Date:
May 24, 2017

Source:
Karolinska Institutet

Summary:
The human brain is much better than previously thought at discovering and avoiding disease, a new study reports. Our sense of vision and smell alone are enough to make us aware that someone has a disease even before it breaks out. And not only aware – we also act upon the information and avoid sick people.

 

Our sense of vision and smell alone are enough to make us aware that someone has a disease even before it breaks out. And not only aware – we also act upon the information and avoid sick people.
Credit: © Augustino / Fotolia

 

 

The human brain is much better than previously thought at discovering and avoiding disease, a new study led by researchers at Karolinska Institutet in Sweden reports. Our sense of vision and smell alone are enough to make us aware that someone has a disease even before it breaks out. And not only aware — we also act upon the information and avoid sick people. The study is published in the scientific journal Proceedings of the National Academy of Sciences (PNAS).

The human immune system is effective at combating disease, but since it entails a great deal of energy expenditure disease avoidance should be part of our survival instinct. A new study now shows that this is indeed the case: the human brain is better than previously thought at discovering early-stage disease in others. Moreover, we also have a tendency to act upon the signals by liking infected people less than healthy ones.

“The study shows us that the human brain is actually very good at discovering this and that this discovery motivates avoidance behaviour,” says principal investigator Professor Mats Olsson at Karolinska Institutet’s Department of Clinical Neuroscience.

By injecting harmless sections of bacteria, the researchers activated the immune response in participants, who developed the classic symptoms of disease — tiredness, pain and fever — for a few hours, during which time smell samples were taken from them and they were photographed and filmed. The injected substance then disappeared from their bodies and with it the symptoms.

Another group of participants were then exposed to these smells and images as well as those of healthy controls, and asked to rate how much they liked the people, while their brain activities were measured in an MR scanner.

They were then asked to state, just by looking at the photographs, which of the participants looked sick, which they considered attractive and which they might consider socialising with.

“Our study shows a significant difference in how people tend to prefer and be more willing to socialise with healthy people than those who are sick and whose immune system we artificially activated,” says Professor Olsson. “We can also see that the brain is good at adding weak signals from multiple senses relating to a person’s state of health.”

This he sees as biological confirmation of the argument that survival naturally entails avoiding infection.

“Common sense tells us that there should be a basic behavioural repertoire that assists the immune system. Avoidance, however, does not necessarily apply if you have a close relationship with the person who is ill,” says Professor Olsson. “For instance, there are few people other than your children who you’d kiss when they have a runny nose. In other words, a disease signal can enhance caring behaviour in close relationships. With this study, we demonstrate that the brain is more sensitive to those signals than we once thought.”

The research has been carried out in collaboration with several parties, especially with the Stress Research Institute at Stockholm University.


Story Source:

Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.


Journal Reference:

  1. Christina Regenbogen, John Axelsson, Julie Lasselin, Danja K. Porada, Tina Sundelin, Moa G. Peter, Mats Lekander, Johan N. Lundström, Mats J. Olsson. Behavioral and neural correlates to multisensory detection of sick humans. Proceedings of the National Academy of Sciences, 2017; 201617357 DOI: 10.1073/pnas.1617357114

 

Source: Karolinska Institutet. “The brain detects disease in others even before it breaks out.” ScienceDaily. ScienceDaily, 24 May 2017. <www.sciencedaily.com/releases/2017/05/170524084650.htm>.

Date:
May 23, 2017

Source:
University of Cambridge

Summary:
A study carried out in mice may help explain why dieting can be an inefficient way to lose weight: key brain cells act as a trigger to prevent us burning calories when food is scarce.

 

Why dieting doesn’t always result in losing weight. Key brain cells act as a trigger to prevent us burning calories when food is scarce.

 

 

A study carried out in mice may help explain why dieting can be an inefficient way to lose weight: key brain cells act as a trigger to prevent us burning calories when food is scarce.

“Weight loss strategies are often inefficient because the body works like a thermostat and couples the amount of calories we burn to the amount of calories we eat,” says Dr Clémence Blouet from the Metabolic Research Laboratories at University of Cambridge. “When we eat less, our body compensates and burns fewer calories, which makes losing weight harder. We know that the brain must regulate this caloric thermostat, but how it adjusts calorie burning to the amount of food we’ve eaten has been something of a mystery.”

Now, in research published in the open access journal eLife, a team of researchers has identified a new mechanism through which the body adapts to low caloric intake and limits weight loss in mice. Mice share a number of important biological and physiological similarities with humans and so are a useful model for studying how our bodies work.

The researchers tested the role of a group of neurons in a brain region known as the hypothalamus. These ‘agouti-related neuropeptide’ (AGRP) neurons are known for their major role in the regulation of appetite: when activated, they make us eat, but when fully inhibited they can lead to almost complete anorexia.

The team used a genetic trick to switch the AGRP neurons ‘on’ and ‘off’ in mice so that they could rapidly and reversibly manipulate the neurons’ activity. They studied the mice in special chambers than can measure energy expenditure, and implanted them with probes to remotely measure their temperature, a proxy for energy expenditure, in different contexts of food availability.

The researchers demonstrated that AGRP neurons are key contributors to the caloric thermostat that regulates our weight, regulating how many calories we burn. The findings suggest that when activated, these neurons make us hungry and drive us to eat — but when there is no food available, they act to spare energy, limiting the number of calories that we burn and hence our weight loss.

As soon as food becomes available and we start eating, the action of the AGRP neurons is interrupted and our energy expenditure goes back up again to normal levels.

