CRISPR: Crispy Fries Your DNA


Story at-a-glance

  • CRISPR gene-editing technology may have significant unintended consequences to your DNA, including large deletions and complex rearrangements
  • The DNA deletions could end up activating genes that should stay “off,” such as cancer-causing genes, as well as silencing those that should be “on”
  • The deletions detected were at a scale of “thousands of bases,” which is more than previously thought and enough to affect adjacent genes
  • As a result of CRISPR-Cas9, DNA may be rearranged, previously distant DNA sequences may become attached, or unrelated sections could be incorporated into the chromosome

By Dr. Mercola

CRISPR gene-editing technology brought science fiction to life with its ability to cut and paste DNA fragments, potentially eliminating serious inherited diseases. CRISPR-Cas9, in particular, has gotten scientists excited because,1 by modifying an enzyme called Cas9, the gene-editing capabilities are significantly improved. That’s not to say they’re perfect, however, as evidenced by a recent study that showed CRISPR may have significant unintended consequences to your DNA, including large deletions and complex rearrangements.2

Many of the concerns to date regarding CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeat, technology have centered on off-target mutations. The featured study, published in Nature Biotechnology, looked at on-target mutations at the site of the “cuts,” revealing potentially dangerous changes that could increase the risk of chronic diseases like cancer.

Is CRISPR Scrambling DNA?

Researchers at the U.K.’s Wellcome Sanger Institute systematically studied mutations from CRISPR-Cas9 in mouse and human cells, focusing on the gene-editing target site. Large genetic rearrangements were observed, including DNA deletions and insertions, that were spotted near the target site.

They were far enough away, however, that standard tests looking for CRISPR-related DNA damage would miss them. The DNA deletions could end up activating genes that should stay “off,” such as cancer-causing genes, as well as silencing those that should be “on.” One of the study’s authors, professor Allan Bradley, said in a statement:3

“This is the first systematic assessment of unexpected events resulting from CRISPR/Cas9 editing in therapeutically relevant cells, and we found that changes in the DNA have been seriously underestimated before now. It is important that anyone thinking of using this technology for gene therapy proceeds with caution, and looks very carefully to check for possible harmful effects.”

The deletions detected were at a scale of “thousands of bases,” which is more than previously thought and enough to affect adjacent genes. For instance, deletions equivalent to thousands of DNA letters were revealed. “In one case, genomes in about two-thirds of the CRISPR’d cells showed the expected small-scale inadvertent havoc, but 21 percent had DNA deletions of more than 250 bases and up to 6,000 bases long,” Scientific American reported.4

The cells targeted by CRISPR try to “stitch things back together,” according to Bradley, “But it doesn’t really know what bits of DNA lie adjacent to each other.” As a result, the DNA may be rearranged, previously distant DNA sequences may become attached, or unrelated sections could be incorporated into the chromosome.5

Cas9, a bacteria enzyme that acts as the “scissors” in CRISPR, actually remains in the body for a period of hours to weeks. Even after the initial DNA segment had been cut out and a new section “pasted” into the gap to repair it, Cas9 continued to make cuts into the DNA. “[T]he scissors continued to cut the DNA over and over again. They found significant areas near the cut site where DNA had been removed, rearranged or inverted,” The Conversation reported.6

Does This Mean CRISPR Isn’t Safe?

It’s too soon to say what the long-term effects of gene-editing technology will be, and there are many variables to the safety equation. The findings likely only apply to CRISPR-Cas9, which cuts through the DNA’s double strand. Other CRISPR technologies exist that may alter only a single strand or not involve cutting at all, instead swapping DNA letters.

There are also CRISPR systems that target RNA instead of DNA and those that could potentially involve only cells isolated from the body, such as white blood cells, which could then be analyzed for potential mutations before being put back into the body.7

The Nature study did make waves in the industry, though, such that within the first 20 minutes of the results being made public three CRISPR companies lost more than $300 million in value.8

Some companies using CRISPR have said they’re already on the lookout for large and small DNA deletions (including one company using the technology to make pig organs that could be transplanted into humans). One company also claims it hasn’t found large deletions in their work on cells that do not divide often (the Nature study used actively dividing cells).9

The researchers are standing by their findings, however, which the journal took one year to publish. During that time, Bradley says, he was asked to conduct additional experiments and “the results all held up.”10 Past studies have also found unexpected mutations, including one based on a study that used CRISPR-Cas9 to restore sight in blind mice by correcting a genetic mutation.

