relevant to the disorder.

The brain doesn’t make this easy. Unlike the snaking bundles of insulated wires in the gizmos we humans devise, the brain’s circuits never come color-coded. Only in recent years have advanced laboratory techniques allowing precise explorations of individual brain circuits become available.

In a study just published in NEURON, intrepid Stanford neuro-spelunker Rob Malenka, MD, PhD – who’s teased apart brain circuitry involved in motivation, depression, friendship, addiction and more – and his Stanford colleagues applied these state-of-the-art techniques to mice.

Mice’s brain wiring diagrams are remarkably similar to ours as long as we’re not talking about high-level skills required for reading, doing arithmetic, telling lies and so forth. But, being four-legged creatures, mice aren’t ideal subjects for studying the order in which they put on their pants.

So Malenka and his team tried a more mouse-adapted approach. Using chocolate pellets as an incentive, the team trained the mice to first poke their noses into one of two recessed ports in a wall, and then to press one of two levers. Only by performing the two tasks in order, and making the correct choices in each case, did a mouse earn a pellet paycheck. Via a combination of highly selective brain-circuit manipulations and electrophysiological and behavioral tests, Malenka’s group was able to pinpoint a specific set of neural connections (running from the motor cortex to the midbrain) that was essential to the mice’s proper execution of these serially ordered tasks.

The findings will help guide research into the brain malfunctions that underlie conditions such as Parkinson’s disease or Huntington’s disease. But of course, this is just one step in a long journey.

Previously: Obscure brain chemical indicted in chronic-pain-induced “Why bother?” syndrome, “Love hormone” may mediate wider range of relationships than previously thought, Revealed: the brain’s molecular mechanism behind why we get the blues and Better than the real thing: how drugs hot wire our brain’s reward circuitry
Photo by Elliott Brown

Immunology, Infectious Disease, Precision health, Research, Stanford News, Transplants

A blood test that monitors for post-lung-transplant rejection and infection

A blood test that monitors for post-lung-transplant rejection and infection

lungsA team under the direction of Stanford bioengineer Steve Quake, PhD, has shown that a noninvasive blood test can accurately diagnose lung-transplant rejection. The test also simultaneously detects infections by patient-imperiling microbes.

About 3,500 lung transplant procedures are performed annually worldwide. But median survival after the graft barely exceeds five years, trailing the outcomes for kidney, heart, liver and other solid organ transplants. Chronic organ rejection is the biggest single factor. Infection (for which recipients are at high risk due, ironically, to their post-transplant regimen of immune-suppressing drugs given to reduce the likelihood of organ rejection) is another leading contributor.

In a study published in Proceedings of the National Academy of Sciences, Quake and his associates demonstrated that the test, which involves high-throughput sequencing of DNA, flags organ rejection by detecting increasing amounts of donor DNA in a recipient’s blood. The relatively low-cost test doesn’t require the highly invasive removal of lung tissue, and it can also screen for myriad bacterial, viral and fungal pathogens.

In another study in 2014, Quake and Stanford colleagues had come up with a similar blood test to determine whether a heart-transplant recipient was headed for organ rejection. The new study expands the test’s applicability to lung transplantation – and suggests that its utility may extend to solid organs in general, including more-frequently performed procedures such as kidney transplantation (more than 17,000 in the United States alone in 2014).

With better than half of all lung-transplant patients suffering organ rejection in just the first year after their operation, this advance holds great clinical potential. Quick, accurate diagnosis is the first step toward appropriate treatment.

Previously: A simple blood test may unearth the earliest signs of heart transplant rejection, Step away from the DNA? Circulating *RNA* in blood gives dynamic information about pregnancy, health and Might kidney-transplant recipients be able to toss their pills?
Photo by Lorraine Santana

Cardiovascular Medicine, Genetics, Research, Stanford News

Close-up look at mutinous mutant molecule implicated in hypertrophic cardiomyopathy

Close-up look at mutinous mutant molecule implicated in hypertrophic cardiomyopathy

heart failureThe healthy human heart is a hard-working muscle: Beating just over 100,000 beats per day,  it pumps five quarts of blood per minute – enough to fill three supertankers worth of blood over the course of an average person’s lifetime.

Like any other mechanical pump, the heart is made up of various components, including different kinds of proteins. One of those proteins, a “molecular motor” called cardiac myosin (there are several varieties of myosin), plays a crucial role. A myosin molecule can oscillate lengthwise, contracting and relaxing by turns. It’s the coordinated oscillations of myriad cardiac myosin molecules that are, in the aggregate, responsible for the heartbeat.

Defective cardiac myosin exacts a severe medical price. Hypertrophic cardiomyopathy, caused by mutations in a gene encoding cardiac myosin, occurs in at least one in 500 people and is a leading cause of heart failure in the United States and worldwide. It’s also the primary cause of sudden deaths due to heart attack in people under age 30.

A mutation known as R403Q, identified a couple of decades ago, ranks among the nastiest and most widely studied of literally hundreds of cardiac-myosin mutations.  The general thinking has been that the mutation results in a “gain of function,” meaning stronger-than-normal myosin contractility.