In addition, the researchers also describe a mechanism through which AGRP neurons regulate their activity by detecting how much energy we have on-board and then controlling how many calories we burn.

“Our findings suggest that a group of neurons in the brain coordinate appetite and energy expenditure, and can turn a switch on and off to burn or spare calories depending on what’s available in the environment,” says Dr Blouet, who led the study. “If food is available, they make us eat, and if food is scarce, they turn our body into saving mode and stop us from burning fat.”

“While this mechanism may have evolved to help us cope with famine, nowadays most people only encounter such a situation when they are deliberately dieting to lose weight. Our work helps explain why for these people, dieting has little effect on its own over a long period. Our bodies compensate for the reduction in calories.”

Dr Luke Burke, the study’s first author, adds: “This study could help in the design of new or improved therapies in future to help reduce overeating and obesity. Until then, best solution for people to lose weight — at least for those who are only moderately overweight — is a combination of exercise and a moderate reduction in caloric intake.”


Story Source:

Materials provided by University of Cambridge. The original story is licensed under a Creative Commons License. Note: Content may be edited for style and length.


Journal Reference:

  1. Luke K Burke, Tamana Darwish, Althea R Cavanaugh, Sam Virtue, Emma Roth, Joanna Morro, Shun-Mei Liu, Jing Xia, Jeffrey W Dalley, Keith Burling, Streamson Chua, Toni Vidal-Puig, Gary J Schwartz, Clémence Blouet. mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice. eLife, 2017; 6 DOI: 10.7554/eLife.22848

 

Source: University of Cambridge. “Why our brain cells may prevent us burning fat when we’re dieting.” ScienceDaily. ScienceDaily, 23 May 2017. <www.sciencedaily.com/releases/2017/05/170523082022.htm>.

Pre-clinical study links gut microbes, immune system to a genetic disorder that can cause stroke and seizures

Date:
May 18, 2017

Source:
NIH/National Institute of Neurological Disorders and Stroke

Summary:
Bacteria in the gut can influence the structure of the brain’s blood vessels, and may be responsible for producing malformations that can lead to stroke or epilepsy, new research suggests. The study adds to an emerging picture that connects intestinal microbes and disorders of the nervous system.

 

A study in mice and humans suggests that bacteria in the gut can influence the structure of the brain’s blood vessels, and may be responsible for producing malformations that can lead to stroke or epilepsy. The research, published in Nature, adds to an emerging picture that connects intestinal microbes and disorders of the nervous system. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH).

Cerebral cavernous malformations (CCMs) are clusters of dilated, thin-walled blood vessels that can lead to seizures or stroke when blood leaks into the surrounding brain tissue. A team of scientists at the University of Pennsylvania investigated the mechanisms that cause CCM lesions to form in genetically engineered mice and discovered an unexpected link to bacteria in the gut. When bacteria were eliminated the number of lesions was greatly diminished.

“This study is exciting because it shows that changes within the body can affect the progression of a disorder caused by a genetic mutation,” said Jim I. Koenig, Ph.D., program director at NINDS.

The researchers were studying a well-established mouse model that forms a significant number of CCMs following the injection of a drug to induce gene deletion. However, when the animals were relocated to a new facility, the frequency of lesion formation decreased to almost zero.

“It was a complete mystery. Suddenly, our normally reliable mouse model was no longer forming the lesions that we expected,” said Mark L. Kahn, M.D., professor of medicine at the University of Pennsylvania, and senior author of the study. “What’s interesting is that this variability in lesion formation is also seen in humans, where patients with the same genetic mutation often have dramatically different disease courses.”

While investigating the cause of this sudden variability, Alan Tang, a graduate student in Dr. Kahn’s lab, noticed that the few mice that continued to form lesions had developed bacterial abscesses in their abdomens — infections that most likely arose due to the abdominal drug injections. The abscesses contained Gram-negative bacteria, and when similar bacterial infections were deliberately induced in the CCM model animals, about half of them developed significant CCMs.

“The mice that formed CCMs also had abscesses in their spleens, which meant that the bacteria had entered the bloodstream from the initial abscess site,” said Tang. “This suggested a connection between the spread of a specific type of bacteria through the bloodstream and the formation of these blood vascular lesions in the brain.”

The question remained as to how bacteria in the blood could influence blood vessel behavior in the brain. Gram-negative bacteria produce molecules called lipopolysaccharides (LPS) that are potent activators of innate immune signaling. When the mice received injections of LPS alone, they formed numerous large CCMs, similar to those produced by bacterial infection. Conversely, when the LPS receptor, TLR4, was genetically removed from these mice they no longer formed CCM lesions. The researchers also found that, in humans, genetic mutations causing an increase in TLR4 expression were associated with a greater risk of forming CCMs.

“We knew that lesion formation could be driven by Gram-negative bacteria in the body through LPS signaling,” said Kahn. “Our next question was whether we could prevent lesions by changing the bacteria in the body.”

The researchers explored changes to the body’s bacteria (microbiome) in two ways. First, newborn CCM mice were raised in either normal housing or under germ-free conditions. Second, these mice were given a course of antibiotics to “reset” their microbiome. In both the germ-free conditions and following the course of antibiotics, the number of lesions was significantly reduced, indicating that both the quantity and quality of the gut microbiome could affect CCM formation. Finally, a drug that specifically blocks TLR4 also produced a significant decrease in lesion formation. This drug has been tested in clinical trials for the treatment of sepsis, and these findings suggest a therapeutic potential for the drug in the treatment of CCMs, although considerable research remains to be done.

“These results are especially exciting because they show that we can take findings in the mouse and possibly apply them at the human patient population,” said Koenig. “The drug used to block TLR4 has already been tested in patients for other conditions, and it may show therapeutic potential in the treatment of CCMs, although considerable research still remains to be done.”

Kahn and his colleagues plan to continue to study the relationship between the microbiome and CCM formation, particularly as it relates to human disease. Although specific gene mutations have been identified in humans that can cause CCMs to form, the size and number varies widely among patients with the same mutations. The group next aims to test the hypothesis that differences in the patients’ microbiomes could explain this variability in lesion number.


Story Source:

Materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Content may be edited for style and length.


Journal Reference:

  1. Alan T. Tang, Jaesung P. Choi, Jonathan J. Kotzin, Yiqing Yang, Courtney C. Hong, Nicholas Hobson, Romuald Girard, Hussein A. Zeineddine, Rhonda Lightle, Thomas Moore, Ying Cao, Robert Shenkar, Mei Chen, Patricia Mericko, Jisheng Yang, Li Li, Ceylan Tanes, Dmytro Kobuley, Urmo Võsa, Kevin J. Whitehead, Dean Y. Li, Lude Franke, Blaine Hart, Markus Schwaninger, Jorge Henao-Mejia, Leslie Morrison, Helen Kim, Issam A. Awad, Xiangjian Zheng, Mark L. Kahn. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature, 2017; 545 (7654): 305 DOI: 10.1038/nature22075

 

Source: NIH/National Institute of Neurological Disorders and Stroke. “Brain blood vessel lesions tied to intestinal bacteria: Pre-clinical study links gut microbes, immune system to a genetic disorder that can cause stroke and seizures.” ScienceDaily. ScienceDaily, 18 May 2017. <www.sciencedaily.com/releases/2017/05/170518140232.htm>.

CTTI Recommendations on Registry Trials

 

Last week, Target Health was honored as Dr. Jules Mitchel joined Dr. John Laschinger (FDA), for a Clinical Trials Transformation Initiative (CTTI) Webinar on CTTI’s recommendations on how to design and use registries for prospective clinical trials. The Webinar attracted more than 200 participants and the questions from the attendees were all “on target.” According to the CTTI website, “CTTI’s recommendations for registry assessment and design can assist in making embedded clinical trials suitable for regulatory purposes. By using registries as a reusable platform for evidence generation, we can improve the efficiency of clinical trials and bring new treatments to patients faster.”

 

The recommendations are now posted on the CTTI website.

 

Holden Beach, NC – Pier, Sunset

 

Dr. Mitchel is in Israel right now at the Biomed meeting, but had the pleasure of being in North Carolina last Wednesday. Our good friend and colleague James Farley was at the meeting and shared some his great photos, in between an intense day of consulting.

 

It’s been a while, since James, photographer extraordinaire, has sent out any photos as he has recently transitioned all of his landscape, architectural and macro/wildlife photography to Advanced Fine Art. These photos were taken at Holden Beach, NC  in mid-April, during Spring Break.

 

According to James, make sure to zoom-in on the viewer! Even on this resampled version, there is a lot of detail!  :-)))  Shot on his Canon 5D Mark IV and 17mm Tilt-shift. The photo under the pier was a 4-second exposure.

 

©Advanced Fine Art 2017

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

Filed Under News | Leave a Comment

Promise in Light Therapy to Treat Chronic Pain

Rats were exposed to room light and fitted with contact lenses, one shown here, that allowed the green spectrum wavelength to pass through the lenses. (Photo: Bob Demers/UANews)

 

Chronic pain is any pain that lasts for more than three 1) ___. The pain can become progressively worse and reoccur intermittently, outlasting the usual healing process. After injured tissue heals, pain is expected to stop once the underlying cause is treated, according to conventional ideas of pain. Chronic pain afflicts over 100 million people across the United States. It diminishes their productivity and their quality of 2) ___ and costs hundreds of billions of dollars each year to medically manage. It shatters people’s emotional wellbeing, tears apart families and claims lives through suicides and accidental drug overdoses. But now researchers at the University of Arizona have found promise in a novel, non-pharmacological approach to managing chronic 3) ___ — treating it with green light-emitting diodes (LED). Results of the study appear in the February 2017 issue of the journal Pain.

 

In the study, rats with neuropathic pain that were bathed in green LED showed more tolerance for thermal and tactile stimulus than rats that were not bathed in 4) ___ LED. In both cases, and of note, no side effects from the therapy were observed, nor was motor or visual performance impaired. The beneficial effects lasted for four days after the rats’ last exposure to the green 5) ___. In addition, no tolerance to the therapy was noted. “Chronic pain is a serious issue afflicting millions of people of all ages,“ says Mohab Ibrahim, UA assistant professor of Anesthesiology and Pharmacology and lead author of the study. “Pain physicians are trained to manage chronic pain in several ways including medication and interventional procedures in a multimodal approach. Opioids, while having many benefits for managing pain, come with serious side 6) ___. We need safer, effective and affordable approaches, used in conjunction with our current tools, to manage chronic pain. While the results of the green LED are still preliminary, it holds significant promise to manage some types of chronic pain.“

 

To receive the green LED exposure, one group of rats were placed in clear plastic containers that were affixed with green LED strips, allowing them to be bathed in green light. Another group of rats was exposed to room light and fitted with contact lenses that allowed the green spectrum wavelength to pass through. Both groups benefitted from the green LED exposure. However, another group of rats was fitted with opaque contact lenses, which blocked the green light from entering their 7) ___ system. These rats did not benefit from the green LED exposure. “While the pain-relieving qualities of green LED are clear, exactly how it works remains a puzzle,” says Rajesh Khanna, UA associate professor of Pharmacology and senior author of the study. “Early studies show that green light is increasing the levels of circulating endogenous opioids, which may explain the pain-relieving effects. Whether this will be observed in 8) ___ is not yet known and needs further work.” Todd Vanderah, professor and chair of Pharmacology and co-author of the study stated that novel non-pharmacological methods are desperately needed to help the millions of individuals suffering from 9) ___ pain. The initial results hint of green LED altering the levels of endogenous substances that may inhibit pain and possibly decrease inflammation of the nervous system is a great breakthrough, he says. Such therapy is inexpensive and can easily be used worldwide.

 

The researchers are now conducting a clinical trial using green LED therapy in people with fibromyalgia, a common source of chronic pain. The hope is that green LED light therapy will alleviate the participants’ pain when used alone or in combination with other treatments including physical 10) ___ or low-dose analgesics.

 

Sources: University of Arizona. “Promise in light therapy to treat chronic pain.” (February 28, 2017); Mohab M. Ibrahim, Amol Patwardhan, Kerry B. Gilbraith, Aubin Moutal, Xiaofang Yang, Lindsey A. Chew, Tally Largent-Milnes, T. Philip Malan, Todd W. Vanderah, Frank Porreca, Rajesh Khanna. Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. PAIN, 2017; 158 (2): 347

 

ANSWERS: 1) months;  2)  life;  3)  pain;  4)  green;  5)  LED;  6)  effects;  7)  visual;  8)  humans;  9)  chronic;  10)  therapy

 

Chronic Pain

Descartes’ pain pathway: “Particles of heat“ (A) activate a spot of skin (B) attached by a fine thread (cc) to a valve in the brain (de) where this activity opens the valve, allowing the animal spirits to flow from a cavity (F) into the muscles causing them to flinch from the stimulus, turn the head and eyes toward the affected body part, and move the hand and turn the body protectively. Illustration of the pain pathway in Rene Descartes’ Traite de l’homme (Treatise of Man) 1664. The long fiber running from the foot to the cavity in the head is pulled by the heat and releases a fluid that makes the muscles contract. Graphic credit: Rene Descartes – Copied from a 345 year old book, Traite de l’homme, Public Domain; Wikipedia Commons

 

Pain has accompanied human beings since the moment this species appeared on Earth. From that moment on, and throughout his long history mankind has tried not only to look for the causes of pain but also to find remedies to relieve pain. The concept of pain has remained a topic of long debate since its emergence in ancient times. The initial ideas of pain were formulated in both the East and the West before 1800. Since 1800, due to the development of experimental sciences, different theories of pain have emerged and become central topics of debate. However, the existing theories of pain may be appropriate for the interpretation of some aspects of pain, but are not yet comprehensive. The history of pain problems is as long as that of human beings; however, the understanding of pain mechanisms is still far from sufficient. Thus, intensive research is required. This historical review mainly focuses on the development of pain theories and the fundamental discoveries in this field. Other historical events associated with pain therapies and remedies are beyond the scope of this review. As long as humans have experienced pain, they have given explanations for its existence and sought soothing agents to dull or cease the painful sensation. Archaeologists have uncovered clay tablets dating back as far as 5,000 BCE which reference the cultivation and use of the opium poppy to bring joy and cease pain. In 800 BCE, the Greek writer Homer wrote in his epic, The Odyssey, of Telemachus, a man who used opium to soothe his pain and forget his worries. While some cultures researched analgesics and allowed or encouraged their use, others perceived pain to be a necessary, integral sensation. Physicians of the 19th century used pain as a diagnostic tool, theorizing that a greater amount of personally perceived pain was correlated to a greater internal vitality, and as a treatment in and of itself, inflicting pain on their patients to rid the patient of evil and unbalanced humors. This article focuses both on the history of how pain has been perceived across time and culture, but also how malleable an individual’s perception of pain can be due to factors like situation, their visual perception of the pain, and previous history with pain.

 

Because of the only relatively recent discovery of neurons and how they conduct and interpret signals, including sensations such as pain, within the body, various theories have been proposed as to the causes of pain and its role or function. Even within seemingly limited groups, such as the ancient Greeks, there were competing theories as to the root cause of pain. Aristotle did not include a sense of pain when he enumerated the five senses; he, like Plato before him, saw pain and pleasure not as sensations but as emotions (“passions of the soul“). Alternatively, Hippocrates believed that pain was caused by an imbalance in the vital fluids of a human. At this time, neither Aristotle nor Hippocrates believed that the brain had any role to play in pain processing but rather implicated the heart as the central organ for the sensation of pain. In the 11th century, Avicenna theorized that there were a number of feeling senses including touch, pain and titillation.

 

Portrait of Rene Descartes: Portrait credit: By After Frans Hals – Andre Hatala [[e.a.] (1997) De eeuw van Rembrandt, Bruxelles: Credit communal de Belgique, ISBN 2-908388-32-4., Public Domain, Wikipedia Commons

 

Even just prior to the scientific Renaissance in Europe, pain was not well understood and it was theorized that pain existed outside of the body, perhaps as a punishment from God, with the only management treatment being prayer. Again, even within the confined group of religious, practicing Christians, more than one theory arose. Alternatively, pain was also theorized to exist as a test or trial on a person. In this case, pain was inflicted by god onto person to reaffirm their faith, or in the example of Jesus, to lend legitimacy and purpose to a trial through suffering. In his 1664 Treatise of Man, Rene Descartes theorized that the body was more similar to a machine, and that pain was a disturbance that passed down along nerve fibers until the disturbance reached the brain. This theory transformed the perception of pain from a spiritual, mystical experience to a physical, mechanical sensation meaning that a cure for such pain could be found by researching and locating pain fibers within the bodies rather than searching for an appeasement for god. This also moved the center of pain sensation and perception from the heart to the brain. Descartes proposed his theory by presenting an image of a man’s hand being struck by a hammer. In between the hand and the brain, Descartes described a hollow tube with a cord beginning at the hand and ending at a bell located in the brain. The blow of the hammer would induce pain in the hand, which would pull the cord in the hand and cause the bell located in the brain to ring, indicating that the brain had received the painful message. Researchers began to pursue physical treatments such as cutting specific pain fibers to prevent the painful signal from cascading to the brain.

