Johns Hopkins researchers say that an experimental anticancer compound appears to have reversed behaviors associated with schizophrenia and restored some lost brain cell function in adolescent mice with a rodent version of the devastating mental illness.
The drug is one of a class of compounds known as PAK inhibitors, which have been shown in animal experiments to confer some protection from brain damage due to Fragile X syndrome, an inherited disease in humans marked by mental retardation. There also is some evidence, experts say, suggesting PAK inhibitors could be used to treat Alzheimer’s disease. And because the PAK protein itself can initiate cancer and cell growth, PAK inhibitors have also been tested for cancer.
In the new Johns Hopkins-led study, reported online March 31 in the Proceedings of the National Academy of Sciences, the researchers found that the compound, called FRAX486, appears to halt an out-of-control biological “pruning” process in the schizophrenic brain during which important neural connections are unnecessarily destroyed. Working with mice that mimic the pathological progression of schizophrenia and related disorders, the researchers were able to partially restore disabled neurons so they could connect to other nerve cells.
The Johns Hopkins team says the findings in teenage mice are an especially promising step in efforts to develop better therapies for schizophrenia in humans, because schizophrenia symptoms typically appear in late adolescence and early adulthood.
“By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit,” says study leader Akira Sawa, M.D., Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing.”
For the mouse experiments, Sawa and his colleagues chemically turned down the expression of a gene known as Disrupted-in-Schizophrenia 1 (DISC1), whose protein appears to regulate the fate of neurons in the cerebral cortex responsible for “higher-order” functions, like information processing.
In studies of rodent brain cells, the researchers found that a DISC1 deficit caused deterioration of vital parts of the neuron called spines, which help neurons communicate with one another.
Reduced amounts of DISC1 protein also impact the development of a protein called Kalirin-7 (KAL7), which is needed to regulate another protein called Rac1. Without enough DISC1, KAL7 can’t adequately control Rac1 production and the development of neuronal spines. Excess Rac1 apparently erases spines and leads to excess PAK in the mice.
By using FRAX486 to reduce the activity of PAK, the researchers were able to protect against the deterioration of the spines caused by too little DISC1, halting the process. This normalized the excess pruning and resulted in the restoration of missing spines. They were able to see this by peering into the brains of the mice with DISC1 mutations on the 35th and 60th day of their lives, the equivalent of adolescence and young adulthood.
Sawa, who is also director of the Johns Hopkins Schizophrenia Center, cautions that it has not yet been shown that PAK is elevated in the brains of people with schizophrenia. Thus, he says, it is important to validate these results by determining whether this haywire PAK cascade is also occurring in humans.
In the mice, the researchers also found that their behavior improved when PAK inhibitors were used. The mice were tested for their reaction to noises. There is a neuropsychiatric phenomenon in which any organism will react less to a strong, startling sound when they have first been primed by hearing a weaker one. In schizophrenia, the first noise makes no impact on the reaction to the second one.
The mice in the study showed improvements in their reactions after being treated with the PAK inhibitor. The drug was given in small doses and appeared to be safe for the animals.
“Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage,” Sawa says. “This compound has the potential to do both.”
Altitude sickness ‘two illnesses’ says Edinburgh University study
Altitude sickness is two illnesses, according to Edinburgh scientists.
The condition, triggered by falling oxygen levels, causes mild sickness, headaches and life-threatening problems affecting the heart, lungs and brain.
Researchers at Edinburgh University said they had shown it is actually “at least two separate syndromes”.
The scientists said climbers and skiers who suffer from the potentially deadly condition could be treated more effectively following the new insight.
Altitude sickness occurs at heights above 2,500 metres.
Using a computer analysis method for grouping genes together, researchers studied patterns of symptoms among people in high altitude areas in Bolivia and Kilimanjaro in Tanzania.
One group experienced disrupted sleep but minimal headache, while another group only reported headaches and little disruption to sleep.
Others meanwhile experienced a mixture of symptoms.
For more than 20 years, the condition has been diagnosed using a symptom score called the Lake Louise consensus.
A score for each symptom, including headache, fatigue and sleep disturbance, is added up and a diagnosed reached.
The findings, which have been published in the PLOS ONE journal, will also be presented at an international altitude sickness meeting later this year.
Dr Ken Baillie, of The Roslin Institute at Edinburgh University, said: “For more than two decades we have thought of altitude sickness as a single disease.
“We have now shown that it is at least two separate syndromes that happen to occur in the same people at a similar time.
“Studying these syndromes in isolation will make it easier to understand the cause of each one, and to test new treatments.”
American Heart Association Rapid Access Journal Report.
- Stroke survivors who consistently control their blood pressure may reduce the likelihood of a second stroke by more than 50 percent.
- Less than a third of stroke survivors maintained consistent blood pressure control more than 75 percent of the time.
Stroke survivors who consistently control their blood pressure may reduce the likelihood of a second stroke by more than half, according to new research in the American Heart Association journal Stroke.
For the study, researchers analyzed the results from the Vitamin Intervention for Stroke Prevention (VISP) trial, which enrolled 3,680 ischemic stroke patients ages 35 and older in 1996-2003. Ischemic strokes are caused by a clot or other blockage in a blood vessel supplying the brain. Participants had been tested for several risk factors, including blood pressure levels at baseline, a month after the start of the study, at six months and every six months thereafter up to 24 months.
Researchers determined results after controlling for age, sex and prior history of stroke, heart disease and other factors. Blood pressure was considered “controlled” at 140 mmHg over 90 mmHg or lower.
- Fewer than 30 percent of stroke survivors studied maintained consistent blood pressure control more than 75 percent of the time.
- Among individuals with elevated blood pressure at baseline (systolic blood pressure over 153 mm Hg), second stroke rate was reduced by 54 percent among participants who kept their blood pressure under control more than 75 percent of the time, compared with those who kept it under control less than 25 percent of the time.
“It’s not enough to control blood pressure some of the time. Averages do not take into account variability in blood pressure readings from one check to the next,” said Amytis Towfighi, M.D., study lead author and assistant professor of neurology at the Keck School of Medicine at the University of Southern California in Los Angeles, Calif. “Fluctuations in blood pressure may be associated with greater cardiovascular risk.”
Changes in care management may be needed to ensure patients maintain consistent control of blood pressure. Rather than check blood pressure during clinic visits only, it should done regularly, perhaps at home by machines that can remotely transmit the data, she said.
“One of the things we really emphasize is getting patients involved in their own care, and learning how to control their risk factors,” said Towfighi, who is also associate chief medical officer at Rancho Los Amigos National Rehabilitation Center in Downey, Calif.
Reducing salt intake, eating a healthy diet (rich in whole grains, fruits and vegetables) and exercising regularly can also reduce stroke risk.
With the low percentage of trial participants controlling their blood pressure from one check to the next, “you can only imagine how poor blood pressure control is outside of the clinical trial setting,” Towfighi said.
In the study, participants with a history of heart attacks were most likely to keep their blood pressure under control most of the time, possibly suggesting patients and healthcare practitioners are more aware of controlling blood pressure after heart attack but less diligent after stroke.
VISP trial participants were from the United States, Canada and Scotland.
Co-authors are Daniela Markovic, M.S., and Bruce Ovbiagele, M.D., M.Sc. Author disclosures are on the manuscript.
The American Heart Association National Scientist Development Award funded this research.
“You are what you remember — your very identity depends on all of the events, people and places you can recall.”
We’ve seen the many ways in which our memory can be our merciless traitor: it is not a recording device but a practitioner of creative plagiarism, a terrible timekeeper, and the bent backbone inthe anatomy of lying. How, then, can this essential human faculty become our ally?
In The Art of Doing: How Superachievers Do What They Do and How They Do It So Well(public library) — a compendium of pragmatic advice on such modern fixations and timeless aspirations as how to create a great company culture (courtesy of Zappos CEO Tony Hsieh) to how to be funny (courtesy of Alec Baldwin) to how to fight for justice (courtesy of Constance Rice) — neurologist, neuropsychiatrist, and prolific brain-book author Richard Restak offers some vital tips on how to optimize your brain, central to which is honing the capacity and performance of your memory:
On a very basic level, you are what you remember — your very identity depends on all of the events, people and places you can recall. Improving your memory will help you develop a quicker, more accurate retrieval of information that will increase your intelligence. Sharpening your short-term or“working” memory requires concentration. For instance, study four unrelated words for 15 seconds, then set an alarm for five minutes. Pay attention to another activity until the alarm sounds. Then try to remember the words. As you get better, change and add to the number of words and increase the amount of time. You can do similar exercises with numbers, visual designs, spoken words or even try to recount the scenes of a television show you just watched.
But this, Restak cautions, can be physically taxing:
When you do these exercises your brain will require extra oxygen, blood and glucose. Just as with physical exercise, this can tire you out. Many “tricks” to sharpen your recall use memory pegs, systems to attach an association or meaning to what you desire to remember. There are visual and story memory systems, some dating back to Ancient Rome. One of these systems is called “the memory palace,”in which you associate the things you want to remember with vivid mental pictures, which you then imaginatively place in a familiar setting such as your living room. Later, you can “tour” in your mind the living room to observe the remembered objects in their familiar places. This technique can be so effective it is often used by memory contest champions.
Just as important as working memory, Restak argues, is emotional memory — an essential psychological tool that has found creative expression in everything from sentimental cartography to object-based storytelling to wearable personal histories. Restak writes:
Another aspect of recall is emotional memory, when we relive how we felt at moments in the past — elated, sad, depressed, or angry. When we lose emotional memory of our own youth, we find that we no longer understand young people. If this forgetting progresses, we begin to lose touch with ourselves. And if we allow our emotional memories to disappear, as happens with Alzheimer’s patients, we will find a stranger staring back at us from the mirror.
He recommends an exercise for reacquainting yourself with your emotional memory, one practiced by cultural icons in their letters to their younger selvesand embedded in the heart of the It Gets Better project:
Find a picture of yourself in which you are half of your present age. Stare at the picture for a while. Then write a letter to your older self from the perspective of the younger you in the photo, expressing all of the younger self’s hopes and concerns about the future. Follow this with a letter back from the present self to the younger you, telling that younger self about all the things they will do in their future and who they will grow into. Hopefully you will uncover feelings and memories of things you haven’t experienced for years.
Restak reminds us of the multi-sensory dimensions of experience:
The olfactory nerve links directly to the emotional centers of the limbic system, so the scents of your past — such as mowed grass, crayons or perfumes — can also bring back emotionally charged memories. Think of Proust and his madeleine.
Complement with this fascinating read on the science of “chunking” and working memory and this guide to the art of revising our inner storytelling, then find more practical modern-day how-to’s on everything from entrepreneurship to comedy to winemaking in The Art of Doing.
MIT scientists report the use of a CRISPR methodology to cure mice of a rare liver disorder caused by a single genetic mutation. They say their study (“Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype”), published in Nature Biotechnology, offers the first evidence that this gene-editing technique can reverse disease symptoms in living animals. CRISPR, which provides a way to snip out mutated DNA and replace it with the correct sequence, holds potential for treating many genetic disorders, according to the research team.
“What’s exciting about this approach is that we can actually correct a defective gene in a living adult animal,” says Daniel Anderson, Ph.D., the Samuel A. Goldblith associate professor of chemical engineering at MIT, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the paper.
The recently developed CRISPR system relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this cellular system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.
At the same time, the researchers also deliver a DNA template strand. When the cell repairs the damage produced by Cas9, it copies from the template, introducing new genetic material into the genome. Scientists envision that this kind of genome editing could one day help treat diseases such as hemophilia, Huntington’s disease, and others that are caused by single mutations.
For this study, the researchers designed three guide RNA strands that target different DNA sequences near the mutation that causes type I tyrosinemia, in a gene that codes for an enzyme called FAH. Patients with this disease, which affects about 1 in 100,000 people, cannot break down the amino acid tyrosine, which accumulates and can lead to liver failure. Current treatments include a low-protein diet and a drug called NTCB, which disrupts tyrosine production.
In experiments with adult mice carrying the mutated form of the FAH enzyme, the researchers delivered RNA guide strands along with the gene for Cas9 and a 199-nucleotide DNA template that includes the correct sequence of the mutated FAH gene.
“Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ~1/250 liver cells,” wrote the investigators. “Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype.”
While the team used a high pressure injection to deliver the CRISPR components, Dr. Anderson envisions that better delivery approaches are possible. His lab is now working on methods that may be safer and more efficient, including targeted nanoparticles.
The first room-temperature, high-sensitivity infrared photodetector has been designed by a team of researchers in the US. The device is based on the “wonder material” graphene and works across the full infrared spectrum. The detector is thin, flexible and transparent, making it highly suitable for applications including wearable electronics, according to the team. The researchers are currently developing an infrared camera by building an array with their graphene photodetectors.
Graphene is a layer of carbon just one atom thick and since it was first isolated in 2004 its remarkable electronic and mechanical properties have been studied by physicists worldwide. Zhaohui Zhong, Ted Norris and colleagues from the University of Michigan have been developing photodetectors that can take advantage of graphene’s unique material properties, including its ultra-broadband light-absorption capability. As graphene is a semimetal, it is capable of absorbing light across a wide spectrum – from ultraviolet to far infrared. This is unlike conventional photodetectors, which are made from semiconductors that can only absorb light at specific wavelengths.
Across the spectrum
As well as in night-vision goggles, infrared detectors have a variety of other uses: they can detect heat leaks, monitor blood flow and identify certain chemicals in the environment. They can even be used to study paintings, looking through multiple layers of paint to determine older versions of an artwork. However, the detectors require a combination of technologies to accurately detect the whole of the infrared spectrum. Indeed, detecting mid-infrared and far-infrared radiation requires the sensors to operate at very cold temperatures, thus making them impractical for everyday use.
