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Beef Stroganoff with Noodles

January 6, 2020

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Target Healthy Eating

On a recent chilly evening, we gathered around this piping hot beef stroganoff, with delicious glasses of the best full-bodied cab, and thought of nothing else but good company and stimulating conversation. Worries faded, time stopped, during this memorable evening. Why not do a repeat of this, serve your guests a memorable recipe, and see where your evening takes you. ©Joyce Hays, Target Health LLC
This is not a recipe for using up leftovers, although, you could do that, I guess. This is a recipe that calls for a very good cut of beef, because the beef should be fairly undercooked. We don't eat beef that often anymore and neither do our friends and relatives. Therefore, I went all out with this beef stroganoff and used filet mignon. We were not disappointed. The outcome was unbelievably delicious. This dish is a savory one. If you want to cut down on the savory flavor, simply lessen the amount of thyme and rosemary you use. You may gasp at the number of garlic I used, however, you would never know from the flavor (unless you use garlic as much as I do), how many garlic cloves there are. Never use cooking wine. Always use a low cost real wine, for recipes that use wine. I've experimented with various noodles and pasta. What works the best for us is not the widest noodles, but the medium width noodle. Enjoy! ©Joyce Hays, Target Health LLC

Ingredients

1 and 1/2 to 2 pounds fillet mignon

2 Tablespoons extra virgin olive oil , divided

1 large onion, sliced

3 anchovies ground with mortar & pestle with 3 garlic cloves

30 fresh garlic cloves, sliced

2 stalks scallion, well chopped

1 pound mushrooms , sliced (not too thin)

3 Tablespoons unsalted butter

2 Tablespoons chickpea flour

1 cup beef broth (low sodium)

1 cup red wine (buy low cost red wine)

1 Tablespoon Dijon mustard

1 cup sour cream

1 Tablespoon fresh thyme, well chopped

1 Tablespoon fresh rosemary, well chopped

1 Tablespoon fresh parsley, well chopped

2 Pinches black pepper (to your taste)

2 Pinches chili flakes (to your taste)

Use medium wide egg noodles

Chopped chives , for garnish (optional)

This recipe, counting the noodles, serves 4 to 6 people.  The cut above is filet mignon and proved to be the very best choice, making the beef stroganoff one of the best recipes served here.  We served it with warm French baguettes & Irish butter, two salads: tiny orange tomatoes and avocado with oil, lemon, garlic; Caesar salad and a green bean side dish.  Dessert was Blueberry Betty, with or without vanilla ice cream, published in this newsletter last fall.  ©Joyce Hays, Target Health LLC

Directions

1.     Boil the wide noodles in (low sodium) beef broth, then save the beef broth for the Stroganoff recipe.

Boiling the noodles in beef broth. Will save left-over broth, to use in the gravy; starch from the noodles will add to the gravy. ©Joyce Hays, Target Health LLC

2.     Do all your chopping, slicing, grinding, cutting

I try not to use salt, whenever I can use anchovies. I grind the anchovies with a few garlic cloves and add this paste to my recipes. I hope this idea catches on. I've never seen it anywhere before. ©Joyce Hays, Target Health LLC
Chopping chives for garnish. Hope I remember to use them later. ©Joyce Hays, Target Health LLC
Chopping the rosemary, thyme and scallions (green onions). ©Joyce Hays, Target Health LLC

3.     If you want to flatten the steaks to about 1/3“ thick, use a rolling pin. Then slice into approximately 1/5“ strips. Or simply cut into strips as long or short as you like. This recipe usually has strips and not chunks of meat.

Cut the beef into strips. ©Joyce Hays, Target Health LLC

4.     Sprinkle the steak strips with pinches of pepper and chili flakes

5.     Heat 1 Tablespoon oil in a large skillet over high heat. Scatter half the beef in the skillet, QUICKLY spread it with tongs. Leave untouched for 30 seconds until browned. Turn beef quickly (as best you can!). Immediately remove onto a plate. Don't worry about raw pieces, they will be cooked again. If you bought an expensive cut of beef, all the more reason, to brown the meat quickly, then remove from heat to a plate.

