Merck Manuals Health Guides Go Digital, and Free

Reuters Health Information

Merck Manuals Health Guides Go Digital, and Free, in Global Push

By Kylie Gumpert

June 17, 2015

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(Reuters) - Merck Manuals, the widely used health guides provided by drugmaker Merck & Co, are moving to a digital-only format in 10 different languages as part of an effort to educate the global community on medical issues.

The new version of Merck Manuals debuted in the U.S. in April, offering free online access to both professional and consumer audiences. The professional manuals have been distributed in print since 1899 and most recently carried a price tag of nearly $80.

New websites will launch in other English-speaking countries in July, while sites translated into nine other languages are expected in the next 12 to 18 months. An English-language mobile app is set to launch by at least early 2016, with translated apps to follow, the company said.

Outside of the U.S. and Canada, the sites and apps will be known as MSD Manuals.
By offering both professional and consumer-oriented content free of charge, users can find what they are looking for in as much detail as they need, said Merck Manuals editor-in-chief Robert Porter. The information is compiled by hundreds of medical experts across the world.
"We would like to show information as a universal right, not a commodity," Porter said in an interview.

Over 100 videos for performing medical procedures will be included in the professional mobile app, "so if you're up the Amazon and haven't delivered a baby in a while, we'll have that available" for healthcare providers, Porter said.

The switch to digital is also an effort to help readers quickly access authoritative health content among the hundreds of results that can pop up in an Internet search.

In a survey of over 2,000 people conducted for Merck Manuals by Harris Poll, 28% of Americans say that overwhelming amounts of information online is their biggest barrier to increasing medical knowledge, while 79% believe that having access to the same information as their doctor would improve how they understand their health.

The new U.S. websites have had about 4 million unique visitors since their April launch, and Merck Manuals will continue to invest millions of dollars each year to maintain the digital publication.

When Gut Bacteria Changes Brain Function

When Gut Bacteria Changes Brain Function

Some researchers believe that the microbiome may play a role in regulating how people think and feel.

Craig Ruttle / AP

• David Kohn
• Jun 24, 2015

By now, the idea that gut bacteria affects a person’s health is not revolutionary. Many people know that these microbes influence digestion, allergies, and metabolism. 

The trend has become almost commonplace: New books appear regularly detailing precisely which diet will lead to optimum bacterial health.

But these microbes’ reach may extend much further, into the human brains. A growing group of researchers around the world are investigating how the microbiome, as this bacterial ecosystem is known, regulates how people think and feel. Scientists have found evidence that this assemblage—about a thousand different species of bacteria, trillions of cells that together weigh between one and three pounds—could play a crucial role in autism, anxiety, depression, and other disorders.

“There’s been an explosion of interest in the connections between the microbiome and the brain,” says Emeran Mayer, a gastroenterologist at the University of California, Los Angeles, who has been studying the topic for the past five years.

Some of the most intriguing work has been done on autism.

For decades, doctors, parents, and researchers have noted that about three-quarters of people with autism also have some gastrointestinal abnormality, like digestive issues, food allergies, or gluten sensitivity. 

This recognition led scientists to examine potential connections between gut microbes and autism; several recent studies have found that autistic people’s microbiome differs significantly from control groups. 

The California Institute of Technology microbiologist Sarkis Mazmanian has focused on a common species called Bacteroides fragilis, which is seen in smaller quantities in some children with autism.

In a paper published two years ago in the journal Cell, Mazmanian and several colleagues fed B. fragilis from humans to mice with symptoms similar to autism. The treatment altered the makeup of the animals’ microbiome, and more importantly, improved their behavior: They became less anxious, communicated more with other mice, and showed less repetitive behavior.

Exactly how the microbes interact with the illness—whether as a trigger or as a shield—remains mostly a mystery. But Mazmanian and his colleagues have identified one possible link: a chemical called 4-ethylphenylsulphate, or 4EPS, which seems to be produced by gut bacteria. They’ve found that mice with symptoms of autism have blood levels of 4EPS more than 40 times higher than other mice. The link between 4EPS levels and the brain isn’t clear, but when the animals were injected with the compound, they developed autism-like symptoms.

“We may be able to reverse these ailments. If you turn off the faucet that produces this compound, then the symptoms disappear.”

 

Mazmanian, who in 2012 was awarded a MacArthur grant for his microbiome work, sees this as a “potential breakthrough” in understanding how microbes contribute to autism and other neurodevelopmental disorders. He says the results so far suggest that adjusting gut bacteria could be a viable treatment for the disease, at least in some patients. “We may be able to reverse these ailments,” he says. “If you turn off the faucet that produces this compound, then the symptoms disappear. That’s what we see in the mouse model.”

