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Mitochondria May Be the Missing Link in Understanding Stress Response

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Scientists have long looked to anatomy and neurology to understand and ameliorate stress responses in humans. Now, a pioneering study, recently published in Proceedings of the National Academy of Sciences, suggests that mitochondria—the tiny energy centers inside our cells, which convert food into ATP, the crucial molecule that stores the energy humans need to do pretty much everything—may play a more significant role in the stress responses of mammals than previously understood, and even in understanding psychiatric and neurologic diseases.

The study was headed by Douglas Wallace, director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia and a leading researcher in the genetics of mitochondria for 40 years. He is among the first to prove that defects in energy metabolism can cause disease.

Wallace and his team found that even slight changes in mitochondrial genes had a large effect on how mammals respond to stress in their environments. Wallace’s team bred mice with different genetic mutations to their mitochondrial DNA (mtDNA). “With these mutants in hand we could expose them to a mild environmental stress, such as 30 minutes in confinement,” Wallace tells mental_floss.

They then measured the neuroendocrine, inflammatory, metabolic, and gene transcription systems, which are the systems most effected by stress. “We found the changes in mitochondrian response had a markedly different response from normal mitochondria,” he says.

They mixed two normal, but different, mtDNAs in mice to prevent maternal inheritance of the mtDNA. This resulted in “hyperexcitable mice with severe learning and memory defects,” according to a press statement

Because humans and mice share a similar degree of variation in their mtDNA, Wallace suspects that the mouse results “might have a comparable effect” in human DNA.

While research is conflicting about how much stress increases risk of disease, psychiatrists have a term for the common physiological decline that happens when people are under continuous stress: allostatic load. “What is the connection between stress and declining bodily functions?" Wallace says. "The intermediate is the mitochondria.”

Wallace believes that the bioenergetics of mitochondrial function is the overlooked piece in understanding everything from psychiatric and neurologic diseases to aging, partly a result of the current “anatomical paradigm” in the scientific community, which focuses mostly on nuclear DNA, anatomy, and neurology. “What’s missed is the realization that mitochondria is much more important than just making ATP," he says. "It has a central regulatory role, because nothing in your body can go forward without energy. Mitochondria is the missing link between human behavior and human physiology.”

For example, he points out that neurons are “extraordinarily energetically demanding,” and that certain diseases could actually be a mitochondria disease. “All the tissues affected in common diseases also have the highest mitochondria energy demand, and it’s hard to see any anatomical difference between a normal and affected patient, because you can’t see energy,” he says. Wallace makes the case that aging could be chalked up to being “fundamentally the decline of the mitochondria’s ability to produce the energy to power the cells to keep us at optimum health.”

Wallace’s colleague Peter Burke has developed a new technique that makes it possible to analyze the energy of a single mitochondrion. “So now we can understand how subtle changes can have big effects on energy production and physiology,” Wallace says.

Wallace believes that further study could reveal ways to observe and even stop changes in the mitochondria before the obvious symptoms of disease have even begun—and that further research will show that changes in these “energetic genes” will be important in understanding diseases. But he’s concerned that the current scientific paradigm will be slow to embrace it, and thus fund it. He hopes it gets much more research, because he believes it could lead to a whole new generation of neuropsychiatric therapeutics: “This study will lead to a revolution in neuroscience," he says. "Whether the neuroscientists will accept it is another question."

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New Technique Can Spot a Heart Attack in the Making Long Before It Happens
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Cardiology experts have developed a noninvasive way of measuring the fat around a person's blood vessels, which could help determine their risk for dangerous cardiac events. The researchers described their technique today in the journal Science Translational Medicine.

Heart attacks are incredibly common, affecting around 750,000 Americans every year. Heart disease is the number one cause of mortality in the U.S., responsible for one out of every four deaths. There are many reasons for this. Among them is the difficulty of identifying at-risk patients before it's too late.

Cardiologists' current method of choice uses a metric called coronary calcification score (CCS) to measure the hardening of a patient's arteries. CCS is a reliable way to predict future heart problems, paper co-author Charalambos Antoniades said in a statement, but it has its limitations.

"When coronary calcification is detected," he said, "it is already too late, as the calcification is not reversible."

And so, rather than measuring calcification, many researchers have begun looking for a way to measure blood vessel inflammation, which is usually a pretty good—and early—predictor of heart disease.