 

 

Scottish anatomist Charles Bell proposed in 1811 that there exist different kinds of sensory receptors, each adapted to respond to only one stimulus type. In 1839 Johannes Muller, having established that a single stimulus type (e.g., a blow, electric current) can produce different sensations depending on the type of nerve stimulated, hypothesized that there is a specific energy, peculiar to each of five nerve types that serve Aristotle’s five senses, and that it is the type of energy that determines the type of sensation each nerve produces. He considered feelings such as itching, pleasure, pain, heat, cold and touch to be varieties of the single sense he called “feeling and touch.“ Muller’s doctrine killed off the ancient idea that nerves carry actual properties or incorporeal copies of the perceived object, marking the beginning of the modern era of sensory psychology, and prompted others to ask, do the nerves that evoke the different qualities of touch and feeling have specific characteristics?

 

Filippo Pacini had isolated receptors in the nervous system which detect pressure and vibrations in 1831. Georg Meissner and Rudolf Wagner described receptors sensitive to light touch in 1852; and Wilhelm Krause found a receptor that responds to gentle vibration in 1860. Moritz Schiff was first to definitively formulate the specificity theory of pain when, in 1858, he demonstrated that touch and pain sensations traveled to the brain along separate spinal cord pathways. In 1882 Magnus Blix reported that specific spots on the skin elicit sensations of either cold or heat when stimulated, and proposed that “the different sensations of cool and warm are caused by stimulation of different, specific receptors in the skin.“ Max von Frey found and described these heat and cold receptors and, in 1896, reported finding “pain spots“ on the skin of human subjects. Von Frey proposed there are low threshold cutaneous spots that elicit the feeling of touch, and high threshold spots that elicit pain, and that pain is a distinct cutaneous sensation, independent of touch, heat and cold, and associated with free nerve endings.

 

In the first volume of his 1794 Zoonomia; or the Laws of Organic Life, Erasmus Darwin supported the idea advanced in Plato’s Timaeus, that pain is not a unique sensory modality, but an emotional state produced by stronger than normal stimuli such as intense light, pressure or temperature. Wilhelm Erb, in 1874, also argued that pain can be generated by any sensory stimulus, provided it is intense enough, and his formulation of the hypothesis became known as the intensive theory. Alfred Goldscheider (1884) confirmed the existence of distinct heat and cold sensors, by evoking heat and cold sensations using a fine needle to penetrate to and electrically stimulate different nerve trunks, bypassing their receptors. Though he failed to find specific pain sensitive spots on the skin, Goldscheider concluded in 1895 that the available evidence supported pain specificity, and held the view until a series of experiments were conducted in 1889 by Bernhard Naunyn. Naunyn had rapidly (60-600 times/second) prodded the skin of tabes dorsalis patients, below their touch threshold (e.g., with a hair), and in 6-20 seconds produced unbearable pain. He obtained similar results using other stimuli including electricity to produce rapid, sub-threshold stimulation, and concluded pain is the product of summation. In 1894 Goldscheider extended the intensive theory, proposing that each tactile nerve fiber can evoke three distinct qualities of sensation – tickle, touch and pain – the quality depending on the intensity of stimulation; and extended Naunyn’s summation idea, proposing that, over time, activity from peripheral fibers may accumulate in the dorsal horn of the spinal cord, and “spill over“ from the peripheral fiber to a pain-signaling spinal cord fiber once a threshold of activity has been crossed. The British psychologist, Edward Titchener, pronounced in his 1896 textbook, “excessive stimulation of any sense organ or direct injury to any sensory nerve occasions the common sensation of pain.“

 

By the mid-1890s, specificity was mainly backed by physiologists (prominently by von Frey) and clinicians; and the intensive theory received most support from psychologists. But after Henry Head in England published a series of clinical observations between 1893 and 1896, and von Frey’s experiments between 1894 and 1897, the psychologists migrated to specificity almost en masse, and by century’s end, most textbooks on physiology and psychology were presenting pain specificity as fact, with Titchener in 1898 now placing “the sensation of pain“ alongside that of pressure, heat and cold. Though the intensive theory no longer featured prominently in textbooks, Goldscheider’s elaboration of it nevertheless stood its ground in opposition to von Frey’s specificity at the frontiers of research, and was supported by some influential theorists well into the mid-twentieth century. William Kenneth Livingston advanced a summation theory in 1943, proposing that high intensity signals, arriving at the spinal cord from damage to nerve or tissue, set up a reverberating, self-exciting loop of activity in a pool of interneurons, and once a threshold of activity is crossed, these interneurons then activate “transmission“ cells which carry the signal to the brain’s pain mechanism.  The reverberating interneuron activity also spreads to other spinal cord cells that trigger a sympathetic nervous system and somatic motor system response; and these responses, as well as fear and other emotions elicited by pain, feed into and perpetuate the reverberating interneuron activity. A similar proposal was made by RW Gerard in 1951, who proposed also that intense peripheral nerve signaling may cause temporary failure of inhibition in spinal cord neurons, allowing them to fire as synchronized pools, with signal volleys strong enough to activate the pain mechanism. Building on John Paul Nafe’s 1934 suggestion that different cutaneous qualities are the product of different temporal and spatial patterns of stimulation, and ignoring a large body of strong evidence for receptor fiber specificity, DC Sinclair and G Weddell’s 1955 “peripheral pattern theory“ proposed that all skin fiber endings (with the exception of those innervating hair cells) are identical, and that pain is produced by intense stimulation of these fibers. In 1953, Willem Noordenbos had observed that a signal carried from the area of injury along large diameter “touch, pressure or vibration“ fibers may inhibit the signal carried by the thinner “pain“ fibers – the ratio of large fiber signal to thin fiber signal determining pain intensity; hence, we rub a smack. This was taken as a demonstration that pattern of stimulation (of large and thin fibers in this instance) modulates pain intensity.