While graphene has been used previously to make photodetectors, these have been limited by their poor sensitivity. With its one-atom thickness, graphene only absorbs about 2.3% of the light incident on it. “The challenge for the current generation of graphene-based detectors is that their sensitivity is typically very poor,” says Zhong. “It’s a hundred to a thousand times lower than what a commercial device would require.” It is this sensitivity that the Michigan researchers’ design has hugely improved upon.
The device itself is made of two graphene sheets with a thin tunnelling-barrier layer between them. When light hits the top layer of graphene, it creates “hot” electrons and holes with high energy. “By designing the material interfaces properly, the hot electrons will tunnel through the barrier layer into the bottom graphene layer, while leaving behind positively charged holes on the top graphene layer,” explains Zhong. “The positively charged holes can produce an electrostatic gating effect and this affects the current readout of the bottom graphene layer.” Measuring the change in current allows the team to detect the brightness of the light incident on the detector. Rather than trying to directly measure the freed electrons, Zhong and colleagues configured the bottom-layer graphene as a field-effect transistor, which provides an intrinsic gain to amplify the tiny current and so overcomes graphene’s natural low sensitivity.
“We can make the entire design super-thin,” says Zhong. “It can be stacked on a contact lens or integrated with a mobile phone.” It can also be scaled down further, and so the team is currently working on making an infrared camera using an array made up of the detectors – Zhong says the prototype will be ready in a few years. He also foresees the use of their detectors in wearable applications because they could potentially be integrated into contact lenses or electronic eyes. “But for now, there are many fundamental scientific, material and engineering challenges that need to be addressed first. Making an infrared camera will be the first step,” says Zhong.
The dangers associated with mercury-based dental fillings are not isolated to just the individuals who receive them, says a new study recently published by the environmental justice group BAN Toxics (BT). Like its name implies, BT is pushing for a ban on mercury use in dentistry due to persistent mercury vapors that threaten not only patients but also dentists, dental assistants, and dental students, all of whom are constantly exposed to mercury-polluted air.
Entitled “What is in the Air: Mercury Vapor Levels in Dental Institutions,” the new study highlights how mercury exposure levels at many dental practices and schools greatly exceed U.S. Environmental Protection Agency (EPA) maximum exposure thresholds. While there is no safe level of exposure to mercury, the levels to which the average dental worker or patient is exposed through the air in practices that use mercury fillings is excessive.
The Agency for Toxic Substances and Disease Registry (ATSDR) has established an action level for mercury exposure of 1,000 nanograms per cubic meter (ng/m3), while the EPA considers exposure levels equaling or exceeding 10,000 ng/m3 to warrant the issuing of an evacuation alert. But based on air tests conducted in five dental offices and three dental supply stores in the Philippines, levels of mercury vapor typically exceed these two limits.
On the low end, mercury was detected in the air at a level of 967 ng/m3, which is just below the ATSDR threshold. But on the high end, mercury was detected at levels exceeding 35,000 ng/m3, which is more than three times the EPA evacuation alert limit. The names of the clinics and stores were not released as part of the study, but due to their varied locations throughout the country, it is reasonable to conclude that mercury pollution is generally problematic in modern dentistry.
“The exposure to toxic mercury vapors in dental institutions is unnecessary and preventable,” says Attorney Richard Gutierrez, executive director of BT, about the shocking findings. “Learning methodologies can be put into place to avoid toxic mercury. This should itself be a strong incentive as well to abandon dental amalgam use in its entirety in the Philippines.”
Why are dentists still using mercury when safer, more effective alternatives already exist?
A growing number of dentists have begun to voluntarily phase out the use of mercury amalgam fillings, which contain about 50 percent mercury, 22-32 percent silver, 14 percent tin and 8 percent copper and other compounds. But there are still many dentists throughout the world that use them, which some are hoping will change.
“Mercury-free alternatives are now widely-available [and are] safer and as cost effective as amalgam,” said Dr. Lillian Lasaten-Ebuen, president of the International Association of Oral Medicine & Toxicology Philippines (IAOMT-Philippines). “Philippine dentistry should move beyond amalgam and we should prepare the future generation of dentists to embrace better and safer alternatives for their patients.”
BT is also calling for dental curriculum in the country to change, excluding dental amalgams as an option for filling caries. A position that the U.S. and other Western nations would do good to adopt, the Philippines plans to completely phase out the use of dental amalgams in the health sector by 2016, according to Inquirer News, as the brain-damaging chemical has no legitimate or safe use in health and medicine.
“We go to our doctors and dentists in order to be well, and mercury has no place in a healthy society,” adds Dr. Lasaten-Ebuen. “We need to uphold our Hippocratic oath as health practitioners, to help the sick and abstain from harming any person.”
Sources for this article include: