Lab Grown Neurons Could Lead Researchers To Better Drugs

Today's post from vectorblog.org (see link below) is somewhat technical but isn't everything you read about stem cell research 'technical'? It's worth reading for neuropathy patients though because it looks at current research across the world which involves 'recreating' nerve cells (neurons) and studying them with a view to creating new drugs designed to target pain signals specifically and that's what we need. Current drugs are prescribed to throw a blanket over the problem and hope that that reduces the strength of the pain signals that so characterise neuropathy symptoms. They often have side-effects as a result, so stem-cell research is clearly the future because then drugs can be developed that target the problem with pinpoint accuracy. It's going to take decades yet but as long as they're going in the right direction, maybe future generations will suffer less than we do.

Modeling pain in a dish: Nociceptors made from skin recreate pain physiology
by Nancy Fliesler on December 12, 2014 
 
Neurons from patients could lead researchers to better drugs for chronic pain. Chronic pain, affecting tens of millions of Americans alone, is debilitating and demoralizing. It has many causes, and in the worst cases, people become “hypersensitized”—their nervous systems fire off pain signals in response to very minor triggers.

There are no good medications to calm these signals, in part because the subjectivity of pain makes it difficult to study, and in part because there haven’t been good research models. Drugs have been tested in animal models and “off the shelf” cell lines, some of them engineered to carry target molecules (such as the ion channels that trigger pain signals). Drug candidates emerging from these studies initially looked promising but haven’t panned out in clinical testing.

“These models don’t tell you what the drug is doing to the whole functioning neuron,” says Elizabeth Buttermore, PhD, a postdoctoral fellow in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “They haven’t been holding up.”

Last month in Nature Neuroscience, Buttermore coauthored a report with Brian Wainger, MD, of Boston Children’s and Massachusetts General Hospital, describing a new model that appears to capture pain physiology in a dish, using skin cells as their raw material. Their model, also a technical breakthrough in stem cell research, offers new opportunities to understand how pain is produced and to discover new analgesics.

A nimbler way to make neurons

Labs all over the world are beginning to reprogram skin cells into cells resembling embryonic stem cells, known as induced pluripotent stem (iPS) cells, and transforming those, in turn, to their cell type of choice. But Buttermore, Wainger and colleagues found that they were able to bypass the somewhat cumbersome step of creating iPS cells.

By adding just five signals (namely, transcription factors) to skin cells from mice and from patients with an inherited pain disorder, they were able to create nociceptors—specialized pain-sensing neurons. Two of these signals hadn’t been known before and were found by examining mature nociceptors from mice.

In tests, the lab-created mouse nociceptors closely resembled “natural” neurons. They functioned, responded to different pain triggers and became hypersensitized to pain just like their real-world counterparts. The lab-created human nociceptors still have some hoops to jump through, but by early measures, they appear to “beautifully model” patients’ neuropathies and pain hypersensitivities, says Clifford Woolf, MB, BCh, PhD, senior investigator on the project and director of the Kirby Center.

The nociceptor model is already revealing new aspects of pain physiology and could ultimately provide a much more realistic platform for testing new drugs. Woolf, who also co-leads the Harvard Stem Cell Institute’s Nervous System Diseases Program has already found this to be true for amyotrophic lateral sclerosis (ALS).

The nociceptor project’s success was a long time in coming. The team had first tried to make nociceptors from embryonic stem cells. “We spent three years trying to recapitulate the developmental steps involved, and it turned out to be a total bust,” said Woolf.

But he refused to pull the plug, and the approach that finally worked turns out to be the most expedient and the most clinically relevant: Skin cells can be collected directly from patients, making it easier to model their different kinds of chronic pain—neuropathies caused by genetic mutations, diabetes or even chemotherapy, which can sensitize patients to pain.

“We’re trying to get to clinical trials with more success,” says Buttermore. “Hopefully, we’ll avoid drugs that don’t work.”

http://vectorblog.org/2014/12/modeling-pain-in-a-dish-nociceptors-made-from-skin-recreate-pain-physiology/?utm_campaign=Q1%202015%20Innovation%20Social&utm_medium=social&utm_source=twitter&utm_content=Vector%20Pain%20in%20a%20Dish&sf34613949=1

PSORIASIS COULD LEAD TO HIGH BP

Patients with severe psoriasis - a common skin disease - are more likely to have uncontrolled hypertension, found a study.

The researchers defined uncontrolled hypertension as blood pressure measured to be at least 140/90 mm Hg.

Additional findings indicated that there is a significant dose-response relationship, meaning that the likelihood of uncontrolled hypertension increases with greater psoriasis severity.