Now, researchers under the direction of Stanford biochemist Jim Spudich, PhD, have for the first time been able to look at the effects of this mutation in human cardiac myosin as opposed to animal models. Spudich, whom I wrote up in 2012 as the winner of that year’s prestigious Lasker Award for Basic Medical Research, is a pioneer in the analysis of myosin and its associated motility-related proteins. Integrating approaches drawn from cell physiology, physics, biochemistry, structural biology and genetics, Spudich and his colleagues have developed methods of  measuring the exact amount of energy consumed in each contraction of a single molecule of myosin. (In my 2012 Lasker Award write-up, I explained myosin’s critical involvement not only in heartbeat but also in all muscular movement and, indeed, all transport of molecular materiel within every living plant or animal cell.)

In a study published in Science Advances, Spudich’s team measured the effects of the R403Q mutation at the single-molecule level and was able to demonstrate tiny, but relevant changes in the power of the mutant myosin molecule.The next step is to, in an even more sophisticated way, measure these effects in a microenvironment more closely approximating that of a living human heart.

R403Q is just the first of several hypertrophic-cardiomyopathy-inducing mutations the team is analyzing, one by one, with their state-of-the-art techniques.

Previously: Stanford molecular-motor maven Jim Spudich wins Lasker Award, Sudden cardiac death has cellular cause, say Stanford researchers and Stanford patient on having her genome sequenced: “This is the right thing to do for our family”
Photo by Sharon Sinclair

Addiction, Behavioral Science, Genetics, Neuroscience, Research, Stanford News

Found: a novel assembly line in brain whose product may prevent alcoholism

Found: a novel assembly line in brain whose product may prevent alcoholism

alcohol silhouette

High-functioning binge drinkers can seem charming and stylish. The ultimate case in point: Nick and Nora of the famed Thirties/Forties “Thin Man” film series (you can skip the ad after the first few seconds).

But alcoholism’s terrific toll is better sighted on city streets than in celluloid skyscraper scenarios. At least half of all homeless people suffer from dependence on one or another addictive drug. (My Stanford Medicine article “The Neuroscience of Need” explores the physiology of addiction.) Alcohol, the most commonly abused of them all (not counting nicotine), has proved to be a particularly hard one to shake.

Alcoholism is an immense national and international health problem,” I wrote the other day in a news release explaining an exciting step toward a possible cure:

More than 200 million people globally, including 18 million Americans, suffer from it. Binge drinking [roughly four drinks in a single session for a man, five for a woman] substantially increases the likelihood of developing alcoholism. As many as one in four American adults report having engaged in binge drinking in the past month.

While there are a few approved drugs that induce great discomfort when a person uses them drinks alcohol, reduce its pleasant effects, or alleviate some of its unpleasant ones, there’s as of yet no “magic bullet” medication that eliminates the powerful cravings driving the addictive behavior to begin with.

But a study, just published in Science, by Stanford neuroscientist Jun Ding, PhD, and his associates, may be holding the ticket to such a medication. In the study, Ding’s team identified a previously unknown biochemical assembly line, in a network of nerve cells strongly tied to addiction, that produces a substance whose effect appears to prevent pleasurable activity from becoming addictive. The substance, known as GABA, acts as a brake on downstream nerve-cell transmission.

Continue Reading »

Infectious Disease, Microbiology, Research, Stanford News

Why C. difficile-defanging mouse cure may work in people, too

Why C. difficile-defanging mouse cure may work in people, too

CdiffI wrote a news release last week about a study just published in Science Translational Medicine. The study, despite it having been conducted in mice, not humans, received a fair amount of coverage – by The Washington Post, Yahoo!, Fox News, NBC, CBS and Reuters, among other places – and deserved the attention it got. It demonstrated the efficacy of a small-molecule drug that can disable the nasty intestinal pathogen C. difficile without killing it – and, importantly, without decimating the “good” bacteria that populate our gut by the trillions.

That’s a big deal. If you want to see a lot of ugly weeds pop up, there’s no better way to go about it than letting your lawn go to hell.

C. difficile – responsible for more than 250,000 hospitalizations and 15,000 deaths per year in the United States and a $4 billion annual health-care tab in the U.S. alone – is typically treated by antibiotics, which have the unfortunate side effect of wiping out much of our intestinal microbe population. That loss of carpeting, ironically, lays the groundwork for a dangerous and all-too-common comeback of C. difficile infection.

A question worth asking about this study, conducted by what-makes-pathogens-tick expert Matt Bogyo, PhD, and a team of Stanford associates: Why should we think that what works in mice is going to work in people?

The only sure answer isn’t a torrent of language but a clinical trial of the drug, ebselen, in real, live people with C. difficile infections or at risk for them. (Bogyo has already started accumulating funding to initiate a trial along those lines.)

But there’s also reassurance to be drawn from the fact that ebselen isn’t an entirely exotic newcomer to the world of medical research. As I noted in my release:

Bogyo and his associates focused on … ebselen because, in addition to having a strong inhibitory effect, ebselen also has been tested in clinical trials for chemotherapy-related hearing loss and for stroke. Preclinical testing provided evidence that ebselen is safe and tolerable, and it has shown no significant adverse effects in ensuing clinical trials.

Continue Reading »

Stanford Medicine Resources: