Physiology

Melatonin: The Dark Side of the Hormone – Psychiatric Times

CONFERENCE REPORTER

Melatonin is ubiquitous. It is present in nearly all life forms, including plants and animals, and even single cell organisms. Evolutionarily, it dates back billions of years serving essential cellular processes with its antioxidant and free radical scavenging functions, and more recently as a key element in the regulation of circadian rhythms and the sleep-wake cycle.1 As humans, we benefit from our endogenous melatonin in support of our complex cellular activity and in helping to orchestrate wide-ranging physiological processes influenced by our circadian system.2 We are not conscious of most melatonin actions, but certainly experience its effects on sleep and waking.

It is useful to think of our endogenous melatonin in 2 ways: 1) reactions occurring intracellularly that do not necessarily involve specific melatonin receptors and 2) the more familiar circadian role associated with regular changes in circulating melatonin and effects on melatonin receptors. Although present in a variety of tissues, circulating melatonin is predominantly produced in the pineal gland under the control of the master circadian clock transcription-translation loops in the hypothalamic suprachiasmatic nucleus (SCN), which is entrained by exposure to the light-dark cycle.3

Normally, plasma melatonin levels are very low during the daytime and gradually rise in the evening as bedtime approaches, typically about 2 hours before a persons natural sleep onset time; however, the actual clock time of the melatonin rise can vary considerably among individuals. Melatonin production also can be suppressed by light exposure, so this can be a factor affecting the circulating levels and sleep patterns. Usually melatonin plateaus at a relatively high level throughout the night and then declines by morning. When the pineal gland produces melatonin, it is immediately released into the bloodstream and cerebrospinal fluid. This pattern of markedly elevated melatonin levels during the nighttime has led to its description as the hormone of darkness. Note that the production of melatonin is primarily under circadian control: while bright light during the nighttime time will suppress it, darkness during the daytime will not turn it on.2

The circulating melatonin levels provide the bodys physiology with a clock and a calendar. Changing melatonin concentrations reinforce circadian activity in nearly all tissues and the changing duration of nighttime melatonin secretion reflects the time of year, especially important for seasonally breeding species.3 As humans, our ability to fall asleep at our typical bedtime and the robustness of our circadian cycle are both reinforced by melatonin interacting with the MT1 and MT2 receptors that are highly concentrated in the SCN. The normally coordinated functioning of homeostatic and circadian processes promotes our nighttime sleep of about 8 hours and our daytime-evening wakefulness of about 16 hours.

From late afternoon into the evening, the SCN-driven circadian system produces arousal that counters the homeostatic sleepiness that has accumulated since the morning awakening, thus allowing sustained functioning into the evening. Typically, we are the most alert in the early evening than any other time of the day or night. With approaching bedtime, the rising melatonin agonist activity at the SCN melatonin receptors decreases the stimulation, leaving the homeostatic sleepiness unopposed, thus facilitating bedtime sleep onset. It is notable that the melatonin action is not sedation, but rather a reduction in the evening circadian arousal.2

In everyday life, we think of melatonin as a widely available, fairly benign, and maybe helpful sleep aid product. In the United States, it is categorized as a dietary supplement, although in some countries it requires a prescription. Unlike official over-the-counter (OTC) products, which are highly regulated (composition, manufacturing, indications, labeling, and marketing), dietary supplements have little oversight. Studies analyzing consumer melatonin products have shown varying amounts of the compounds, as well as the presence of other unlabeled and sometimes surprising ingredients.4

Does exogenous melatonin taken as a dietary supplement enhance sleep? Is it safe?

There is a reasonable argument that taking evening melatonin might augment the natural process of reducing circadian arousal to help people fall asleep more quickly. In general, meta-analyses and systematic reviews of evening melatonin doses compared with placebo show statistically significant improvements in sleep onset that are of questionable clinical significance with a benefit of about 4 to 12 minutes.5-7 Studies have shown little or no benefit for sleep maintenance or total sleep time. The best evidence is for people having a circadian rhythm phase delay (night owls), blind individuals with the non-24-hour sleep-wake rhythm disorder, and some children with neurodevelopmental disorders.3 However, much of the research with melatonin has been with few subjects, mixed clinical populations, and for short durations, all limiting the quality of the evidence.