The researchers sequenced the entire genome of the CRISPR-edited mice to search for mutations. In addition to the intended genetic edit, they found more than 100 additional deletions and insertions along with more than 1,500 single-nucleotide mutations.11 The study was later retracted, however, due to insufficient data and a need for more research to confirm the results.12

CRISPR-Edited Cells Could Cause Cancer

Revealing the many complexities of gene editing, CRISPR-Cas9 also leads to the activation of the p53 gene, which works to either repair the DNA break or kill off the CRISPR-edited cell.13

CRISPR actually has a low efficacy rate for this reason, and CRISPR-edited cells that survive are able to do so because of a dysfunctional p53. The problem is that p53 dysfunction is also linked to cancer (including close to half of ovarian and colorectal cancers and a sizable portion of lung, pancreatic, stomach, breast and liver cancers as well).14

In one recent study, researchers were able to boost average insertion or deletion efficiency to greater than 80 percent, but that was because of a dysfunctional p53 gene,15 which would mean the cells could be predisposed to cancer. The researchers noted, ” … it will be critical to ensure that [CRISPR-edited cells] have a functional p53 before and after engineering.”16

A second study, this one by the Karolinska Institute in Sweden, found similar results and concluded, ” … p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.”17

Some have suggested that if CRISPR could cure one chronic or terminal disease at the “cost” of an increased cancer risk later,18 it could still be a beneficial technology, but most agree that more work is needed and caution warranted.

A CRISPR clinical trial in people with cancer is already underway in China, and the technology has been used to edit human embryos made from sperm from men carrying inherited disease mutations. The researchers successfully altered the DNA in a way that would eliminate or correct the genes causing the inherited disease.19

If the embryos were implanted into a womb and allowed to grow, the process, which is known as germline engineering, would result in the first genetically modified children — and any engineered changes would be passed on to their own children. A February 2017 report issued by the U.S. National Academies of Sciences (NAS) basically set the stage for allowing research on germline modification (such as embryos, eggs and sperm) and CRISPR, but only for the purpose of eliminating serious diseases.

In the U.S., a first of its kind human trial involving CRISPR is currently recruiting participants with certain types of cancer. The trial is going to attempt to use CRISPR to modify immune cells to make them attack tumor cells more effectively. As far as risks from potential mutations, it’s anyone’s guess, but lead researcher Dr. Edward Stadtmauer of the University of Pennsylvania told Scientific American, “We are doing extensive testing of the final cellular product as well as the cells within the patient.”20

Are ‘Designer Babies’ Next?

It’s easy to argue for the merits of CRISPR when you put it in the context of curing deafness, inherited diseases or cancer, and at least 17 clinical trials using gene-editing technologies to tackle everything from gastrointestinal cancer to tumors of the central nervous system to sickle cell disease have been registered in the U.S.21 Another use of the technology entirely is the creation of “designer babies” with a certain eye color or increased intelligence.

About 40 countries have already banned the genetic engineering of human embryos and 15 of 22 European countries prohibit germ line modification.22 In the U.S., the NAS report specifically said research into CRISPR and germline modification could not be for “enhancing traits or abilities beyond ordinary health.” Still, using gene editing to create designer babies is a question of when, not if, with some experts saying it could occur in a matter of decades.23

There are both safety and ethical considerations to think about. With some proponents saying it would be unethical not to use the technology. For instance, Julian Savulescu, an ethicist at the University of Oxford, told Science News he believes parents would be morally obligated to use gene-editing technology to keep their children healthy.

“If CRISPR could … improve impulse control and give a child a greater range of opportunities, then I’d have to say we have the same moral obligation to use CRISPR as we do to provide education, to provide an adequate diet …”24 Others have suggested CRISPR could represent a new form of eugenics, especially since it can only be done via in vitro fertilization (IVF), putting it out of reach of many people financially and potentially expanding inequality gaps.

On the other hand, some argue that countries with national health care could provide free coverage for gene editing, possibly helping to reduce inequalities.25 It’s questions like these that make determining the safety of CRISPR and other gene-editing technology more important now than ever before.

What Does a CRISPR-Enabled Future Hold?

We’ve already entered the era of genetic engineering and CRISPR represents just one piece of the puzzle. It’s an exciting time that could lead to major advances in diseases such as sickle-cell anemia, certain forms of blindness, muscular dystrophy, HIV and cancer, but also one that brings the potential for serious harm. In addition to work in human and animal cells, gene-edited crops, in which DNA is tweaked or snipped out at a precise location, have already been created — and eaten.

To date, the technology has been used to produce soybeans with altered fatty acid profiles, potatoes that take longer to turn brown and potatoes that remain fresher longer and do not produce carcinogens when fried. The latter could be sold as early as 2019.

The gene-editing science, in both plants and animals, is progressing far faster than long-term effects can be fully realized or understood. There are many opportunities for advancement to be had, but they must come with the understanding that unintended mutations with potentially irreversible effects could be part of the package.

Watch the video.URL:https://youtu.be/faSoxyiAAPE

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First drug for smallpox approved


https://business.medicaldialogues.in/first-drug-for-smallpox-approved/

Afraid of Falling? For Older Adults, the Dutch Have a Cure


A course teaching older people how to fall, and not to fall, in Leusden, the Netherlands. 

LEUSDEN, Netherlands — The shouts of schoolchildren playing outside echoed through the gymnasium where an obstacle course was being set up.

There was the “Belgian sidewalk,” a wooden contraption designed to simulate loose tiles; a “sloping slope,” ramps angled at an ankle-unfriendly 45 degrees; and others like “the slalom” and “the pirouette.”

They were not for the children, though, but for a class where the students ranged in age from 65 to 94. The obstacle course was clinically devised to teach them how to navigate treacherous ground without having to worry about falling, and how to fall if they did.

“It’s not a bad thing to be afraid of falling, but it puts you at higher risk of falling,” said Diedeke van Wijk, a physiotherapist who runs WIJKfysio and teaches the course three times a year in Leusden, a bedroom community just outside Amersfoort, in the center of the country.

The Dutch, like many elsewhere, are living longer than in previous generations, often alone. As they do, courses that teach them not only how to avoid falling, but how to fall correctly, are gaining popularity.

From left, Riet van Velzen, 79, Ria Kocks, 78, Nanda Silkens, 79, Loes Bloemdal, 80, and Hans Kuhn, 85, learning a better way to stand up and sit down. 
Ben Koops, 82, navigating an obstacle called the “tilting shelf.” 

This one, called Vallen Verleden Tijd course, roughly translates as “Falling is in the past.” Hundreds of similar courses are taught by registered by physio- and occupational therapists across the Netherlands.

Yet falling courses — especially clinically tested ones — are a fairly recent phenomenon, according to Richard de Ruiter, of the Sint Maartenskliniek in Nijmegen, the foundation hospital that developed this particular course.

Virtually unheard-of just a decade ago, the courses are now common enough that the government rates them. Certain forms of Dutch health insurance even cover part of the costs.

While the students are older, not all of them seemed particularly frail. Herman van Lovink, 88, arrived on his bike. So did Annie Houtveen, 75. But some arrived with walkers and canes, and others were carefully guided by relatives.

Ms. Kuhn walking in the gym’s schoolyard. 

Falling can be a serious thing for older adults. Aging causes the bones to become brittle, and broken ones do not heal as readily.

Today, 18.5 percent of the Dutch population — roughly 3.2 million people — is 65 or older, according to official statistics. In 1950, about the time some of the younger course participants were born, people 65 or older made up just 7.7 percent of the population.

Across the Netherlands, 3,884 people 65 or older died as result of a fall in 2016, a 38 percent increase from two years earlier.

Experts say the rise in fatalities reflects the overall aging of the population, and also factors such as the growing use of certain medications or general inactivity.

“It’s same as with young children: More and more old people have an inactive lifestyle,” said Saskia Kloet, a program manager at VeiligheidNL, an institution that offers similar courses.

Even inactivity in one’s 30s or 40s could lead to problems later in life, she noted.

Like many people her age, Hans Kuhn, 85, worried that her daily routine — and the ability to live alone — would end if she ever lost her balance and fell.

She has lived in her house for decades, and alone since her partner died years ago. Its steeply winding staircase is equipped with a motorized chair on a rail to help reach upper floors. “I only use it when I have to bring lots of heavy things upstairs,” said Ms. Kuhn, herself a retired physiotherapist.

Ms. Kuhn’s entire house is a study in efficiency and simple modifications that can make all the difference for an older person. Hand grips are installed in just the right places, as well as ramps to accommodate her two walkers.

There is a stationary exercise bike to keep her moving, and a weight machine made from a big can of beans and string to maintain her upper body strength.

Even as she feels herself grow frailer and less flexible, she knows how to stay fit. “My main problem is I’m very afraid of falling,” she said.

Ms. Kuhn’s bedroom, right, and home trainer. The house is a study in simple modifications that can make all the difference for an older person.
Ms. Kuhn exercising at home with a self-made weight system made out of a rope and a can of beans. 

So she joined the course, which meets twice a week. On Tuesdays, the students build confidence by walking and re-walking the obstacle course. Thursdays are reserved for the actual falls.

In order to learn, the students start by approaching the mats slowly, lowering themselves down at first. Over the weeks, they learn to fall.

“Naturally, they are not interested in courses on falling at first, but once they see that they can do it, then it’s fun,” Ms. Kloet said. “But there is also a very important social aspect.”

Indeed, seeing one another helplessly sprawled across the gym mats gave way to giggling and plenty of dry comments, knowing jokes, general ribbing and hilarity.

“Stop your chattering,” Ms. van Wijk warned a group of well-dressed women who were supposed to be concentrating on the correct way to let themselves fall onto the foot-thick blue mat.

“I would,” said Loes Bloemdal, 80, laughing. “But I have no one to talk with all day.”

Ms. Silkens, right, and Frans Poss, 94, left, training on how to fall and get up.
The students start by lowering themselves down onto the mats slowly. Over the weeks, they learn to fall. 

In preparing their bodies for a possibly apocalyptic event, the students appeared to forget about their age.

Mr. van Lovink, the cyclist, asked if they would learn standing on one leg. “Why would you want to do that?” replied Ms. van Wijk.

“To be able to put on my pants,” Mr. van Lovink said seriously, but to the amusement of his classmates.

Ms. van Wijk advised them all to always sit when putting on their pants.

“That’s the power of physiotherapy with geriatrics,” she said. “You practice the things you know you can do, and not the things you can’t.”

Medical Marijuana a Hit With Seniors


Seniors are giving rave reviews for medical marijuana.