 

Ronald Melzack and Patrick Wall introduced their “gate control“ theory of pain in the 1965 Science article “Pain Mechanisms: A New Theory“. The authors proposed that both thin (pain) and large diameter (touch, pressure, vibration) nerve fibers carry information from the site of injury to two destinations in the dorsal horn of the spinal cord: transmission cells that carry the pain signal up to the brain, and inhibitory interneurons that impede transmission cell activity. Activity in both thin and large diameter fibers excites transmission cells. Thin fiber activity impedes the inhibitory cells (tending to allow the transmission cell to fire) and large diameter fiber activity excites the inhibitory cells (tending to inhibit transmission cell activity). So, the large fiber (touch, pressure, vibration) activity relative to thin fiber activity at the inhibitory cell, the less pain is felt. The authors had drawn a neural “circuit diagram“ to explain why we rub a smack. They pictured not only a signal traveling from the site of injury to the inhibitory and transmission cells and up the spinal cord to the brain, but also a signal traveling from the site of injury directly up the cord to the brain (bypassing the inhibitory and transmission cells) where, depending on the state of the brain, it may trigger a signal back down the spinal cord to modulate inhibitory cell activity (and so pain intensity). The theory offered a physiological explanation for the previously observed effect of psychology on pain perception. In 1975, well after the time of Descartes, the International Association for the Study of Pain sought a consensus definition for pain, finalizing “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage“ as the final definition. It is clear from this definition that while it is understood that pain is a physical phenomenon, the emotional state of a person, as well as the context or situation associated with the pain also impacts the perception of the nociceptive or noxious event. For example, if a human experiences a painful event associated with any form of trauma (an accident, disease, etc.), a reoccurrence of similar physical pain will not only inflict physical trauma but also the emotional and mental trauma first associated with the painful event. Research has shown that should a similar injury occur to two people, one person who associates large emotional consequence to the pain and the other person who does not, the person who associates a large consequence on the pain event will feel a more intense physical pain that the person who does not associate a large emotional consequence with the pain.

 

Modern research has gathered considerable amounts of evidence that support the theory that pain is not only a physical phenomenon but rather a biopsychosocial phenomenon, encompassing culture, nociceptive stimuli, and the environment in the experience and perception of pain. For example, the Sun Dance is a ritual performed by traditional groups of Native Americans. In this ritual, cuts are made into the chest of a young man. Strips of leather are slipped through the cuts, and poles are tied to the leather. This ritual lasts for hours and undoubtedly generates large amounts of nociceptive signaling, however the pain may not be perceived as noxious or even perceived at all. The ritual is designed around overcoming and transcending the effects of pain, where pain is either welcomed or simply not perceived. Additional research has shown that the experience of pain is shaped by a plethora of contextual factors, including vision. Researchers have found that when a subject views the area of their body that is being stimulated, the subject will report a lowered amount of perceived pain. For example, one research study used a heat stimulation on their subjects’ hands. When the subject was directed to look at their hand when the painful heat stimulus was applied, the subject experienced an analgesic effect and reported a higher temperature pain threshold. Additionally, when the view of their hand was increased, the analgesic effect also increased and vice versa. This research demonstrated how the perception of pain relies on visual input. The use of fMRI to study brain activity confirms the link between visual perception and pain perception. It has been found that the brain regions that convey the perception of pain are the same regions that encode the size of visual inputs. One specific area, the magnitude-related insula of the insular cortex, functions to perceive the size of a visual stimulation and integrate the concept of that size across various sensory systems, including the perception of pain. This area also overlaps with the nociceptive-specific insula, part of the insula that selectively processes nociception, leading to the conclusion that there is an interaction and interface between the two areas. This interaction tells the individual how much relative pain they are experiencing, leading to the subjective perception of pain based on the current visual stimulus.

 

Humans have always sought to understand why they experience pain and how that pain comes about. While pain was previously thought to be the work of evil spirits, it is now understood to be a neurological signal. However, the perception of pain is not absolute and can be impacted by various factors in including the context surrounding the painful stimulus, the visual perception of the stimulus, and an individual’s personal history with pain.

High Blood Pressure Linked to Racial Segregation In Neighborhoods

 

Despite cross-sectional evidence linking racial residential segregation to hypertension prevalence among non-Hispanic blacks, it remains unclear how changes in exposure to neighborhood segregation may be associated with changes in blood pressure. As a result, a study published on line (15 May 2017) in JAMA Internal Medicine, was performed to examine the association of changes in neighborhood-level racial residential segregation with changes in systolic and diastolic blood pressure over a 25-year period.