The inflammation itself can be hard to see without entering a patient's body. But recent studies have shown that it rarely travels alone: Blood vessels that are inflamed are also often wrapped in larger fat cells than healthy vessels. 

With this link in mind, Antoniades and his colleagues decided to try measuring the fat cells instead. They reviewed computed tomography scans from 453 patients about to undergo heart surgery, and used these data to create what they call the fat attenuation index (FAI). The higher a patient's FAI, the more inflammation they had, and the more advanced or severe their heart disease. 

The researchers then compared the FAI of 40 additional patients with the results of invasive scans of the inflammation in their hearts. Sure enough, each patient's FAI matched the swelling onscreen.

There are many benefits to using FAI, the authors say. Not only is it noninvasive and accurate, but it can be used in tandem with CCS and other methods for an even more complete picture. The next step will be validating the test's safety and accuracy in clinical trials.

FAI scans "could help direct these new types of treatments to the appropriate subgroups of patients at greatest risk," Antoniades says, "reducing costs and targeting more powerful drugs to the patients who will benefit most."

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Don't Panic About the Plague
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If reports of measles and whooping cough making a reappearance aren't alarming enough, the news that three people in New Mexico have contracted plague this year might have you on edge. But these aren't the only recent cases of plague in the state—the disease appeared in both 2016 and 2015, causing one death—or even in the U.S.

In 2015, a child contracted the plague in Yosemite National Park, and so did a tourist from Georgia; park officials closed a campground where they discovered two dead squirrels infected with the disease. That same year in Colorado, a pitbull infected four humans with pneumonic plague before being put down, and two other Colorado residents died from plague, including a 16-year-old boy.

It all seems very scary, but don't go sealing yourself in protective gear yet. There's less to fear about plague than you may think. While the public is prone to panic that a medieval illness, which wiped out a quarter of Europe in the Middle Ages during the Black Death, has suddenly arisen from obscurity, the truth is: Plague never left.

Though we haven't seen a widespread epidemic of plague since the early 20th century, thanks to advances in sanitation and medicine, and there hasn't been a human-to-human case of transmission in America since 1924, an average of seven new cases are reported every year in the U.S. From 2010 to 2015, there were 3248 cases, including 584 deaths, reported worldwide, according to the World Health Organization.

Yersinia pestis, the flea-borne bacteria that's most often responsible for plague, infects rodents; humans are “incidental hosts,” who can acquire the infection if bitten by an infected flea or rodent. Compared to the 14th century, when the Black Death spread wildly, or the late 19th century, when 10 million people died of the disease after it traveled from Hong Kong to port cities worldwide, most people today live in more sanitary conditions and have less frequent contact with the rodents most likely to carry the infected fleas. Today, 95 percent of plague cases originate in parts of sub-Saharan Africa and Madagascar.

The most common of the three strains of plague is the notorious bubonic plague, which causes painful swollen lymph nodes (also called buboes) and was responsible for Europe's Black Death—so named because internal hemorrhages caused by the infection make the skin appear black. But the pitbull that infected four Colorado residents carried the rarer respiratory strain of pneumonic plague, which is contagious when the infected person coughs up infected particulates. There is also septicemic plague, the most lethal form, which infects the blood, and most often occurs when plague virus has gone undetected and is allowed to spread.

In the U.S., you're generally only at risk of contracting plague in late spring to early fall if you've been in a rural or semi-rural area of the West, especially New Mexico, Arizona, or Colorado, and have had contact with fleas or rodents including ground squirrels, chipmunks, prairie dogs, or rats. And even then, the risk is low.

Only the pneumatic version of plague is contagious from human to human (though untreated bubonic plague can become pneumonic), but you have to be coughed upon, or receive fluid from an infected person upon an open wound or directly into your mouth or nose.

Plague symptoms mimic any flu—fever, chills, headache, difficulty breathing or coughing—but people have been known to cough up blood with the pneumonic variety. If you've been in a rural area, or camping, and come down with these symptoms two to three days later, it's best to go to a hospital.

Now for some good news: While untreated plague is quite deadly, people with plague who are treated with antibiotics within 24 hours of infection have strong recovery rates.

So while it's good to be aware and take precautions, the chances of another plague pandemic remain slim.

This story was originally published in 2015 and has been updated. 


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