In a new survey, those who turned to it for treating chronic pain reported it reduced pain and decreased the need for opioid painkillers.

Nine out of 10 liked it so much they said they’d recommend medical pot to others.

“I was on Percocet and replaced it with medical marijuana. Thank you, thank you, thank you,” said one senior.

Another patient put it this way: “It [medical marijuana] is extremely effective and has allowed me to function in my work and life again. It has not completely taken away the pain, but allows me to manage it.”

Study co-author Dr. Diana Martins-Welch said, “The impact of medical marijuana was overwhelmingly positive. Medical marijuana led them to taking less medications overall — opioids and non-opioids — and they had better function and better quality of life.” Martins-Welch is a physician in the division of geriatric and palliative medicine at Northwell Health, in Great Neck, N.Y.

The biggest complaint the researchers heard about medical marijuana was the cost. “It’s an out-of-pocket expense. Insurance doesn’t cover it because it’s federally illegal,” Martins-Welch explained.

As for unwelcome side effects, Martins-Welch said sedation was what she heard about the most. “A lot of people don’t like feeling sleepy,” she said.

It’s also important to work with your doctor to find the right dose, since pain experts say that too little or too much doesn’t ease pain.

Thirty-one states have some type of medical marijuana law on the books, according to the National Conference of State Legislators.

“Every state has its own laws, like what a qualifying condition is. There are a lot of differences. And you can’t take a product from one state and cross another state line,” Martins-Welch said.

According to federal law, medical marijuana is still illegal in the United States. “There are legal fears. Some practitioners worry that the DEA [U.S. Drug Enforcement Administration] might come after them,” she added.

Medical marijuana is different than just picking up some pot and smoking it.

“The goal with medical marijuana is to find the dose that gives a therapeutic benefit without a high, or slowing reaction time or causing sedation,” Martins-Welch said. “To find that right dose, we start low and go slow.”

In fact, it’s important to work with a doctor because there’s a “therapeutic window” with THC, the active component in marijuana that causes the high, according to Dr. Mark Wallace, a board member of the American Pain Society.

If you get a dose that’s within that window, the pain is relieved. If you get too little, you won’t get pain relief, and if you go over the therapeutic window, pain is actually worsened, Wallace explained.

The study included a 20-question survey of nearly 150 seniors who had used medical marijuana for chronic pain. The seniors had received their medical marijuana from dispensaries in New York or Minnesota.

The average age of the seniors was 61 to 70, and 54 percent were female. Many (45 percent) used a vaporized oil in an e-cigarette device. Twenty-eight percent used a medical marijuana pill.

Twenty-one percent said they used medical marijuana daily, while 23 percent said they used it twice a day. Another 39 percent said they used it more than twice a day, the researchers noted.

About half the time, medical marijuana had been recommended by a doctor. One-quarter of the seniors decided to try medical marijuana at the urging of a friend or family member. Almost all — 91 percent — would recommend medical marijuana to someone else.

When asked how medical marijuana affected their pain levels, the seniors reported going from a 9 (on a pain scale of zero to 10) down to 5.6 a month after starting the medical marijuana.

Wallace said he’s seen many positive results from the use of medical marijuana in his patients.

“The geriatric population is my fastest-growing patient population. With medical marijuana, I’m taking more patients off opioids,” he said.

“There’s never been a reported death from medical marijuana, yet there are 19,000 deaths a year from prescription opioids. Medical cannabis is probably safer than a lot of drugs we give,” Wallace said.

Medical marijuana can also stimulate appetite, Martins-Welch said, which is a “godsend for cancer patients,” though extra eating may not be a welcome side effect for everyone.

Martins-Welch said it’s best to discuss potential drug interactions with your doctor, but it’s usually OK to mix marijuana and opioids. She said she’d caution against mixing medical marijuana with alcohol.

The study findings were presented recently at the American Geriatrics Society meeting in Orlando, Fla. Studies presented at meetings are typically viewed as preliminary until they’ve been published in a peer-reviewed journal.

How a light touch can spur severe itching


Summary:
Scientists have found that itching caused by touch is directly related to the number of touch receptors embedded in the skin. The team found, in mice, that fewer receptors make it more likely touch will induce itching.

Hongzhen Hu, Ph.D., shown in his laboratory at the Washington University Center for the Study of Itch, has found that itching caused by touch is directly related to the number of touch receptors embedded in the skin. His team found, in mice, that fewer receptors make it more likely touching will induce itching.

For some people, particularly those who are elderly, even a light touch of the skin or contact with clothing can lead to unbearable itching. What’s worse, anti-itch treatments, including hydrocortisone, don’t provide much relief for this type of itching.

Now, researchers at Washington University School of Medicine in St Louis have discovered, in mice, why a touch can cause such severe itching and, in the process, identified some possible therapeutic targets.

Their research, published May 4 in the journal Science, indicates that itching caused by touch is directly related to the number of touch receptors embedded in the skin. The fewer the receptors, the more likely it is that touching will induce itching.