Scientists have also gathered evidence that gut bacteria can influence anxiety and depression. Stephen Collins, a gastroenterology researcher at McMaster University in Hamilton, Ontario, has found that strains of two bacteria, lactobacillus and bifidobacterium, reduce anxiety-like behavior in mice (scientists don’t call it “anxiety” because you can’t ask a mouse how it’s feeling). 

Humans also carry strains of these bacteria in their guts. In one study, he and his colleague collected gut bacteria from a strain of mice prone to anxious behavior, and then transplanted these microbes into another strain inclined to be calm. The result: The tranquil animals appeared to become anxious.

Overall, both of these microbes seem to be major players in the gut-brain axis. John Cryan, a neuroscientist at the University College of Cork in Ireland, has examined the effects of both of them on depression in animals. In a 2010 paper published in Neuroscience, he gave mice either bifidobacterium or the antidepressant Lexapro; he then subjected them to a series of stressful situations, including a test which measured how long they continued to swim in a tank of water with no way out. (They were pulled out after a short period of time, before they drowned.) The microbe and the drug were both effective at increasing the animals’ perseverance, and reducing levels of hormones linked to stress. Another experiment, this time using lactobacillus, had similar results. Cryan is launching a study with humans (using measurements other than the forced swim test to gauge subjects’ response).

Related Story

In Autism, the Importance of the Gut

So far, most microbiome-based brain research has been in mice. But there have already been a few studies involving humans. Last year, for example, Collins transferred gut bacteria from anxious humans into “germ-free” mice—animals that had been raised (very carefully) so their guts contained no bacteria at all. After the transplant, these animals also behaved more anxiously.

Other research has examined entire humans, not just their bugs. A paper published in the May 2015 issue of Psychopharmacology by the Oxford University neurobiologist Phil Burnet looked at whether a prebiotic—a group of carbohydrates that provide sustenance for gut bacteria—affected stress levels among a group of 45 healthy volunteers. Some subjects were fed 5.5 grams of a powdered carbohydrate known as galactooligosaccharide, or GOS, while others were given a placebo. Previous studies in mice by the same scientists had shown that this carb fostered growth of Lactobacillus and Bifidobacteria; the mice with more of these microbes also had increased levels of several neurotransmitters that affect anxiety, including one called brain-derived neurotrophic factor.

In this experiment, subjects who ingested GOS showed lower levels of a key stress hormone, cortisol, and in a test involving a series of words flashed quickly on a screen, the GOS group also focused more on positive information and less on negative. This test is often used to measure levels of anxiety and depression, since in these conditions anxious and depressed patients often focus inordinately on the threatening or negative stimuli. Burnet and his colleagues note that the results are similar to those seen when subjects take anti-depressants or anti-anxiety medications.

Perhaps the most well-known human study was done by Mayer, the UCLA researcher. He recruited 25 subjects, all healthy women; for four weeks, 12 of them ate a cup of commercially available yogurt twice a day, while the rest didn’t. Yogurt is a probiotic, meaning it contains live bacteria, in this case strains of four species, bifidobacterium, streptococcus, lactococcus, and lactobacillus. Before and after the study, subjects were given brain scans to gauge their response to a series of images of facial expressions—happiness, sadness, anger, and so on.

“This was not what we expected, that eating yogurt twice a day for a few weeks would do something to your brain.”

 

To Mayer’s surprise, the results, which were published in 2013 in the journal Gastroenterology, showed significant differences between the two groups; the yogurt eaters reacted more calmly to the images than the control group. “The contrast was clear,” says Mayer. “This was not what we expected, that eating a yogurt twice a day for a few weeks would do something to your brain.” He thinks the bacteria in the yogurt changed the makeup of the subjects’ gut microbes, and that this led to the production of compounds that modified brain chemistry.

It’s not yet clear how the microbiome alters the brain. Most researchers agree that microbes probably influence the brain via multiple mechanisms.

Scientists have found that gut bacteria produce neurotransmitters such as serotonin, dopamine and GABA, all of which play a key role in mood (many antidepressants increase levels of these same compounds). Certain organisms also affect how people metabolize these compounds, effectively regulating the amount that circulates in the blood and brain. Gut bacteria may also generate other neuroactive chemicals, including one called butyrate, that have been linked to reduced anxiety and depression. Cryan and others have also shown that some microbes can activate the vagus nerve, the main line of communication between the gut and the brain.

In addition, the microbiome is intertwined with the immune system, which itself influences mood and behavior.

This interconnection of bugs and brain seems credible, too, from an evolutionary perspective. After all, bacteria have lived inside humans for millions of years. Cryan suggests that over time, at least a few microbes have developed ways to shape their hosts’ behavior for their own ends. Modifying mood is a plausible microbial survival strategy, he argues that “happy people tend to be more social. And the more social we are, the more chances the microbes have to exchange and spread.”