The patients with the highest risk of having uncontrolled blood pressure, are those with moderate to severe psoriasis, which is defined as having at least three percent of one's body surface affected by the disease, the findings showed.

"To our knowledge, ours is the first study to evaluate the effect of objectively determined psoriasis severity on blood pressure control," said co-first author on the study Junko Takeshita from the University of Pennsylvania in the US.

The researchers examined data from a random sample of psoriasis patients included in The Health Improvement Network (THIN), an electronic medical database based in Britain.

"Over the last several years, studies have shown that psoriasis, specifically severe psoriasis, is an independent risk factor for a variety of comorbidities, putting patients suffering with this common skin disease at an increased risk of other conditions such as heart attack and stroke," Takeshita added.

"Knowing that psoriasis is tied to other health conditions, it's vital that we have a better understanding of the systemic effects it has on other areas of the body so that we can more closely monitor these patients and provide better and preventative care" Takeshita concluded.

The findings appeared in the journal JAMA Dermatology.

Damaged Small Nerves Lead To Damaged Longer Nerves

Today's post from painnewsnetwork.org (see link below) covers a story that appeared about three weeks ago on this blog but this time it's much more understandable for the casual neuropathy reader. It talks about the discovery that the early symptoms of neuropathy that are often diagnosed as small fibre neuropathy, are in fact a warning signal of much greater deterioration of the longer nerves in the future. Many of you reading this will be having a 'duh' moment of 'So tell us something we didn't already know!' However, medical science likes things neatly packaged and labelled and the idea that small fibre neuropathy could lead to damage of other nerve sorts and much wider symptoms was not easily accepted. It was always thought that the longer nerves degraded first but these recent studies show that in fact it is just as likely that the short nerves begin the process leading to longer nerve degeneration. It's an interesting article which if you have any of the tingling, burning symptoms we're so accustomed too, may apply to you too.

Neuropathy More Damaging Than Previously Thought
By Pat Anson, Editor April 11, 2016
 
A tingling, sometimes painful sensation in the hands and feet – the early stages of small fiber neuropathy -- may be more damaging to the peripheral nervous system than previously thought, according to new research published in JAMA Neurology.

A 3-year study by Johns Hopkins neurologists found that patients with small fiber neuropathy showed unexpected deterioration over the entire length of sensory nerve fibers, not just nerve fibers at the surface of the skin.

“I liken small fiber neuropathy to the canary in the coal mine,” says senior author Michael Polydefkis, MD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab. “It signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people’s quality of life. The results of this new study add urgency to the need for more screening of those with the condition and faster intervention.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association. Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or alcoholism.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can eventually lead to injuries, chronic foot ulcers and even amputations.

Polydefkis and his colleagues found that small fiber nerve damage occurs even in patients with prediabetes, and the early symptoms of burning pain may be less benign than most clinicians think. Routine nerve tests, like nerve conduction, often fail to identify nerve damage because they mostly assess injury to large diameter nerve fibers.

In an effort to measure nerve damage more accurately, Johns Hopkins researchers took small samples of skin — the size of a large freckle — from 52 patients diagnosed with small fiber neuropathy and from 10 healthy controls. Skin samples were taken from the ankle, the lower thigh near the knee and the upper thigh. Three years later, samples from the same area in the same patients were taken for comparison.

Microscopic analysis of the skin samples showed that patients with small fiber neuropathy initially had fewer nerve fibers on the ankle compared to the upper thigh, demonstrating the most nerve damage was further down the leg. But after three years, researchers found that longer nerve fibers were also lost from the lower and upper thighs, something that was not expected.

“We are all taught in medical school that the longest nerves degrade first, and we show that this isn’t always the case,” says lead author Mohammad Khoshnoodi, MD, assistant professor of neurology at Johns Hopkins,

Patients with prediabetes or diabetes had at least 50 percent fewer small nerve fibers in their ankles initially than those participants with an unknown cause for their small fiber neuropathy, indicating these patients started the study with more damage to their small nerve fibers.

The patients with prediabetes continued to have worsening damage to their small nerve fibers over the course of the study, losing about 10 percent of their nerve fiber density each year at all sites tested along the leg. Patients with diabetes also lost similar rates of nerve fibers along the three sites of the leg.

“I expected that people with diabetes would do worse, but I didn’t really expect people with prediabetes to experience a similar rate of degradation of their small nerve fibers,” says Polydefkis.