“Itching caused by touch becomes more common as we age and is especially problematic for people with dry skin or who already suffer from chronic itching,” said senior investigator Hongzhen Hu, PhD, an associate professor of anesthesiology who conducts research as part of the university’s Center for the Study of Itch. “It can be more than a nuisance, and there are no drugs available to treat this type of itching, so we wanted to identify the underlying causes in hopes of finding better ways to treat it.”

Studying mice, the scientists discovered that the number of touch receptors called Merkel cells in the skin declined as the animals aged. They also found fewer of these touch receptors in animals with dry skin. Not having as many Merkel cells made itch problems more likely when the animals were poked with a hairlike nylon device that scientists use to study itch responses.

“As the number of Merkel cells went down, problems with touch-related itch went up,” Hu said. “What exactly Merkel cells do has not been clear, but our findings suggest they help control the itch response. When you lose these cells, their ability to inhibit itch also is lost.”

In additional work, the researchers turned to genetically engineered mice whose Merkel cells could be activated with a chemical compound. When the animals were given the compound, they were less likely to scratch when touched with the hairlike device.

“This gives us hope that if we can control the activity of the Merkel cells themselves, we may be able to control this type of itching,” said first author Jing Feng, PhD, a postdoctoral fellow at the School of Medicine.

The researchers also identified a second potential therapeutic target — a protein on the Merkel cells that appears to control itch. The protein, called Piezo2, is made on the membranes of the cells. In the mouse experiments, the researchers found that the Piezo2 protein played a role in controlling Merkel cells as they tamped down itch.

Hu and Feng now are analyzing skin samples from patients suffering from touch-related itch problems. Those patients were treated by Brian S. Kim, MD, an assistant professor of medicine and co-director of the Center for the Study of Itch.

“As people age, their skin changes, and for some people this can lead to severe, intractable itching,” Kim said. “For example, many of my patients with severe, chronic itch associated with aging cannot tolerate certain types of clothing. That observation fits with Dr. Hu’s findings that these receptors in the skin suppress itch, but with aging, the cells disappear, and normal touch sensations can be perceived by some patients as pathologic itch.”

If the skin biopsy samples from Kim’s patients show that they have depleted numbers of Merkel cells, activating such cells in patients may help relieve itching the same way it did for mice in the study.

Journal Reference:

  1. Jing Feng, Jialie Luo, Pu Yang, Junhui Du, Brian S. Kim, Hongzhen Hu. Piezo2 channel–Merkel cell signaling modulates the conversion of touch to itch. Science, 2018; 360 (6388): 530 DOI: 10.1126/science.aar5703

First 3D-printed human corneas


The first human corneas have been 3D-printed by scientists. It means the technique could be used in the future to ensure an unlimited supply of corneas.

Dr. Steve Swioklo and Professor Che Connon with a dyed cornea.
 

The first human corneas have been 3D printed by scientists at Newcastle University, UK.

It means the technique could be used in the future to ensure an unlimited supply of corneas.

As the outermost layer of the human eye, the cornea has an important role in focusing vision.

Yet there is a significant shortage of corneas available to transplant, with 10 million people worldwide requiring surgery to prevent corneal blindness as a result of diseases such as trachoma, an infectious eye disorder.

In addition, almost 5 million people suffer total blindness due to corneal scarring caused by burns, lacerations, abrasion or disease.

The proof-of-concept research, published today in Experimental Eye Research, reports how stem cells (human corneal stromal cells) from a healthy donor cornea were mixed together with alginate and collagen to create a solution that could be printed, a ‘bio-ink’.

Using a simple low-cost 3D bio-printer, the bio-ink was successfully extruded in concentric circles to form the shape of a human cornea. It took less than 10 minutes to print.

The stem cells were then shown to culture — or grow.

Che Connon, Professor of Tissue Engineering at Newcastle University, who led the work, said: “Many teams across the world have been chasing the ideal bio-ink to make this process feasible.

“Our unique gel — a combination of alginate and collagen — keeps the stem cells alive whilst producing a material which is stiff enough to hold its shape but soft enough to be squeezed out the nozzle of a 3D printer.

“This builds upon our previous work in which we kept cells alive for weeks at room temperature within a similar hydrogel. Now we have a ready to use bio-ink containing stem cells allowing users to start printing tissues without having to worry about growing the cells separately.”

The scientists, including first author and PhD student Ms Abigail Isaacson from the Institute of Genetic Medicine, Newcastle University, also demonstrated that they could build a cornea to match a patient’s unique specifications.

The dimensions of the printed tissue were originally taken from an actual cornea. By scanning a patient’s eye, they could use the data to rapidly print a cornea which matched the size and shape.

Professor Connon added: “Our 3D printed corneas will now have to undergo further testing and it will be several years before we could be in the position where we are using them for transplants.

“However, what we have shown is that it is feasible to print corneas using coordinates taken from a patient eye and that this approach has potential to combat the world-wide shortage.”

Reference:

3D Bioprinting of a Corneal Stroma Equivalent. Abigail Isaacson, Stephen Swioklo, Che J. Connon. Experimental Eye Research.