As scientists learn more about how the gut-brain microbial network operates, Cryan thinks it could be hacked to treat psychiatric disorders. “These bacteria could eventually be used the way we now use Prozac or Valium,” he says. And because these microbes have eons of experience modifying our brains, they are likely to be more precise and subtle than current pharmacological approaches, which could mean fewer side effects. “I think these microbes will have a real effect on how we treat these disorders,” Cryan says. “This is a whole new way to modulate brain function.”

About the Author

• David Kohn is a science writer based in Baltimore.

“Young Blood” Anti-Aging Mechanism Called into Question

A protein in the blood of young mice that seemed to rejuvenate older animals may do the opposite

By Sara Reardon and Nature magazine | May 22, 2015

For decades, scientists have sought to understand the anti-ageing effects of parabiosis, a technique in which researchers sew a young mouse and an old mouse together so that they share a circulatory system.

eigenes Bildmaterial/Wikimedia Commons

The hunt for the fountain of youth is back to square one—at least for those seeking it in blood. New findings cast doubt on research that attempted to explain why the muscles of an old animal can be rejuvenated with a dose of blood from a young animal.

For decades, scientists have sought to understand the anti-ageing effects of parabiosis, a technique in which researchers sew a young mouse and an old mouse together so that they share a circulatory system. 
The young mouse’s blood seems to rejuvenate the old mouse, regenerating its wasting muscles and restoring its cognitive abilities.
 On the basis of those results, at least one company is attempting to replicate the effect in humans using blood plasma from healthy young people to treat patients with Alzheimer’s disease. 

In 2013, a team led by Amy Wagers, a stem-cell researcher at Harvard University in Cambridge, Massachusetts, seemed to offer an explanation for this blood-doping effect. 
The scientists found that levels of a protein called GDF11 decreased in the blood of mice as they grew older. When the researchers injected the protein into the heart muscle of old mice, it became ‘younger’—thinner and better able to pump blood. 

Two subsequent studies by Wagers and her colleagues found that GDF11 boosted the growth of new blood vessels and neurons in the brain and spurred stem cells to regenerate skeletal muscle at the sites of injuries.

Rejuvenation riddle

Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. 

But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle—the opposite effect to that seen by Wagers and her team.

For GDF11, “You could imagine that when it came out last year that it helped muscle, it was quite a surprise,” says David Glass, executive director of the muscle diseases group at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts. “Did we miss something?”

Glass and his colleagues set out to determine why GDF11 had this apparent effect. 
 First, they tested the antibodies and other reagents that Wagers’ group had used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11.

When the Novartis team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age—just as levels of myostatin do. 

That contradicts what Wagers’ group had found.

Glass’s team next used a combination of chemicals to injure a mouse’s skeletal muscles, and then regularly injected the animal with three times as much GDF11 as Wagers and her team had used. 
Rather than regenerating the muscle, Glass found, GDF11 seemed to make the damage worse by inhibiting the muscles’ ability to repair themselves. 

He and his colleagues report their results on 19 May in Cell Metabolism.

Glass says that although his group’s results do not explain why parabiosis works, they could help to explain the mechanism behind bimagrumab, an experimental Novartis treatment for muscle weakness and wasting. 

The drug, which is currently in clinical trials, blocks myostatin—and perhaps GDF11 as well.

Meticulous methods
 
Thomas Rando, a stem-cell biologist at Stanford University in California, praises the attention to detail in the methods used by Glass and his team. “They did a very thorough and rigorous job,” he says. 

He does not see the findings as a setback for the field, because they confirmed what researchers had expected before the studies by Wagers and her colleagues. “If this paper was published first, it would not have been surprising,” he says.

Wagers, however, stands by her findings. She says that although at first glance the Novartis group’s data seem to conflict with her team’s results, there could be multiple forms of GDF11 and that perhaps only one decreases with age.

 Both papers suggest that having either too much or too little GDF11 could be harmful, she says. 
She adds that the Novartis group injured the muscle more extensively and then treated it with more GDF11 than her group had done, so the results may not be directly comparable.

“We look forward to addressing the differences in the studies with additional data very soon,” Wagers says.

Rando expects that researchers will now investigate the finding that GDF11 affects the growth of neurons and blood vessels in the brain. “I’m not sure which result is going to stand the test of time,” he says.


See subsequent posting on: Peptides Follistatin  a Myostatin   precursor 

National Institute of Health follistatin 

They were asking the wrong question , I believe .

Esther Gokhale's Five Tips For Better Posture And Less Back Pain

Esther Gokhale's Five Tips For Better Posture And Less Back Pain

From NPR June 14/2015
http://www.npr.org/sections/goatsandsoda/2015/06/08/412314701/lost-posture-why-indigenous-cultures-dont-have-back-pain?utm_source=npr_newsletter&utm_medium=email&utm_content=20150614&utm_campaign=mostemailed&utm_term=nprnews

 

Try these exercises while you're working at your desk, sitting at the dinner table or walking around, Esther Gokhale recommends.

1. Do a shoulder roll: Americans tend to scrunch their shoulders forward, so our arms are in front of our bodies. That's not how people in indigenous cultures carry their arms, Gokhale says. To fix that, gently pull your shoulders up, push them back and then let them drop — like a shoulder roll. Now your arms should dangle by your side, with your thumbs pointing out. "This is the way all your ancestors parked their shoulders," she says. "This is the natural architecture for our species."

2. Lengthen your spine: Adding extra length to your spine is easy, Gokhale says. Being careful not to arch your back, take a deep breath in and grow tall. Then maintain that height as you exhale. Repeat: Breathe in, grow even taller and maintain that new height as you exhale. "It takes some effort, but it really strengthens your abdominal muscles," Gokhale says.

3. Squeeze, squeeze your glute muscles when you walk: In many indigenous cultures, people squeeze their gluteus medius muscles every time they take a step. That's one reason they have such shapely buttocks muscles that support their lower backs. Gokhale says you can start developing the same type of derrière by tightening the buttocks muscles when you take each step. "The gluteus medius is the one you're after here. It's the one high up on your bum," Gokhale says. "It's the muscle that keeps you perky, at any age."

4. Don't put your chin up: Instead, add length to your neck by taking a lightweight object, like a bean bag or folded washcloth, and balance it on the top of your crown. Try to push your head against the object. "This will lengthen the back of your neck and allow your chin to angle down — not in an exaggerated way, but in a relaxed manner," Gokhale says.

5. Don't sit up straight! "That's just arching your back and getting you into all sorts of trouble," Gokhale says. Instead do a shoulder roll to open up the chest and take a deep breath to stretch and lengthen the spine.

[Added June 10] 
So Gokhale studied findings from anthropologists, such as Noelle Perez-Christiaens, who analyzed postures of indigenous populations. And she studied physiotherapy methods, such as the Alexander Technique and the Feldenkrais Method.

And the original post  ...

Primal posture: 

 Ubong tribesmen in Borneo (right) display the perfect J-shaped spines. 
A woman in Burkina Faso (left) holds her baby so that his spine stays straight. The center image shows the S-shaped spine drawn in a modern anatomy book (Fig. I) and the J-shaped spine (Fig. II) drawn in the 1897 anatomy book Traite d'Anatomie Humaine.

Courtesy of Esther Gokhale and Ian Mackenzie/Nomads of the Dawn 

 

 

 

Editor's note, June 10: We have added an acknowledgement of several sources that Esther Gokhale used while developing her theories on back pain. These include physiotherapy methods, such as the Alexander Technique and the Feldenkrais Method, and the work of anthropologist Noelle Perez-Christiaens.
Back pain is a tricky beast. Most Americans will at some point have a problem with their backs. And for an unlucky third, treatments won't work, and the problem will become chronic.

i

Many ancient statues, such as this one from Greece, display a J-shaped spine. The statue's back is nearly flat until the bottom, where it curves so the buttocks are behind the spine.

Courtesy of Esther Gokhale/Gerard Mackworth-Young 

 

Believe it or not, there are a few cultures in the world where back pain hardly exists. One indigenous tribe in central India reported essentially none. And the discs in their backs showed little signs of degeneration as people aged.

An acupuncturist in Palo Alto, Calif., thinks she has figured out why. She has traveled around the world studying cultures with low rates of back pain — how they stand, sit and walk. Now she's sharing their secrets with back pain sufferers across the U.S.

About two decades ago, Esther Gokhale started to struggle with her own back after she had her first child. "I had excruciating pain. I couldn't sleep at night," she says. "I was walking around the block every two hours. I was just crippled."

Gokhale had a herniated disc. Eventually she had surgery to fix it. But a year later, it happened again. "They wanted to do another back surgery. You don't want to make a habit out of back surgery," she says.

This time around, Gokhale wanted to find a permanent fix for her back. And she wasn't convinced Western medicine could do that. So Gokhale started to think outside the box.

She had an idea: "Go to populations where they don't have these huge problems and see what they're doing."

Then over the next decade, Gokhale went to cultures around the world that live far away from modern life. She went to the mountains in Ecuador, tiny fishing towns in Portugal and remote villages of West Africa.

"I went to villages where every kid under age 4 was crying because they were frightened to see somebody with white skin — they'd never seen a white person before," she says.

Gokhale took photos and videos of people who walked with water buckets on their heads, collected firewood or sat on the ground weaving, for hours.

"I have a picture in my book of these two women who spend seven to nine hours everyday, bent over, gathering water chestnuts," Gokhale says. "They're quite old. But the truth is they don't have a back pain."

She tried to figure out what all these different people had in common. The first thing that popped out was the shape of their spines. "They have this regal posture, and it's very compelling."

And it's quite different than American spines.

If you look at an American's spine from the side, or profile, it's shaped like the letter S. It curves at the top and then back again at the bottom.

But Gokhale didn't see those two big curves in people who don't have back pain. "That S shape is actually not natural," she says. "It's a J-shaped spine that you want."

In fact, if you look at drawings from Leonardo da Vinci — or a Gray's Anatomy book from 1901 — the spine isn't shaped like a sharp, curvy S. It's much flatter, all the way down the back. Then at the bottom, it curves to stick the buttocks out. So the spine looks more like the letter J.

"The J-shaped spine is what you see in Greek statues. It's what you see in young children. It's good design," Gokhale says.

So Gokhale worked to get her spine into the J shape. And gradually her back pain went away.

i

Healthy spines in the Western world: The J-shaped spine is often seen in photographs from the late 19th and early 20th centuries.

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MT2, Melanotan II (Afamelanotide)

Trade Names:	MT2, Melanotan
Chemical Names:	Afamelanotide
Routes:	Subcutaneous Injection

Melanotan II (MT2) was first synthesized at the University of Arizona in the 1980’s. Melanotan II is a peptide originally developed as a skin tanning agent, but subsequently investigated as a potential treatment for sexual dysfunction. 

To date there is no medically approved drug that contains the Melanotan II peptide, instead all available products are from commercial labs that are allowed to produce and distribute peptides as research products.

Even though the only Melanotan II peptides  available to the general public are unlicensed and unregulated drugs, thousands of people use it daily. A number of health and drug control agencies around the world issued warnings to the potential of health risks associated with unregulated medications.
Regardless of all the warnings the popularity of MT2 seems to be on the increase. One obvious reason for the popularity of MT2 is that it actually works and results are noticed fairly quickly. 
Another cause for the thriving trade of MT2 is that it’s not illegal to buy, import or use in most countries.

Since there’s no brand name  product available no official guideline has yet been established on the correct usage of this peptide. However through trial and error and experimentation the MT2 community developed a variety of protocols. The most popular and effective protocols are those that make use of a “loading” phase followed by a “maintenance” phase.

The loading phase is normally limited to about 3 to 5 days and in this time dosages of 0.5 to 1mg are injected subcutaneously nightly. Near the end of this phase one or two tanning sessions are taken so that the tanning process can be kick started. It’s very important to expose all parts of the body to equal amounts of sunlight or ultraviolet radiation. 

This is to allow for a uniform tan and to limit chances of dark or lighter spots. Results are rapid and care should be taken not to overdo usage  as that will result in an abnormally dark appearance.

The purpose of the maintenance phase is to prolong the period for which the tanned skin is required. Usually a dose of 0.5mg is taken 1-2 times per week. This might be altered depending on how the person reacts. If the tan is getting lighter the dosage might be increased or the period between injections shortened. If the tan is getting to dark the dosage can be lowered or the injection frequency decreased.


 
A number of initial side-effects can be expected when first using MT2, this is due to the structure of the molecule not entirely mimicking that of natural human a-MSH (alpha-melanocyte stimulating hormone) hormone.

 The body’s immune system will recognize it as being foreign and thus an allergic response may occur.

Facial flushing similar to initial Vitamin B3 Niacin non flushing formula. 
The melanotan flushing effects are less pronounced and usually transient within 30-45 minutes. Again prophylactic use of a small dose of benedryll  prior to using the peptide will eliminate or lower this initial side possible side effect.
Allerdryl/benedryl  can be  used as a preventive for those people who are especially sensitive to taking MT2.
Just as well, much lower concentrations of the injected drug would also lessen the side-effects.

 Some people find that taking the first few shots at night before bed lowers or reduces the initial flushing side effects.
Any transient nausea can be eliminated by ingesting a small amount of ginger, prior to using the peptide.

 The lyophilized powder may be stored at 4 C for several months . When you reconstitute to nominal volume and store at -20 C, the reconstituted product should be stable for 24 months. 
Best long-term storage solution is to store in lyophilized powder form at -20C. The reconstituted solution is best injected with an insulin syringe.

Use a 1 Ml insulin with a 31 gauge needle. 
Start with 0.5 Iu to 1.0 Iu on the scale of 10.

Reconstituting with 2.5 ml of sterile Na solution will allow for proper dosing.
5-10Iu on a regular 100Iu insulin syringe usually works best.

As with any herbal, peptide or medication always go slow to gauge individual sensitivity.

If you feel unwell, always seek medical attention, call the Telehealth 24/7 

1-866-797-0000     TTY : 1-866-797-0007

Gut Feelings–the "Second Brain" in Our Gastrointestinal Systems [Excerpt]

There is a superhighway between the brain and GI system that holds great sway over humans

By Justin Sonnenburg and Erica Sonnenburg | May 1, 2015

Penguin Press

More on this Topic

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  Eat, Move, Think: Living Healthy

From The Good Gut: Taking Control of Your Weight, Your Mood and Your Long-Term Health, by Justin Sonnenburg and Erica Sonnenburg, PhDs. Reprinted by arrangement with Penguin Press, a member of Penguin Group (USA), LLC, a Penguin Random House Company. Copyright © Justin Sonnenburg and Erica Sonnenburg, 2015.

A primal connection exists between our brain and our gut. 

 

We often talk about a “gut feeling” when we meet someone for the first time. 
We’re told to “trust our gut instinct” when making a difficult decision or that it’s “gut check time” when faced with a situation that tests our nerve and determination.
This mind-gut connection is not just metaphorical.

 Our brain and gut are connected by an extensive network of neurons and a highway of chemicals and hormones that constantly provide feedback about how hungry we are, whether or not we’re experiencing stress, or if we’ve ingested a disease-causing microbe. 

This information superhighway is called the brain-gut axis and it provides constant updates on the state of affairs at your two ends. That sinking feeling in the pit of your stomach after looking at your postholiday credit card bill is a vivid example of the brain-gut connection at work. 
You’re stressed and your gut knows it—immediately.

The enteric nervous system is often referred to as our body’s second brain. 
There are hundreds of million of neurons connecting the brain to the enteric nervous system, the part of the nervous system that is tasked with controlling the gastrointestinal system. 

This vast web of connections monitors the entire digestive tract from the esophagus to the anus. The enteric nervous system is so extensive that it can operate as an independent entity without input from our central nervous system, although they are in regular communication. 

While our “second” brain cannot compose a symphony or paint a masterpiece the way the brain in our skull can, it does perform an important role in managing the workings of our inner tube. The network of neurons in the gut is as plentiful and complex as the network of neurons in our spinal cord, which may seem overly complex just to keep track of digestion. Why is our gut the only organ in our body that needs its own “brain”? Is it just to manage the process of digestion? Or could it be that one job of our second brain is to listen in on the trillions of microbes residing in the gut?

Operations of the enteric nervous system are overseen by the brain and central nervous system. The central nervous system is in communication with the gut via the sympathetic and parasympathetic branches of the autonomic nervous system, the involuntary arm of the nervous system that controls heart rate, breathing, and digestion. The autonomic nervous system is tasked with the job of regulating the speed at which food transits through the gut, the secretion of acid in our stomach, and the production of mucus on the intestinal lining.

 The hypothalamic-pituitary-adrenal axis, or HPA axis, is another mechanism by which the brain can communicate with the gut to help control digestion through the action of hormones.

This circuitry of neurons, hormones, and chemical neurotransmitters not only sends messages to the brain about the status of our gut, it allows for the brain to directly impact the gut environment. The rate at which food is being moved and how much mucus is lining the gut—both of which can be controlled by the central nervous system—have a direct impact on the environmental conditions the microbiota experiences.

Like any ecosystem inhabited by competing species, the environment within the gut dictates which inhabitants thrive. Just as creatures adapted to a moist rain forest would struggle in the desert, microbes relying on the mucus layer will struggle in a gut where mucus is exceedingly sparse and thin. Bulk up the mucus, and the mucus-adapted microbes can stage a comeback. 
The nervous system, through its ability to affect gut transit time and mucus secretion, can help dictate which microbes inhabit the gut. In this case, even if the decisions are not conscious, it’s mind over microbes.

What about the microbial side? When the microbiota adjusts to a change in diet or to a stress-induced decrease in gut transit time, is the brain made aware of this modification? 

Does the brain-gut axis run in one direction only, with all signals going from brain to gut, or are some signals going the other way? 
Is that voice in your head that is asking for a snack coming from your mind or is it emanating from the insatiable masses in your bowels?

Recent evidence indicates that not only is our brain “aware” of our gut microbes, but these bacteria can influence our perception of the world and alter our behavior. It is becoming clear that the influence of our microbiota reaches far beyond the gut to affect an aspect of our biology few would have predicted—our mind.

For example, the gut microbiota influences the body’s level of the potent neurotransmitter serotonin, which regulates feelings of happiness. Some of the most prescribed drugs in the U.S. for treating anxiety and depression, like Prozac, Zoloft, and Paxil, work by modulating levels of serotonin. And serotonin is likely just one of a numerous biochemical messengers dictating our mood and behavior that the microbiota impacts.

Delta sleep-inducing peptide

Home > July 2001 - Volume 18 - Issue 7 > Delta sleep-inducing peptide

European Journal of Anaesthesiology:

July 2001 - Volume 18 - Issue 7 - pp 419-422

Delta sleep-inducing peptide

Pollard, B. J.¹; Pomfrett, C. J. D.²

Free Access

Article Outline

Author Information

¹Professor of Anaesthesia, University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

²Lecturer in the Neurophysiology of Anaesthesia, University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

Delta sleep-inducing peptide (DSIP) is a naturally occurring substance, which was originally isolated from rabbit brain in 1977 [¹]. This curious substance is a nonapeptide that is normally synthesized in the hypothalamus and targets multiple sites including some within the brainstem [²]. 

As its name suggests DSIP promotes sleep and this has been demonstrated in rabbits, mice, rats, cats and human beings [^3–5]. In fact DSIP promotes a particular type of sleep which is characterized by an increase in the delta rhythm of the EEG.

DSIP is normally present in minute amounts in the blood. Brain and plasma DSIP concentrations exhibit a marked diurnal variation [⁶] and there has been shown to be a correlation between DSIP plasma concentrations and circadian rhythm in human beings. Concentrations are low in the mornings and higher in the afternoons. An elevation of endogenous DSIP concentration has been shown to be associated with suppression of both slow-wave sleep and rapid-eye-movement sleep and interestingly also with body temperature [⁷]. Plasma concentrations of DSIP are influenced by the initiation of sleep [⁸]. Patients with Cushing’s syndrome suffer from a lack of slow-wave sleep but the diurnal variation in slow-wave and rapid-eye-movement sleep in those patients appears to be similar to that in normal patients [⁹].

When compared with most other peptides, DSIP is unusual in that it can freely cross the blood–brain barrier and is readily absorbed from the gut without being denatured by enzymes [^10,11]. 

DSIP is present in relatively high concentrations in human milk (10–30 ng mL^–1). Any mother who has breast-fed her babies will attest to the ability of a feed to induce sleep. However, a feed of artificial milk may have a similar effect, and it is not known whether DSIP concentrations are related to the sleep–wake cycle in human neonates [¹²].

DSIP has been synthesized
Administration of the synthetic substance does not induce tolerance [¹³]. 

DSIP can be assayed by several techniques including radioimmunoassay (RIA), enzyme immunoassay and high-performance liquid chromatography with RIA [^14–16]. 

DSIP has a half-life in human plasma of between 7 and 8 min [²]. It is degraded in blood, the pathway involving the amino-peptidases [¹⁷]. 

A potential drug interaction might therefore be envisaged between DSIP and drugs which inhibit or are themselves metabolized by peptidases.  

Captopril is one such agent and patients currently undergoing treatment with any of the angiotensin-converting enzyme inhibitors should probably be excluded from any DSIP treatment protocol until further studies have been undertaken.

DSIP and sleep

The innate controlling mechanisms of sleep have fascinated scientists for generations and many different endogenous compounds have been proposed as controllers of sleep over the years. These include cholecystokinin, prostaglandin I2 and various unknown substances labelled ‘sleep-promoting substances’. Indeed, the majority of humoral mediators seem to have some relation to sleep by, for example, affecting circadian rhythms or arousal states. In some cases, however, it is not clear if the humoral mediator is driving the sleep pattern or responding to the sleep pattern.

Since the discovery of DSIP a number of studies have been undertaken to test the hypothesis that DSIP may be the principal endogenous sleep factor. 

It is reported to increase the ‘pressure to sleep’ in human subjects who have been injected with small doses and this, together with its ability to induce delta-wave sleep, led to its consideration as a treatment for insomnia. A number of studies have examined this use with varied success [^18–21].

DSIP has been described as a sleep-promoting substance rather than a sedative.

 There is a modulating effect on sleep and wake functions with a greater activity in circumstances where sleep is disturbed. 

There are minimal effects in healthy subjects who are not suffering from sleep disturbance [²²]. 

DSIP is not a night sedation drug which needs to be given just before retiring. 

A dose of DSIP given during the course of the day will promote improved sleep on the next night and for several nights thereafter. 

Despite these clear short-term benefits, however, doubt has been cast on whether or not DSIP treatment will prove to be of major benefit in long-term management of insomnia.

Studies have been undertaken in patients suffering from the sleep apnoea syndrome and from narcolepsy. Unfortunately, no difference in DSIP concentrations has been found between those patients and normal patients [²³]. DSIP may, paradoxically, be of use in the treatment of narcolepsy and it is possible that it exerts its effect by restoring circadian rhythms [²⁴]. When single and multiple injections of DSIP were given in a controlled double-blind study, disturbed sleep was normalized and better performance and increased alertness was seen during awake cycles together with improved stress tolerance and coping behaviour [²²].

Non-sleep effects

DSIP has been shown to have an anticonvulsant action in the rat. The threshold to NMDA- and picrotoxin-induced convulsions is increased by DSIP [^25,26]. 

This anticonvulsant effect may undergo a diurnal variation with greater antiepileptic activity seen at night [²⁷]. 
 DSIP is not unique in possessing a diurnal variation in anticonvulsant activity as melatonin, b-endorphin and dexamphetamine all reduce seizure threshold during the day and it is possible that DSIP simply represents one of the endogenous controls of brain excitability [²⁸]. 
DSIP has an antinociceptive action in mice, an effect which is blocked by naloxone [²⁹].

A neuroprotective effect has been demonstrated in rats subjected to bilateral carotid ligation [³⁰]. 
A reduced mortality was observed together with a reduction in postischaemia function. DSIP also reduced brain swelling in a model of toxic cerebral oedema in the rat [³¹].

-

DSIP attenuates emotional and psychological responses to stress and also reduces the central amine responses to stress in rats [³²]. 

The action of corticotrophin releasing factor on the pituitary gland in the rat is attenuated with a consequential inhibition of pituitary adrenocorticotrophic hormone (ACTH) secretion [³³]. 
The situation is less clear in man as although one study confirmed this finding [³⁴] another reported no inhibitory effect on the adrenocortical axis to both physiological and stressor stimuli [³⁵].

 DSIP had no effect on growth hormone or prolactin concentrations when administered to human volunteers [³⁶]. 
In one study, infusions of 3 or 4 mg (an enormous dose) had no effect on ACTH levels or on cortisol secretion [³⁵] although in another study DSIP 25 nmol kg^–1 significantly decreased ACTH concentrations [³⁶].

DSIP concentrations change during certain psychiatric disorders.

Patients suffering from schizophrenia and depression have lower plasma and cerebrospinal fluid concentrations of DSIP than comparable normal volunteers [³⁷]. 
Concentrations were also inversely correlated with sleep disturbance in those patients.

As might be expected of any substance which is naturally occurring, side-effects are uncommon. 

Normally, concentrations would be very low and therefore the injection of large, probably non-physiological doses might be expected to at least produce some unwanted effect.

No significant side-effects have so far been reported with DSIP. 

In some human studies, transient headache, nausea and vertigo have been reported. DSIP actually appears to be incredibly safe as its LD₅₀ has never been determined because it has never so far proved possible to kill an animal whatever the dose of DSIP administered.

Clinical uses

Clinical uses for DSIP already exist. 

The agent has been used for the treatment of alcohol and opioid withdrawal with some success [³⁸]. 

Clinical symptoms and signs disappear after injection of DSIP although some patients have reported occasional headaches.

DSIP possesses a number of other apparently unrelated properties. 

In hypertensive rats, 200 μg kg⁻¹ day⁻¹of DSIP for 10 days had an antihypertensive effect [³⁹]. 

DSIP has also been reported to possess antimetastatic activity [⁴⁰]. It may also reduce amphetamine-induced hyperthermia and may be beneficial in some chronic pain conditions [⁴¹].

An interesting study reported in 1986 injected DSIP and several analogues of the peptide directly into the cerebral ventricle of rats. 

DSIP did not increase sleep and this was thought to be due to its very rapid metabolism. 

However, two of the analogues did induce sleep but one produced arousal. It would appear therefore that there might be the potential for not only sleep but sleep reversal within the analogues of DSIP [⁴²].

The molecular sites for the action of anaesthetic agents are being identified. 

Volatile agents appear to act on specific sites of the GABA-A and glycine receptors, whereas ketamine and xenon act on the NMDA receptors. 

These sites are reproducible and clearly defined, but what is their natural purpose, as neither volatile anaesthetic agents nor xenon are usually found in physiological systems? It is possible, but has yet to be demonstrated, that DSIP and other neuroactive peptides selectively bind to these regions of GABA-A, glycine and/or NMDA receptors.

Is DSIP of relevance to the anaesthesiologist?

Anaesthesia is physiologically distinct from natural sleep and anaesthetic agents appear to work on receptor mechanisms normally dedicated to the control of brain metabolism. 

Conventional sleep staging does not indicate the depth of anaesthesia; rapid-eye movements (REM) and other characteristics of natural sleep are not seen during anaesthesia. It is possible, however, that anaesthesia is mimicking a natural phenomenon such as hibernation by copying the action of natural neuroactive peptides such as DSIP.

What is the significance of DSIP to anaesthesia? Could DSIP be the body’s natural anaesthetic? Is activation of the DSIP receptors related to the state of anaesthesia? These questions must remain speculative for the present.
Whether or not DSIP is the body’s natural anaesthetic, or a substance closely involved in this process, it may not prove to be possible to administer it in a way which could be regarded as anaesthesia. 
Could it therefore be used as the body’s natural sedative? No studies have been performed to investigate this possible use although it would theoretically seem to have potential.

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