6.     Add remaining 1 Tablespoon oil and repeat with remaining beef. Set aside the seared beef strips. Use the same pan for the next step.

Once the strips of beef are semi cooked (as you see above), remove them from the heat to a plate and set aside. Use the same pan for the next step. ©Joyce Hays, Target Health LLC

7.     Turn heat down to medium high. Add butter, melt. Then add onions and garlic, cook for 1 minute, while stirring, then add mushrooms.

8.     Add all chopped herbs and stir in. Save some chopped parsley for garnish later, with the chives.

9.     Cook mushrooms until golden. Scrape bottom of fry pan to get all those tasty bits off and incorporated, so the gravy becomes delicious.

First sauteed the onions, garlic, anchovy paste, then the herbs and mushrooms. Everything smells good. ©Joyce Hays, Target Health LLC

10.  Next, add flour, cook, stirring, for 1 minute.

Flour just added and being stirred into the mushroom mixture. ©Joyce Hays, Target Health LLC

11.  Add 1 cup of the beef the broth while stirring. Once incorporated, add slowly while stirring, the cup of red wine.

Broth then wine added. ©Joyce Hays, Target Health LLC

12.  Now, add sour cream and mustard, stirring until incorporated.

Sour cream added and about to be stirred into the gravy. ©Joyce Hays, Target Health LLC

13.  Bring to a simmer, then reduce heat to medium low, until it thickens. This is your gravy, so get it to the consistency you want. I would say about 3 to 5 minutes.

14.  Finally, add all the beef back in, including any juice on the plate. Simmer for 1 minute, then remove from stove immediately.

Beef is added back, just before serving. All you want to do is to warm up the meat and gravy and it cooks while it's warmed up. ©Joyce Hays, Target Health LLC

Serve over medium-width egg noodles, or pasta or rice, sprinkled with parsley and chives if desired.

Served this beef stroganoff several times over the holidays. Here the chopped chives have been sprinkled as a garnish just before serving. ©Joyce Hays, Target Health LLC
Beef Stroganoff and smooth full bodied red wine, are a pair to remember. ©Joyce Hays, Target Health LLC
A delicious meal for a cold winter evening! ©Joyce Hays, Target Health LLC
For all the evenings we served beef stroganoff, we also served either Paul Hobbs cab or Paul Hobbs pinot noir. ©Joyce Hays, Target Health LLC

Bon Appetit!

From Our Table to Yours

Have a Great Week Everyone!

New Treatment Approved For Adults With Migraine

January 6, 2020

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Regulatory

Migraine headache pain is often described as an intense throbbing or pulsating pain in one area of the head. Additional symptoms include nausea and/or vomiting and sensitivity to light and sound. Approximately one third of individuals who suffer from migraine also experience aura shortly before the migraine. An aura can appear as flashing lights, zig-zag lines, or a temporary loss of vision. Migraines can often be triggered by various factors including stress, hormone changes, bright or flashing lights, lack of food or sleep and diet. Migraine is three times more common in women than in men and affects more than 10% of people worldwide.

The FDA has approved Ubrelvy (ubrogepant) tablets for the acute (immediate) treatment of migraine with or without aura (a sensory phenomenon or visual disturbance) in adults. Ubrelvy is not indicated for the preventive treatment of migraine. It is the first drug in the class of oral calcitonin gene-related peptide receptor antagonists approved for the acute treatment of migraine. The effectiveness of Ubrelvy for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials. In these studies, 1,439 adult patients with a history of migraine, with and without aura, received the approved doses of Ubrelvy to treat an ongoing migraine. In both studies, the percentages of patients achieving pain freedom two hours after treatment (defined as a reduction in headache severity from moderate or severe pain to no pain), and whose most bothersome migraine symptom (nausea, light sensitivity or sound sensitivity) stopped two hours after treatment, were significantly greater among patients receiving Ubrelvy at all doses compared to those receiving placebo. Patients were allowed to take their usual acute treatment of migraine at least two hours after taking Ubrelvy.

The most common side effects that patients in the clinical trials reported were nausea, tiredness and dry mouth. Ubrelvy is contraindicated for co-administration with strong CYP3A4 inhibitors.

The FDA granted the approval of Ubrelvy to Allergan USA, Inc.

Emerging Parasitic Disease Mimics Symptoms of Visceral Leishmaniasis

January 6, 2020

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Tropical Medicine

Leishmaniasis is a parasitic disease found in parts of the tropics, subtropics, and southern Europe. It is classified as a neglected tropical disease and is often transmitted by the bite of some sand flies. The most common forms of leishmaniasis are cutaneous, which causes skin sores, and visceral, which affects several internal organs (usually spleen, liver, and bone marrow). According to the World Health Organization, each year between 50,000 and 90,000 people become sick with visceral leishmaniasis (kala-azar), a form of the disease that attacks the internal organs and is fatal in more than 95% of cases left untreated. During the last several decades, rare cases have been described in patients co-infected with both Leishmania and other groups of protozoan parasites that usually infect insects, including Crithidia.

The current study published online in Emerging Infectious Diseases (1 October 2019), showed that parasites isolated from a Brazilian patient confirmed that Crithidia parasites also can infect people. The study suggests that transmission of a protozoan parasite from insects may also cause leishmaniasis-like symptoms in people. However, the parasite, does not respond to treatment with standard leishmaniasis drugs. The 63-year-old patient reported in this study, initially sought treatment for the symptoms of visceral leishmaniasis, including weight loss, fever, anemia, and an enlarged liver and spleen. However, after eight months of standard leishmaniasis treatment, the patient's symptoms had not improved. The patient developed widespread skin lesions with poorly defined edges (unlike the small lesions with well-defined edges that sometimes appear after treatment for visceral leishmaniasis) and ultimately died. To determine the cause of disease, the authors cultured parasites taken from the patient's bone marrow and skin lesions, sequenced their genomes, and discovered that the parasites were not closely related to known disease-causing Leishmania parasites. Instead, they were more closely related to Crithidia fasciculata, a parasite that usually colonizes mosquitoes. To confirm that these Crithidia parasites could infect mammals, the authors exposed mice to the parasites isolated from the patient, both intravenously and by injection into the skin, and found that both types of parasite infected the liver. The parasites collected from the patient's skin also caused skin lesions in the mice.

The study raises concerns that the Brazilian patient might not be an isolated case. If Crithidia infections represent an emerging infectious disease in people, there will be an urgent need to develop novel effective treatments. The authors expressed concern that the disease may be mosquito-borne because Anopheles and Culex mosquitoes can host the Crithidia parasite. More research will be needed to find other human cases, confirm the parasite's range and host species, and discover potential treatments.

Human Brains Appear Uniquely Tuned For Musical Pitch

January 6, 2020

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Neurology

In 2012, Joyce Hays and Jules Mitchel attended a Symposium on Music, the Brain, Medicine and Wellness in celebration with the 40th Anniversary of the Santa Fe Chamber Music Festival, in Santa Fe, New Mexico. The conference, led by musician scientists, presented the state of the science in: the impact of music on 1) the developing brain, 2) cognition, 3) language, 4) memory, and 5) emotion. The symposium also showed how the use of music can promote healing in patients with serious medical conditions including cancer, neurologic diseases, and developmental disorders, and the influence of music on the well-being of individuals and their communities.

According to an article published in Nature Neuroscience (10 June 2019), a study involving primates suggest that speech and music may have shaped the human brain's hearing circuits. According to the authors, it was found that human brains are more sensitive to pitch, the harmonic sounds we hear when listening to music, than the macaque monkey, one of our evolutionary relatives. The project, Sound Health, is a joint project of the National Institutes of Health and the John F. Kennedy Center for the Performing Arts, and aims to understand the role of music in health.

The study apparently started with a friendly bet between two of the authors when  both were working at the Massachusetts Institute of Technology (MIT). One team had been searching for differences between how human and monkey brains control vision only to discover that there are very few, as the brain mapping studies suggested that humans and monkeys see the world in very similar ways. But then, one of the authors heard about some studies on hearing being done by his co-author, who, at the time, was a post-doctoral fellow at MIT.

That is when they both got the idea to compare music perception of humans with that of monkeys. Based on his studies, one of the authors  bet that they would see no differences. To test this, the authors played a series of harmonic sounds, or tones, to healthy volunteers and monkeys. Meanwhile, functional magnetic resonance imaging (fMRI) was used to monitor brain activity in response to the sounds. The authors also monitored brain activity in response to sounds of toneless noises that were designed to match the frequency levels of each tone played.

At first glance, the scans looked similar and confirmed previous studies. Maps of the auditory cortex of human and monkey brains had similar hot spots of activity regardless of whether the sounds contained tones. However, when the authors looked more closely at the data, they found evidence suggesting the human brain was highly sensitive to tones. The human auditory cortex was much more responsive than the monkey cortex when they looked at the relative activity between tones and equivalent noisy sounds. According to the authors, it was found that human and monkey brains had very similar responses to sounds in any given frequency range. It was only when added tonal structure was added to the sounds that some of these same regions of the human brain became more responsive. Thus, it was concluded that the results suggest the macaque monkey may experience music and other sounds differently. In contrast, the macaque's experience of the visual world is probably very similar to humans.

Further experiments supported these results. Slightly raising the volume of the tonal sounds had little effect on the tone sensitivity observed in the brains of two monkeys. Finally, the authors saw similar results when they used sounds that contained more natural harmonies for monkeys by playing recordings of macaque calls. Brain scans showed that the human auditory cortex was much more responsive than the monkey cortex when they compared relative activity between the calls and toneless, noisy versions of the calls. According to the authors, this finding suggests that speech and music may have fundamentally changed the way our brain processes pitch, and it may also help explain why it has been so hard for scientists to train monkeys to perform auditory tasks that humans find relatively effortless.

Additional videos:

Human Brain Prefers Pitch

Mapping Musical Pitch in the Brain

Pitch in the Brain

Chronic Pain

January 6, 2020

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History of Medicine

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.

ATP: Biological Transfer of Energy

January 6, 2020

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Quiz

Diagram of a typical animal cell. Organelles are labelled as follows: Nucleolus Nucleus Ribosomes (dots on rough reticulum walls) Vesicle Rough endoplasmic reticulum Golgi apparatus (or “Golgi body“) Cytoskeleton Smooth endoplasmic reticulum Mitochondrion Vacuole Cytosol Lysosome Centriole Cell membrane. By Kelvinsong - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=22952603
Diagram of a mitochondrion - Source: By Kelvinsong - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=27715320
Electron transport chain in the mitochondrial intermembrane spaceGraphic credit: By T-Fork - http://commons.wikimedia.org/wiki/File:ETC_electron_transport_chain.svg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=17593027

Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of biological research that includes the study of the transformation of energy in living organisms and the study of thousands of different cellular processes such as cellular respiration and the many other metabolic and enzymatic processes that lead to production and utilization of energy in forms such as 1) ___ ___, or ATP molecules. The goal of bioenergetics is to describe how living organisms acquire and transform 2) ___ in order to perform biological work. The study of metabolic pathways is thus essential to bioenergetics.

Energy homeostasis is the homeostatic control of energy 3) ___ - the difference between energy obtained through food consumption and energy expenditure - in living systems. Bioenergetics is the part of biochemistry concerned with the energy involved in making and breaking of chemical bonds in the 4) ___ found in biological organisms. It can also be defined as the study of energy relationships and energy transformations and transductions in living organisms. The ability to harness energy from a variety of metabolic pathways is a property of all living 5) ___. Growth, development, anabolism and catabolism are some of the central processes in the study of biological organisms, because the role of energy is fundamental to such biological processes. Life is dependent on energy transformations. Living organisms survive because of exchange of energy between living tissues/ cells and the outside environment. Some organisms, such as autotrophs, can acquire energy from 6) ___ (through photosynthesis) without needing to consume nutrients and break them down. Other organisms, like heterotrophs, must intake nutrients from food to be able to sustain energy by breaking down chemical bonds in nutrients during metabolic processes such as glycolysis and the citric acid cycle. Importantly, as a direct consequence of the First Law of Thermodynamics, autotrophs and heterotrophs participate in a universal metabolic network. By eating autotrophs, or 7) ___, heterotrophs harness energy that was initially transformed by the plants during photosynthesis.

In a living organism, chemical bonds are broken and made as part of the exchange and transformation of energy. Energy is available for work (such as mechanical work) or for other processes (such as chemical synthesis and anabolic processes in growth), when weak bonds are broken and stronger bonds are made. The production of stronger bonds allows release of usable energy. Adenosine triphosphate (ATP) is the main “energy currency“ for organisms; the goal of metabolic and catabolic processes is to synthesize ATP from available starting materials (from the environment), and to break down ATP (into adenosine diphosphate (ADP) an inorganic phosphate) by utilizing it in biological processes. In a cell, the ratio of ATP to ADP concentrations is known as the “energy charge“ of the cell. A cell can use this energy charge to relay information about cellular needs; if there is more ATP than ADP available, the cell can use ATP to do work, but if there is more ADP than ATP available, the cell must synthesize ATP via oxidative phosphorylation. Living organisms produce ATP from energy sources via oxidative phosphorylation. The terminal phosphate bonds of ATP are relatively weak compared with the stronger bonds formed when ATP is hydrolyzed (broken down by water) to adenosine diphosphate and inorganic phosphate. Here it is the thermodynamically favorable free energy of hydrolysis that results in energy release; the phosphoanhydride bond between the terminal phosphate group and the rest of the ATP molecule does not itself contain this energy. An organism's stockpile of ATP is used as a battery to store energy in 8) ___. Utilization of chemical energy from such molecular bond rearrangement powers biological processes in every biological organism.

Living organisms obtain energy from organic and inorganic materials; i.e. ATP can be synthesized from a variety of biochemical precursors. For example, lithotrophs can oxidize minerals such as nitrates or forms of sulfur, such as elemental sulfur, sulfites, and hydrogen sulfide to produce ATP. In photosynthesis, autotrophs produce ATP using light energy, whereas heterotrophs must consume organic compounds, mostly including carbohydrates, fats, and proteins. The amount of energy actually obtained by the organism is lower than the amount present in the food; there are losses in digestion, metabolism, and thermogenesis. Environmental materials that an organism intakes are generally combined with oxygen to release energy, although some can also be oxidized anaerobically by various organisms. The bonds holding the molecules of nutrients together and in particular the bonds holding molecules of free oxygen together are relatively weak compared with the chemical 9) ___ holding carbon dioxide and water together. The utilization of these materials is a form of slow combustion because the nutrients are reacted with 10) ___ (the materials are oxidized slowly enough that the organisms do not actually produce fire). The oxidation releases energy because stronger bonds (bonds within water and carbon dioxide) have been formed. This net energy may evolve as heat, which may be used by the organism for other purposes, such as breaking other bonds to do chemistry required for survival.

ANSWERS: 1) adenosine triphosphate; 2) energy; 3) balance; 4) molecules; 5) organisms; 6) sunlight; 7) plants; 8) cells; 9) bonds; 10) oxygen

Happy New Year 2020 to Our Friends and Colleagues From All Over the Word

January 6, 2020

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What's New

To our friends, colleagues and loyal readers throughout the world, wishing you a Happy New Year as we all return to work in 2020.  Thus, let this be the year of clear vision followed by a decade of visionary thinking.

The American Optometric Association explains that 20/20 vision refers to someone's visual acuity - the clarity or sharpness of vision - measured at a distance of 20 feet without vision correction (such as eyeglasses or contact lenses). So, if you have 20/20 vision, you can see clearly at 20 feet what typically should be seen at that distance. But if you have 20/100 vision, you must be as close as 20 feet to see what a person with normal vision can see at a 100-foot distance.

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. Also visit the Target Health Eating Website to see all of the fantastic recipes since 2012.

Joyce Hays, Founder and Editor in Chief of On Target

Dr. Jules T. Mitchel, Editor

Shrimp and Chicken, Fried Rice with Scallion Garnish

December 16, 2019

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Target Healthy Eating

This turned out to be an absolutely delicious recipe that we experimented with many times, before publishing it for our wonderful readers. Let me give you a few tips that you may already be aware of: When I cook rice I never use water. I use either chicken broth or coconut milk. If there is any liquid left over, I save it to use in another recipe. The rice used in this particular iteration happened to be cooked in coconut milk. The other tip is: for this recipe, only use left-over rice, or rice that's cooked the day before and refrigerated overnight. Rice made the same day, is not as firm and doesn't taste the same, when mixed with all the other ingredients. Although, I didn't use any butter in this recipe, I have read that butter combined with soy sauce, goes through a chemical process that yields a special umami flavor. I plan to try this soon in another shrimp recipe that I will call: Shanghai Shrimp. (watch for it) ©Joyce Hays, Target Health LLC
A perfect, healthy, comfort food for a winter evening. This is so good, you don't need to plan to serve anything else. Just make a big batch of this and watch how fast it disappears. ©Joyce Hays, Target Health LLC

Ingredients

1 chicken breast, cut into strips, before cooking, or cut into smaller pieces. (your choice)

1 onion, chopped

2 Tablespoons peanut oil

Sesame oil for cooking

1 medium or large carrot, cut into small diced (square) pieces. (Or you decide the shape of the carrots)

1 pound (or more) fresh shrimp, shelled & deveined by fish monger. Leave shrimp whole or cut into pieces (your choice)

10 fresh garlic cloves minced

1 package frozen peas, thaw first

6 eggs, whisked (use as many eggs as you like)

4 cups jasmine rice, cooked, cooled, then refrigerated overnight

2 pinches chili flakes (more to your taste)

3 Tablespoons lite or low sodium Soy Sauce

2 stalks scallions, chop well, on an angle. (I only used the green part)

1/2 teaspoon oyster sauce

Easy to find ingredients. Don't forget to use left-over rice, or cook your rice the day before, then refrigerate. ©Joyce Hays, Target Health LLC

Directions

  1. Take your pre-cooked rice out of fridge and let it reach room temperature.
  2. Do all your chopping, cleaning, cutting, cutting, slicing, whisking.
Whisk the eggs, then set aside until needed. ©Joyce Hays, Target Health LLC
Chopping the scallions, then setting aside. ©Joyce Hays, Target Health LLC
Cutting carrots. You can cut them in small dices, if you want to. ©Joyce Hays, Target Health LLC
Chopping the garlic and onion. ©Joyce Hays, Target Health LLC
Have your fish monger clean and devein the shrimp. But clean them again at home before you cook them. ©Joyce Hays, Target Health LLC
Slice chicken breast in long strips or cut the chicken in smaller dice shapes. ©Joyce Hays, Target Health LLC
  1. Heat 1 Tablespoon of oil in a medium wok or skillet. Add the chopped onion and garlic and cook until soft.
  2. Add carrots to the cooked onions and cook for 5 minutes.
First, the chopped onion and garlic were cooked in sesame oil. Then the carrots were added. ©Joyce Hays, Target Health LLC
    5. Meanwhile, in a separate skillet cook the strips of chicken until tender and done. Remove from pan and set aside.
Cooking the chicken strips in sesame oil or use peanut oil. ©Joyce Hays, Target Health LLC
    6. In the same skillet, cook the shrimp until opaque and tender about 1 minute on each side. Remove shrimp from heat and set aside.


Cooking the shrimp in sesame oil, then remove from pan and set aside. ©Joyce Hays, Target Health LLC
    7. In the same pan as the shrimp, heat 1 Tablespoon of sesame oil and add in eggs stirring constantly until fluffy and not runny. When half or nearly done, remove eggs from heat and set aside.