From Chaos To Calm: A Life Changed By Ketamine


An anesthetic and sometimes-party drug, ketamine is helping some patients calm the symptoms of mental disorders.

For six years now, life has been really good for James. He has a great job as the creative director of an advertising firm in New York City. He enjoys spending time with his wife and kids.

And it has all been possible, he says, because for the past six years he has been taking a drug called ketamine.

Before ketamine, James was unable to work or focus his thoughts. His mind was filled with violent images. And his mood could go from ebullient to dark in a matter of minutes.

Ketamine “helped me get my life back,” says James, who asked that we not use his last name to protect his career.

Ketamine was developed as a human and animal anesthetic in the 1960s. And almost from the time it reached the market it has also been used as a mind-bending party drug.

But ketamine’s story took a surprising turn in 2006, when researchers at the National Institutes of Health showed that an intravenous dose could relieve severe depression in a matter of hours. Since then, doctors have prescribed ketamine “off label” to thousands of depressed patients who don’t respond to other drugs.

And pharmaceutical companies are testing several new ketamine-related drugs to treat depression. Johnson & Johnson expects to seek approval for its nasal spray esketamine later this year, though the approval would be limited to use in a clinical setting.

Meanwhile, doctors have begun trying ketamine on patients with a wide range of psychiatric disorders other than depression. And there is now growing evidence it can help people with anxiety, bipolar disorder, post-traumatic stress disorder, and perhaps even obsessive-compulsive disorder.

“I think it’s actually one of the biggest advances in psychiatry in a very long time,” says Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and director of the Developmental Biopsychiatry Research Program at McLean Hospital.

Ketamine may also offer new hope for people like James who have symptoms of several different psychiatric disorders.

James had a happy childhood, he says. But his thoughts were out of control. “I always felt like I was crossing a freeway and my thoughts were just racing past me,” he says.

He spent much of his childhood terrified of “an unknown, an ambiguous force out there.” The fear was “overwhelming,” he says. “I literally slept with the cover over my head with just room to breathe through my mouth until I went to college.”

And there was something else about James: his body temperature.

“I overheated constantly,” he says. “I would wear shorts all year long. In my 20s in my apartment I would sleep with the windows open in the middle of the winter.”

In his late 20s, James saw a doctor who told him he had attention deficit hyperactivity disorder. So he started taking stimulants.

At first, the pills helped him focus. Then they didn’t, no matter how many he took.

He’d done well as an idea guy in the advertising industry. But now James was trying to work at home, and it wasn’t going well.

“ADHD pills will make you interested in anything,” he says. “So I was putting the desk together and taking the desk apart. I was putting a laptop stand together and taking it apart. I was going in a massive downward spiral.”

James had always suffered from mood swings. But now they were rapid and extreme. And he couldn’t stop thinking about gruesome scenarios, like a murderer coming for his family.

“My wife took a summer off to be with me because she was scared of what was going to happen to me,” he says. “She would go to work for a few hours, then rush home. There would be times I’d call her just screaming, ‘Please come home. I can’t get through another minute.’ ”

Eventually, James found his way to Dr. Demitri Papolos, an associate professor of clinical psychiatry at Albert Einstein College of Medicine.

“He was like a whirling dervish when he came into my office,” Papolos says. “He was extremely fearful and scanning the environment all the time and he overheated at the drop of a hat.”

Papolos diagnosed James with a variant of bipolar disorder he calls the “fear of harm phenotype.” It typically appears in childhood and often doesn’t respond to traditional psychiatric drugs.

But Papolos has found that the condition does respond to ketamine. “It’s been transformational,” he says.

In January, Papolos published a study of 45 children with the problem. They inhaled a nasal mist containing ketamine about twice a week. Nearly all got dramatically better.

Scientists still aren’t sure why ketamine works, but there’s evidence that it encourages the brain to rewire, to alter the connections between cells. That process has been linked to recovery from depression. And it may also explain why ketamine helps people who have symptoms associated with several different psychiatric disorders.

“I think it’s having multiple effects, and that means it’s probably useful for multiple different disorders,” Teicher says.

One of those effects involves a part of the brain involved in temperature regulation. And that could explain why patients like James usually stop overheating once they are taking ketamine.

James started taking a ketamine nasal spray every other day. He says his response was dramatic.

“One day I turn to my wife and I’m like, ‘I feel calm today. I don’t know if it’s the sun coming in, I don’t know if it’s just the way we’re sitting here, but I feel like I could go and sit at the computer and work.’ ”

The next day, James did sit down at his computer. A month later, he was back at work.

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No more sweet tooth? Scientists switch off pleasure from food in brains of mice


Altering activity in brain’s emotion center can eliminate the natural craving for sweet; findings could inform treatments for eating disorders

New research in mice has revealed that the brain’s underlying desire for sweet, and its distaste for bitter, can be erased by manipulating neurons in the amygdala, the emotion center of the brain. The research points to new strategies for understanding and treating eating disorders including obesity and anorexia nervosa.

Brain illustration

New research in mice has revealed that the brain’s underlying desire for sweet, and its distaste for bitter, can be erased by manipulating neurons in the amygdala, the emotion center of the brain.