Clinical trial assessments of melatonin safety share the same study limitations, so high-quality data are not available. The more common adverse event reports include daytime drowsiness and nightmares, though the rates are low. Generally, melatonin is well tolerated in these placebo comparison studies with typical consumer product doses.8

A darker side of both endogenous and exogenous melatonin has been emerging in recent years with investigations of circadian rhythms and metabolism, specifically examining glucose tolerance, insulin release and sensitivity, weight gain, and the timing of food intake.9,10 The circadian regulation of metabolism is just right for people who are active, get plenty of light exposure, and have their meals during the daytime, and who are in the dark sleeping during the nighttime. In our society, many people eat at irregular times, including late in the evening and during the night, when our circadian system expects us to be fasting. An evening meal will result in higher glucose and insulin levels compared with the identical meal eaten early in the day. Over time these elevated evening glucose and insulin levels increase the risk for obesity and type 2 diabetes mellitus. The timing of food intake in relation to our evening melatonin rise appears to be an important factor.

McHill and colleagues11 studied the sleep-wake patterns of healthy young adults over a 30-day period that included 1 week of monitoring the timing and content of all food they ate, and also an overnight laboratory assessment of their melatonin patterns and body composition. They found a significant relationship between the timing of food consumption relative to melatonin onset and the percentage of body fat and body mass index, controlling for the actual clock time, caloric amount, activity or exercise level, and sleep duration. Eating food later in the day had a detrimental effect.

These findings are consistent with studies demonstrating the weight loss and metabolic benefits of time restricted eating routines where people consume their meals on a relatively early schedule and fast through the evening and nighttime. Avoiding evening eating close to and following our melatonin rise appears to have advantageous metabolic effects.9

If we should avoid eating and digesting food close to our evening endogenous melatonin rise, what are the implications for using exogenous melatonin as a sleep aid? There is evidence that taking melatonin also leads to impairment in glucose tolerance. Rubio-Sastre and colleagues12 studied 21 healthy women, giving them either melatonin 5 mg or a placebo in the morning and evening on different days. An oral glucose tolerance test monitoring glucose and insulin levels for 3 hours began 15 minutes after each dose. Finding that the melatonin use was associated with elevated glucose levels at both time points, they concluded that the optimum timing for melatonin doses should be at least 2 hours after the last meal.

Perhaps the best plan for melatonin to help with sleep is to give our own circadian rhythm and melatonin release a chance to do the job.10 Maintaining regular sleep-wake hours, plenty of daytime activity and light exposure, and early meal timing should aid in stabilizing the circadian cycle. Avoiding bright light in the evening for a few hours prior to bedtime should limit the suppression of melatonin, especially if using reddish low color-temperature lighting, now readily available with LED products. Using electronic screens (eg, phones, tablets, laptops) held close to the face should be limited as bedtime approacheseven when using those devices with blue spectrum-blocking apps or filters. These good sleep habits that facilitate earlier and higher melatonin release may be the solution to achieve an earlier sleep onset.

If one is inclined to take a dose of melatonin to enhance sleep, it probably will help the most when taken prior to bedtime, but ideally well after the last meal.3,11,12 Even very low doses result in blood levels hundreds to thousands of time higher than the normal endogenous circulating amount. Low doses should be as effective as high doses, since the primary action of melatonin is not sedation. The ultimate benefit in helping people fall asleep more quickly may take several days or weeks as melatonin advances and stabilizes the circadian system.

The bottom line

The bright side of this hormone of darkness is the extraordinary roles it serves in stabilizing our cellular and circadian functioning. If we manage to live our lives closer to our natural circadian physiology, we can avoid melatonins potential metabolic darkness.

Dr Neubauer is associate professor in the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. He spoke at PsychCongress 2020 in a presentation titled Melatonin: What, Why, and Why Not? The author reports he is a consultant with Eisai Inc and Abbott Laboratories.

References

1. Zhao D, Yu Y, Shen Y, et al. Melatonin synthesis and function: Evolutionary history in animals and plants. Front Endocrinol (Lausanne). 2019;10:249.

2. Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie. 2015;61(2-3):77-84.

3. Arendt J. Melatonin: Countering chaotic time cues. Front Endocrinol (Lausanne). 2019;10:391.

4. Erland LA, Saxena PK. Melatonin natural health products and supplements: Presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275-281.

5. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2005;20(12):1151-1158.

6. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. BMJ. 2006;332(7538):385-393.

7. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev. 2005;9(1):41-50.

8. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81.

9. Garaulet M, Qian J, Florez JC, et al. Melatonin effects on glucose metabolism: Time to unlock the controversy. Trends Endocrinol Metab. 2020;31(3):192-204.