 

This observational study examined longitudinal data of 2,280 black participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective investigation of adults aged 18 to 30 years who underwent baseline examinations in field centers in 4 US locations from March 25, 1985, to June 7, 1986, and then were re-examined for the next 25 years. Racial residential segregation was assessed using the Getis-Ord Gi statistic, a measure of SD between the neighborhood’s racial composition (i.e., percentage of black residents) and the surrounding area’s racial composition. Segregation was categorized as high (Gi* >1.96), medium (Gi* 0-1.96), and low (Gi* <0). Fixed-effects linear regression modeling was used to estimate the associations of within-person change in exposure to segregation and within-person change in blood pressure while tightly controlling for time-invariant confounders. Data analyses were performed between August 4, 2016, and February 9, 2017. The main outcome measures were within-person changes in systolic and diastolic blood pressure across 6 examinations over 25 years.

 

Results showed that of the 2,280 participants at baseline, 974 (42.7%) were men and 1306 (57.3%) were women. Of these, 1861 (81.6%) were living in a high-segregation neighborhood; 278 (12.2%), a medium-segregation neighborhood; and 141 (6.2%), a low-segregation neighborhood. Systolic blood pressure increased by a mean of 0.16 (95% CI, 0.06-0.26) mm Hg with each 1-SD increase in segregation score after adjusting for interactions of time with age, gender, and field center. Of the 1,861 participants (81.6%) who lived in high-segregation neighborhoods at baseline, reductions in exposure to segregation were associated with reductions in systolic blood pressure. Mean differences in systolic blood pressure were -1.33 (95% CI, -2.26 to -0.40) mm Hg when comparing high-segregation with medium-segregation neighborhoods and -1.19 (95% CI, -2.08 to -0.31) mm Hg when comparing high-segregation with low-segregation neighborhoods after adjustment for time and interactions of time with baseline age, sex, and field center. Changes in segregation were not associated with changes in diastolic blood pressure.

 

According to the authors, decreases in exposure to racial residential segregation are associated with reductions in systolic blood pressure, and that this study adds to the small but growing body of evidence that policies that reduce segregation may have meaningful health benefits. Living in racially segregated neighborhoods is associated with a rise in the blood pressure of black adults, while moving away from segregated areas is associated with a decrease – and significant enough to lead to reductions in heart attacks and strokes, a National Institutes of Health-funded study has found. The findings  offer further evidence that policies to reduce residential racial segregation may have meaningful health benefits, especially for African-Americans, who suffer the highest rates of hypertension of any group in the United States.

 

Residential segregation, the separation of groups into different neighborhoods by race, has long been identified as a major cause of health disparities between blacks and whites. This is the first study to explore whether increases or decreases in residential segregation specifically affect blood pressure.

 

Antibodies From Ebola Survivor Protect Mice and Ferrets Against Related Viruses

 

The fight to contain the 2013-16 Ebola outbreak in West Africa was hampered by the lack of an effective treatment or vaccine. Now, according to an article published in the journal Cell (May 2017), researchers have studied the blood of an Ebola survivor, searching for human antibodies that might effectively treat not only people infected with Ebola virus, but those infected with related viruses as well. Two such antibodies have been identified that hold promise as Ebola treatments.

 

Previously, researchers had discovered only one antibody — from a mouse — capable of protecting mice against multiple different species in the ebolavirus lineage. To find similar broadly protective human antibodies, the authors surveyed 349 human monoclonal antibodies derived from the blood of one survivor of the recent West African Ebola outbreak, which was caused by Zaire ebolavirus. They searched specifically for antibodies that might neutralize all five common ebolavirus species.

 

The authors mined the human immune response to natural infection by the Ebola virus and found two antibodies, ADI-15878 and ADI-15742, which recognized the GP fusion loop-a section of a protein found on the surface of the Ebola virus. By analyzing the structure of these antibodies and testing their action on the viruses, the researchers determined that when given access to the GP fusion loop, the antibodies could likely block the five related ebolaviruses from entering a host cell. Moreover, when tested with human cells in a laboratory setting, the antibodies protected the cells from becoming infected with several different virulent ebolaviruses.

 

To further investigate these findings, the authors tested the antibodies in three animal models: wild-type mice, mice genetically altered to be susceptible to Sudan ebolavirus, and ferrets. Treating wild-type mice with the antibodies after exposure to the Zaire ebolavirus appeared to have a protective effect, as did treating the altered mice after exposure to Sudan ebolavirus. The ferrets experienced a protective effect from the antibodies after exposure to Bundibugyo ebolavirus. However, in the ferrets exposed to the Bundibugyo virus and treated with ADI-15742, the virus developed a single mutation that enabled it to escape the antibody’s effects. In addition, neither antibody conferred protection against the related Lloviu or Marburg viruses when tested in human cells in the laboratory setting. Still, the researchers suggest that these broadly neutralizing antibodies could provide the basis for a candidate treatment, but further exploration is needed. These findings may help inform the development of therapeutic pan-ebolavirus antibodies, as well as vaccines for potential use in the event of another Ebola outbreak.

 

FDA Expands Approved Use of Kalydeco to Treat Additional Mutations of Cystic Fibrosis

 

Cystic fibrosis is a rare disease that affects about 30,000 people in the United States and affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

 

The FDA has expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

 

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to Kalydeco. When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated. Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene, function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

 

Kalydeco is indicated for patients aged 2 and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3 percent of the cystic fibrosis population, impacting approximately 900 patients. Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.

 

Common side effects of Kalydeco include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Kalydeco is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts. Co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of Kalydeco, which may diminish effectiveness, and is therefore not recommended.

 

Kalydeco is manufactured for Boston-based Vertex Pharmaceuticals Inc.

 

Asparagus Ribbon Salad with Lemon, Parmesan & Pine Nuts

I think a well known Manhattan restaurant was the first to introduce ribbon salads; it was either, Union Square Cafe or Gramercy Tavern, I’m not completely sure, but it certainly is a sign of Spring when local asparagus turned into ribbons, start to show up on tables and menus. Let me share my adapted version with you. ©Joyce Hays, Target Health Inc.

 

 

Ingredients

 

2/3 cup pine nuts, toasted, plus extra (toasted) for garnish

1 pound fresh, (organic) locally grown fat asparagus, rinsed

1 lemon, halved

1.5 Tablespoons fresh lemon juice

Zest of 1/2 lemon

Lemon circles, for garnish

2.5 Tablespoons extra virgin olive oil

1 or 2 fresh garlic clove, juiced (squeezed)

1 Tablespoon fresh chives, minced

Pinch turmeric (that comes with black pepper, already mixed in)

Pinch black mustard seeds, toasted

Pinch chili flakes

Pinch, black pepper

1 cup freshly grated Parmesan

 

When I think of Spring, from a cooking perspective, I always think of fresh shoots of asparagus, coming up through mulched garden soil. Since, they’re grown everywhere, buy your fresh ingredients, grown locally . ©Joyce Hays, Target Health Inc.

 

 

Directions

 

1. Rinse the chives, then chop and set aside.

 

Chopping chives. ©Joyce Hays, Target Health Inc.

 

 

2. Toast the pine nuts and the black mustard seeds together. Keep your eye on them and stir constantly so they don’t burn. You’ll have to do them over if they burn. Set aside

 

Toast the pine nuts and black mustard seeds together; then set aside. ©Joyce Hays, Target Health Inc.

 

 

3. Rinse the asparagus, then make the asparagus ribbons

4. To shave the asparagus lay a stalk flat on a cutting board, holding it at the base. Usually, with asparagus recipes, you snap off the tough bottom, that are too tough to eat. In this recipe, don’t snap them off, so you have something to hold onto when you make the asparagus ribbons.

5. Gripping the base, at about where the pale base turns green, use a vegetable peeler to shave the stalk in long, even strips all the way through the tip. Be sure to peel the asparagus ribbon, all the way to the end of the tip. Some of your ribbons will have part or all of the tip and others won’t. That’s okay. The end result will be a lovely variety of ribbons.

6. The best peeler to use, is the Y-shape one. Peel again until you’re about half way through the stalk, then turn over and peel the other side. When you reach the point that the peeler will no longer shave the spear, rest the spear on top of a wooden spoon (or wooden spatula) with a flat handle, to elevate the spear and take the last two or three strips. Peel all of the asparagus spears, like this.

 

Nice to be able to look out your kitchen window onto a garden or a backyard. However, I’m satisfied looking out onto our block with many trees, and over-looking a little church that fills the air with music – choir rehearsal. With my window open or closed, the lovely sound has a calming effect. ©Joyce Hays, Target Health Inc.

 

This is the Y-shape peeler you should use. I got this either at Williams-Sonoma or Amazon. ©Joyce Hays, Target Health Inc.

 

 

7. Combine asparagus shavings, toasted pine nuts and toasted black mustard seeds, in a large salad (serving) bowl, and toss gently. Save some of the nuts for garnish.

 

8. In a small bowl, place the minced chives and the garlic juice in the bottom of the bowl and cover with olive oil. Add lemon juice, zest, turmeric and pinch chili flakes, and whisk until smooth.

 

Easy dressing to make. ©Joyce Hays, Target Health Inc.

 

 

9. Pour this dressing over the asparagus mixture and toss gently with salad servers, to lightly coat all of the asparagus ribbons. Toss gently. Taste and adjust seasoning, if needed.

 

Last toss; about to bring to table. ©Joyce Hays, Target Health Inc.

 

 

10. Finally, sprinkle the salad with the freshly grated parmesan, a few extra (toasted) pine nuts and toss. Place the lemon circles around the bowl for decoration, or on individual plates. Serve immediately.

 

Easy to make and delicious! ©Joyce Hays, Target Health Inc.

 

This is a healthy, truly flavorful salad. With some excellent bread and an icy white wine (or not), you really have enough for a summer lunch and or dinner. ©Joyce Hays, Target Health Inc.

 

Two of the seven theater clubs we support (RoundAbout Theater and Manhattan Theater Club), started years ago with very little financing. They struggled on, in various off Broadway locations, for many years, until today each owns several Broadway theaters and, each has been nominated for many Tony Awards. Last week, at RoundAbout’s American Airlines Theater, we saw some great theater in Arthur Miller’s, The Price. The surprise of the year, is the emergence of Danny DeVito, giving a great memorable performance, not to be missed. His beautifully created character will knock your socks off. Although, he’s made a name for himself on the screen and in other entertainment ventures, he belongs on the stage in live theater. He is a gem! Run to see this show before it closes. It has a limited engagement.

 

Danny DeVito in 2013; Born, Daniel Michael DeVito Jr, November 17, 1944 (ago 72)

 

Photo credit: Gage Skidmore [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons – File:Danny DeVito by Gage Skidmore 3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=50628181

 

Serve your favorite, well chilled white wine with the asparagus ribbon salad. This Pouilly-Fuisse was perfect. ©Joyce Hays, Target Health Inc.

 

From Our Table to Yours

Bon Appetit!

 

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