The study showed that removing an animal’s capacity to crave or despise a taste had no impact on its ability to identify it. The findings suggest that the brain’s complex taste system — which produces an array of thoughts, memories and emotions when tasting food — are actually discrete units that can be individually isolated, modified or removed all together. The research points to new strategies for understanding and treating eating disorders including obesity and anorexia nervosa.

The research was published today in Nature.

“When our brain senses a taste it not only identifies its quality, it choreographs a wonderful symphony of neuronal signals that link that experience to its context, hedonic value, memories, emotions and the other senses, to produce a coherent response,” said Charles S. Zuker, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper’s senior author.

Today’s study builds upon earlier work by Dr. Zuker and his team to map the brain’s taste system. Previously, the researchers revealed that when the tongue encounters one of the five tastes — sweet, bitter, salty, sour or umami — specialized cells on the tongue send signals to specialized regions of the brain so as to identify the taste, and trigger the appropriate actions and behaviors.

To shed light on that experience, the scientists focused on sweet and bitter taste and the amygdala, a brain region known to be important for making value judgments about sensory information. Previous research by Dr. Zuker, a professor of biochemistry and molecular biophysics and of neuroscience and a Howard Hughes Medical Institute Investigator at Columbia University Irving Medical Center, and others showed that the amygdala connects directly to the taste cortex.

“Our earlier work revealed a clear divide between the sweet and bitter regions of the taste cortex,” said Li Wang, PhD, a postdoctoral research scientist in the Zuker lab and the paper’s first author. “This new study showed that same division continued all the way into the amygdala. This segregation between sweet and bitter regions in both the taste cortex and amygdala meant we could independently manipulate these brain regions and monitor any resulting changes in behavior.”

The scientists performed several experiments in which the sweet or bitter connections to the amygdala were artificially switched on, like flicking a series of light switches. When the sweet connections were turned on, the animals responded to water just as if it were sugar. And by manipulating the same types of connections, the researchers could even change the perceived quality of a taste, turning sweet into an aversive taste, or bitter into an attractive one.

In contrast, when the researchers instead turned off the amygdala connections but left the taste cortex untouched, the mice could still recognize and distinguish sweet from bitter, but now lacked the basic emotional reactions, like preference for sugar or aversion to bitter.

“It would be like taking a bite of your favorite chocolate cake but not deriving any enjoyment from doing so,” said Dr. Wang. “After a few bites, you may stop eating, whereas otherwise you would have scarfed it down.”

Usually, the identity of a food and the pleasure one feels when eating it are intertwined. But the researchers showed that these components can be isolated from each other, and then manipulated separately. This suggests that the amygdala could be a promising area of focus when looking for strategies to treat eating disorders.

In the immediate future, Drs. Zuker and Wang are investigating additional brain regions that serve critical roles in the taste system. For example, the taste cortex also links directly to regions involved in motor actions, learning and memory.

“Our goal is to piece together how those regions add meaning and context to taste,” said Dr. Wang. “We hope our investigations will help to decipher how the brain processes sensory information and brings richness to our sensory experiences.”

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Age related BP targets for chronic kidney disease patients work better


A cautious approach to lowering blood pressure (BP) in elderly patients with chronic kidney disease (CKD) is recommended, said US-based researchers. Treatment of hypertension in younger patients with CKD can follow current clinical guidelines, they added.

“Hypertension affects almost all patients with CKD, and is one of the few conditions that is treatable with a wide array of medications,” said lead author Professor Casaba P. Kovesdy, from the Division of Nephrology, Memphis Veterans Affairs Medical Center, Memphis, Tennessee, US.

Kovesdy and team examined systolic BP (SBP) and diastolic BP (DBP) with all-cause mortality, together with the incidence of chronic heart disease (CHD), ischaemic stroke, and end stage renal disease (ESRD) in 339,887 patients with CKD. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.08660815]

During the 4.8 year median follow-up 100,763 patients died (95 percent confidence interval [CI], 62.6- 63.4). Mortality rates were high in older SBP patients. SBP ≥ 140mmHg and <120 mmHg was associated with higher mortality rates across all age groups. Lowest mortality was seen in SBP 120-139 mmHg for patients <80 years, and SBP 120-159 mmHg for patients ≥80 years.

Compared to SBP of 130-139 mmHg, SBP ≥170mmHg in patients aged <50, 50-59, 60-69, 70-79, and ≥80 years were adjusted hazard ratio [aHR], 1.95, 95 percent CI, 1.34-2.84; aHR, 2.01, 95 percent CI, 1.75-2.30; aHR, 1.68, 95 percent CI, 1.49-1.89; aHR, 1.39, 95 percent CI, 1.25-1.54; and aHR, 1.30, 95 percent CI, 1.17-1.44, respectively.

Lower DBP was associated with high mortality. DBP of 70-79 mmHg in patients <50 years and 80-89 mmHg in patients ≥50 years had the lowest mortality.

CHD was experienced in 9,450 patients during the study period (95 percent CI, 9.6-10.0). Higher SBP was associated with higher CHD rates in patients <80 years. However, lowest CHD rates were associated with SBP<110 mmHg in patients <70 years and SBP<140 mmHg in patients ≥70 years. DBP on the other hand had no association with CHD.

Ischaemic stroke was experienced by 14,557 patients (95 percent CI, 10.2-10.6). While higher SPB was associated with higher stroke rates across all age groups, DBP showed no association. Lowest stroke risk was seen in patients with SBP <100mmHg.

ESRD rates were found to be lower in older individuals compared to younger patients. ESRD was seen in 5,161 patients (95 percent CI, 3.2-3.3). DBP was found to have no association with ESRD, but high SBP was associated with high ESRD incidence. Patients <80 years with SBP ≥170mmHg had high ESRD risk, but SBP <170mmHg in this age group had no associated risk.

“Our results reinforce the significant association of elevated SBP with all the studied outcomes but suggest weak association in the elderly, especially in patients aged ≥80years,” said Kovesdy. “The best outcomes were seen with SBP of 120-130 mmHg in patients <80 years and of 120-159 mmHg in those ≥80years.”

In a separate editorial, Assistant Professor Jessica W. Weiss from the Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, US said that the study by Kovesdy and team added to the collective understanding of the relationship between BP and a wide range of various clinical outcomes in older adults with CKD, a group rarely studied. This, she said, may be useful in guiding the design of future studies in this area. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.03100316]

“These results may also add a note of caution to newfound enthusiasm for lower BP targets after the release of the SPRINT* via the suggestion that harm may persist at upper and lower extremes of BP among populations more comorbid and complex than those evaluated in the setting of a clinical trial,” said Weiss.

 

Evolocumab plus statin potentially reduces atherosclerosis progression in GLAGOV study


The addition of evolocumab to statin therapy in individuals with angiographic coronary disease appeared to encourage coronary atherosclerosis regression, as demonstrated in the GLAGOV* trial presented at the Scientific Sessions of the American Heart Association (AHA 2016) held in New Orleans, Louisiana, US.

In comparison with patients on statin alone who experienced a nonsignificant 0.05 percent increase in percent atheroma volume (PAV), those on combined therapy of statin and evolocumab had a 0.95 percent reduction in PAV (difference, -1.0 percent, 95 percent confidence interval [CI], -1.8 to -0.64 percent; p<0.001). Normalized total atheroma volume (TAV) decreased by 0.9 mm3 (nonsignificant) in those on statin alone compared with 5.8 mm3 in those on statin and evolocumab (difference, -4.9 mm3, 95 percent CI, -7.3 to -2.5; p<0.001). [AHA 2016, LBCT 03; JAMA 2016;doi:10.1001/jama.2016.16951]

Plaque regression occurred in a greater number of patients on evolocumab and statin compared with those on statin alone (64.3 percent vs 47.3 percent; difference, 17.0 percent, 95 percent CI, 10.4 to 23.6 percent; p<0.001 for PAV and 61.5 percent vs 48.9 percent; difference, 12.5 percent, 95 percent CI, 5.9 to 19.2 percent; p<0.001 for TAV).

“We are really reducing plaque burden in the coronaries if we can get [low-density lipoprotein cholesterol (LDL-C)] down to these very low levels,” said study chair Dr Steven Nissen from the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings. “It turns out that a little bit of change in plaque volume translates into a very big change in plaque behaviour.”

“[These findings] suggest a new era in lipid management,” said discussant Dr Raul Santos from the University of São Paulo, Brazil.

Evolocumab appeared to be well tolerated with comparable incidences of injection site reactions (0.4 percent vs 0 percent), myalgia (7.0 percent vs 5.8 percent), neurocognitive events (1.4 percent vs 1.2 percent), and new onset diabetes (3.6 percent vs 3.7 percent) for evolocumab plus statin vs statin monotherapy, respectively.

In this double-blind, placebo-controlled, multicentre trial, participants (n=968, mean age 59.8 years; 72 percent male) with angiographic coronary disease, LDL-C levels ≥80 mg/dL or 60–80 mg/dL with additional high-risk features, and on stable statin therapy were randomized to receive monthly subcutaneous injections of the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab (420 mg) or placebo for 76 weeks. After angiography, participants underwent intravascular ultrasound (IVUS) of the same artery at baseline and at week 78.

“Both the primary and secondary IVUS efficacy measures showed atherosclerosis regression … in patients treated with the combination of evolocumab and statins and absence of regression in patients treated with a statin alone,” said study lead investigator Dr Steven Nicholls, also from the Cleveland Clinic. “These findings provide evidence that PCSK9 inhibition produces incremental benefits on coronary disease progression in statin-treated patients.”

“Over the last 4 decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL,” said Nissen, who acknowledged the limitations of the trial such as the small number of patients and short treatment period. “IVUS is a useful measure of disease activity, but the critical determination of benefit and risk will require completion of large outcome trials currently underway,” he said.

Other factors that could potentially influence disease progression in the setting of very low LDL-C levels also need to be investigated, said Nicholls.

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