Researchers caution that their study was small, and that other factors such as high blood sugar, smoking, high blood pressure and high cholesterol, may also have contributed to the decline in nerve fibers.

http://www.painnewsnetwork.org/stories/2016/4/11/neuropathy-more-damaging-than-previously-thought

NEW INFORMATION ABOUT HOW NEURONS ACT COULD LEAD TO BRAIN DISORDER ADVANCEMENTS

Neurons are electrically charged cells, located in the nervous system, that interpret and transmit information using electrical and chemical signals. Now, researchers at the University of Missouri have determined that individual neurons can react differently to electrical signals at the molecular level and in different ways -- even among neurons of the same type. This variability may be important in discovering underlying problems associated with brain disorders and neural diseases such as epilepsy.

"Genetic mutations found in neurological disorders create imbalances in the inward and outward flow of electrical current through cells," said David Schulz, associate professor in the Division of Biological Sciences in the College of Arts and Science and a researcher in the Interdisciplinary Neuroscience Program at MU. "Often, neurons react to electrical signals, or voltage, and compensate by altering their own electrical outputs. The variability in these imbalances, even among multiple cells of the same kind within the brain, is one of the major problems scientists face when trying to design therapeutics for disorders like epilepsy. Seizures in individuals can be caused by different imbalances -- therefore getting to the root of how neurons act individually makes our studies important."

Schulz and his team previously proved that two identical neurons can reach the same electrical activity in different ways. In his new study, Schulz hypothesized that neurons might use the cell's genetic code, or its messenger RNA (mRNA), to "fine tune" the production of proteins, helping individual cells react accordingly.

Using clusters of neurons obtained from Jonah crabs, Schulz and his team experimentally altered electrical input and output in the neurons and measured the messenger RNA (mRNA) levels found within the cells. Invertebrates like crabs are useful in neuroscience research because their neurons are simple enough to observe and study, but advanced enough that they can be "scaled up" to apply to higher organisms, Schulz said.

They found that when normal patterns of stimulation were maintained, cells engaged the correct ratios of mRNA to produce the proteins needed to help keep electrical impulses in order; however, when normal patterns of activity were not maintained, this fundamentally changed the cells at the molecular level.

"We were the first to show that the correct ratios of mRNAs are actively maintained by the actual activity or voltage of the cell, and not chemical feedback," Schulz said. "These results represent a novel aspect of regulation that might be useful for developing therapeutics for neuronal disorders later."

Schulz' study, "Activity-dependent feedback regulates correlated ion channel mRNA levels in single identified motor neurons," was published in the August 18^th edition ofCurrent Biology.

ORGANIC ELECTRONICS COULD LEAD TO CHEAP WEARABLE MEDICAL SENSORS

Future fitness trackers could soon add blood-oxygen levels to the list of vital signs measured with new technology developed by engineers at UC Berkeley.

"There are various pulse oximeters already on the market that measure pulse rate and blood-oxygen saturation levels, but those devices use rigid conventional electronics, and they are usually fixed to the fingers or earlobe," said Ana Arias, an associate professor of electrical engineering and computer sciences and head of the UC Berkeley team that is developing a new organic optoelectronic sensor.

By switching from silicon to an organic, or carbon-based, design, the researchers were able to create a device that could ultimately be thin, cheap and flexible enough to be slapped on like a Band-Aid during that jog around the track or hike up the hill.

The engineers put the new prototype up against a conventional pulse oximeter and found that the pulse and oxygen readings were just as accurate.

The research team reported its findings in the journal Nature Communications.

Giving silicon a run for its money

A conventional pulse oximeter typically uses light-emitting diodes (LEDs) to send red and infrared light through a fingertip or earlobe. Sensors detect how much light makes it through to the other side. Bright, oxygen-rich blood absorbs more infrared light, while the darker hues of oxygen-poor blood absorb more red light. The ratio of the two wavelengths reveals how much oxygen is in the blood.

For the organic sensors, Arias and her team of graduate students -- Claire Lochner, Yasser Khan and Adrien Pierre -- used red and green light, which yield comparable differences to red and infrared when it comes to distinguishing high and low levels of oxygen in the blood.

Using a solution-based processing system, the researchers deposited the green and red organic LEDs and the translucent light detectors onto a flexible piece of plastic. By detecting the pattern of fresh arterial blood flow, the device can calculate a pulse.

"We showed that if you take measurements with different wavelengths, it works, and if you use unconventional semiconductors, it works," said Arias. "Because organic electronics are flexible, they can easily conform to the body."

Arias added that because the components of conventional oximeters are relatively expensive, healthcare providers will choose to disinfect them if they become contaminated. In contrast, "organic electronics are cheap enough that they are disposable like a Band-Aid after use," she said.