Partially cooking these eggs. This is the point when we stopped cooking the eggs and removed from heat. ©Joyce Hays, Target Health LLC
    8. To the onion, garlic, carrot mixture, add the thawed out peas and stir until heated through.
Added the peas to the pan with garlic, onion and carrots. ©Joyce Hays, Target Health LLC


    9. Add the pre-cooked rice to the pan and stir in all the condiments like, oyster sauce, soy sauce and chili flakes. Stir well.
Just added the rice to the pan. Stirring all ingredients together. ©Joyce Hays, Target Health LLC
Stirring in low sodium soy sauce, oyster sauce and chili flakes. ©Joyce Hays, Target Health LLC
Stirring in all of the partially cooked eggs. ©Joyce Hays, Target Health LLC


  1. Finally, add the partially cooked eggs and half the scallions and stir everything together until all ingredients are well combined
  2. Add the shrimp and stir in well.
Look at how beautiful this dish is becoming, as the shrimp get stirred in. ©Joyce Hays, Target Health LLC


    12. Add the chicken and combine well with all other ingredients.
Finally, adding the chicken and we're almost done. ©Joyce Hays, Target Health LLC


    13. Garnish with the other half of the chopped scallions. (Optional)Sprinkle with toasted sesame seeds if you like this idea.
Last, garnish with chopped scallions and get ready for a delicious dinner. ©Joyce Hays, Target Health LLC


We started this meal with chilled white wine and an avocado salad with tiny orange tomatoes (oil & lemon dressing, with touch of garlic). Then out came the chicken and shrimp fried rice with some cauliflower on the side. Jules gave my recipe five stars and couldn't stop eating it. I must admit it is extremely flavorful. BTW, the chicken was for him and the shrimp was for me; that's why I included both of these proteins. Nice touch, don't you think? We had red grapes and blueberry amaretto cake for dessert.

Wonderful way to begin the weekend!

Target Health LLC is now an "East meets West" company and we couldn't be more pleased. The world needs more partnerships, not less. On our recipe page, we're delighted to accept the challenge of trying out new ingredients and flavors and want to share with you, whatever we discover. ©Joyce Hays, Target Health LLC

Bon Appetit!

From Our Table to Yours

Have a Great Week Everyone!

Accelerated Approval for First Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation

December 16, 2019

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Regulatory

Duchenne muscular dystrophy (DMD) is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide. People with DMD progressively lose the ability to perform activities independently and often require a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

The FDA has granted accelerated approval to Vyondys 53 (golodirsen) injection to treat Duchenne muscular dystrophy (DMD) patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. It is estimated that about 8% of patients with DMD have this mutation. Vyondys 53 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (i.e., how patients feel or function or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Vyondys 53 is based on the surrogate endpoint of an increase in dystrophin production in the skeletal muscle observed in some patients treated with the drug. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease and the lack of available therapy.

Vyondys 53 was evaluated in a two-part clinical study. The first part included 12 DMD patients, with eight patients receiving Vyondys 53 and four receiving placebo. The second part of the study was open-label, and included the 12 patients enrolled in part one of the study, and 13 additional patients who had not previously received the treatment. In the study, dystrophin levels increased, on average, from 0.10% of normal at baseline to 1.02% of normal after 48 weeks of treatment with the drug or longer.

As part of the accelerated approval process, the FDA is requiring the company to conduct a clinical trial to confirm the drug's clinical benefit. The ongoing study is designed to assess whether Vyondys 53 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects reported by participants receiving Vyondys 53 in clinical studies were headache, fever (pyrexia), cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in patients who were treated with Vyondys 53. Additionally, renal toxicity was observed in animals who received golodirsen. Although renal toxicity was not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in patients taking Vyondys 53.

The FDA granted this application Fast Track and Priority Review designations. Vyondys 53 also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. In addition, the manufacturer received a rare pediatric disease priority review voucher. The FDA's rare pediatric disease priority review voucher program is intended to encourage development of new drugs and biologics to prevent and treat rare diseases in children.

Approval of Vyondys 53 was granted to Sarepta Therapeutics of Cambridge, Massachusetts.

Immunotherapy Drug Improves Outcomes for Some Children with Relapsed Leukemia

December 16, 2019

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Oncology

When children have B-cell acute lymphoblastic leukemia (B-ALL) that relapses after their initial treatment, they are typically given chemotherapy. The first four to six weeks of chemotherapy, the reinduction phase, is commonly followed by additional intensive chemotherapy, or consolidation treatment, to further reduce disease levels. Following this, hematopoietic stem cell transplant is considered the best treatment for approximately half of patients, based on factors such as whether relapse occurred during initial treatment or shortly after it was completed.

However, chemotherapy can produce severe side effects in some patients and is sometimes ineffective in reducing leukemia levels to the low levels needed prior to transplant. As a result, patients may not be able to proceed to transplant or transplant may be delayed, which increases the risk that the leukemia will return. New findings from a clinical trial show that treatment with the immunotherapy drug blinatumomab is superior to standard chemotherapy for children and young adults with high- or intermediate-risk B-cell acute lymphoblastic leukemia (B-ALL) that has relapsed. Those treated with blinatumomab had longer survival, experienced fewer severe side effects, had a higher rate of undetectable residual disease, and were more likely to proceed to a stem cell transplant.

The findings were presented as a late-breaking abstract at the American Society of Hematology (ASH) annual meeting on Dec. 10, 2019. The trial was led by the Children's Oncology Group (COG), part of the National Cancer Institute (NCI)-sponsored National Clinical Trials Network. NCI is part of the National Institutes of Health. Amgen reviewed the trial protocol and amendments and provided the study drug under a Cooperative Research and Development Agreement with NCI. The COG study investigated blinatumomab as an alternative type of consolidation treatment to follow the reinduction phase. Blinatumomab is a type of immunotherapy that works by binding to two different molecules: CD19, a protein, or antigen, expressed on the surface of B-ALL cells, and CD3, an antigen expressed on T cells. By bringing T cells close to leukemia cells, the immunotherapy helps the T cells recognize and kill the cancer cells. Blinatumomab has been approved by the U.S. Food and Drug Administration (FDA) for adults and children with B-ALL that has returned or has not responded to treatment. FDA has also granted accelerated approval to the drug-meaning confirmatory trials must show it has clinical benefit-for some adults and children undergoing treatment for B-ALL who achieve complete remission but still have small amounts of leukemia detectable using very sensitive methods.

Investigators in this study wanted to see if blinatumomab could increase rates of survival free from leukemia and be less toxic than intensive chemotherapy in children and young adults undergoing consolidation treatment. The trial report was based on 208 children and young adults aged 1-30 with relapsed B-ALL who had received reinduction chemotherapy and were considered to have high- or intermediate-risk disease. They were randomly assigned to receive either two rounds of intensive chemotherapy or two 4-week rounds of treatment with blinatumomab before proceeding to a transplant. (A separate part of the study addressed children with low-risk disease.)

Results showed that after a median follow-up time of 1.4 years, those in the blinatumomab group had higher rates of 2-year disease-free survival, the primary outcome of the study, than those who received intensive chemotherapy (59.3 + 5.4% vs. 41 + 6.2%). Those treated with blinatumomab also had higher rates of overall survival (79.4 + 4.5% vs. 59.2 + 6%), fewer severe side effects, a higher rate of undetectable residual disease (79% vs. 21%), and a higher rate of proceeding to stem cell transplant (73% vs. 45%).

At a planned interim analysis, an independent data safety monitoring committee concluded that the outcome for children treated with blinatumomab was superior to that of children treated with chemotherapy only and recommended that enrollment to the high- and intermediate-risk part of the trial be stopped. Future clinical trials will study whether blinatumomab's effects in relapsed B-ALL can be enhanced by combining it with other immunotherapy and will test whether adding the drug to standard chemotherapy for children and young adults with newly diagnosed B-ALL is beneficial.

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