10. Stenvers DJ, Scheer, FAJL, Schrauwen P, et al. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2019;15(2):75-89.

11. McHill AW, Phillips AJ, Czeisler CA, et al. Later circadian timing of food intake is associated with increased body fat. Am J Clin Nutr. 2017;106(5):1213-1219.

12. Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening.Sleep. 2014;37(10):1715-1719.

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Melatonin: The Dark Side of the Hormone - Psychiatric Times

Physiology

Nutrition and the Wisdom of Ethnic Cuisine: A Japanese Doctor’s Perspective – Nippon.com

When it comes to healthy eating, one size does not fit all. Japanese cooking, with its emphasis on rice, fish, and vegetables, may not be the best diet for everyone, but it is marvelously suited to the physiology of the Japanese, writes physician and writer Okuda Masako.

The popularity of Japanese cuisine has soared in recent decades, and one reason is undoubtedly its healthful image. The average lifespan of the Japanese people climbed rapidly after World War II. By around 1980, Japan had the highest life expectancy of any country in the world, and it still ranks near the top. (The worlds oldest living person is also a Japanese woman.) Amid a slew of investigations into the secrets of Japanese longevity, attention quickly centered on the benefits of washoku, traditional Japanese cooking.

My research and experience have taught me that the optimal diet depends on a variety of hereditary and environmental factors. But there is no denying that washoku has contributed to the health and longevity of the Japanese people. Let us begin by examining how.

In terms of health and long life, the biggest physiological factor the Japanese have going for them is a low risk of atherosclerosis. Atherosclerosis occurs when fats and other substances build up along the walls of arteries, restricting or even blocking blood flow. In the brain, such a blockage is known as a cerebral infarction (stroke); in the heart, it is called a myocardial infarction (heart attack). The incidence of myocardial infarction in Japan is among the lowest in the world.

Scientists believe that both genetics and diet play a role in protecting Japanese arteries. One factor is a high level of good cholesterol, or HDL (high-density lipoproteins), in the blood. In a 2008 study, Japanese HDL levels were found to be roughly 10% higher than those of white Americans on average. Another reason is that fish is a big part of the traditional Japanese diet, and fish contains EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), two polyunsaturated fatty acids that help prevent hardening of the arteries. Since ancient times, the Japanese have been eating oily fish like mackerel, sardines, yellowtail tuna, and eel, which are abundant off the coast of Japan and are rich in EPA and DHA. In a 2015 study, the average concentration of DHA in Japanese maternal milk was determined to be up to six times that found in Western countries and about twice that found in China.

A second major contributor to Japanese health is the gut microbiota, the many and varied microorganisms living in the intestinal tract. A 2016 analysis of the intestinal microbiota of subjects from 12 countries found that the Japanese had the highest counts of beneficial bifidobacteria. (Interestingly, the gut microbiome of the Chinese subjects was closer to that of the Western subjects studied.) This can probably be attributed to the high fiber content of the traditional Japanese diet, with its emphasis on grains and vegetables. Dietary fiber provides a good nutritional environment for beneficial microbes and helps cleanse the gut of the harmful substances that unhealthy bacteria produce. Since it takes a generation or more to permanently alter the gut microbiota, todays Japanese probably owe their intestinal health to the dietary habits of their parents and grandparents.

All of this might lead one to the conclusion that eating washoku will automatically make one healthier. Unfortunately, it is not quite so simple. In general, the traditional diets that developed in various parts of the world were optimally adapted to the local environment and the needs of the native population. The physiology of the native population, in return, adapted to the diet.

There are obvious physical differences between Japanese people and Westerners. But the differences go beyond hair texture and eye color. There are also disparities in musculature, body fat, and body temperature, as well as various factors that affect digestion and metabolism of alcohol: hormone and enzyme secretion, the shape of the stomach, the composition of the gut flora, and so forth. Race is not just skin-deep.

The Japanese stomach is adapted to consumption of grain.

Figure 1 illustrates the stomach shapes typically found in Japanese people on the one hand and people of Westerners extraction on the other. The differences are the result of disparities in the traditional diet.

The Japanese have long relied on rice and other grains as their dietary staple. Grains are a good source of energy, but whole grains in particular take time to digest because of their high fiber content. The Japanese stomach is vertically elongated so as to store, mix, and break down such food before it continues on into the intestines. The intestines, in turn, are rich in the kinds of bacteria that help digest and extract nutrition from starchy foods.

By contrast, the traditional European diet, with its emphasis on meat and dairy products, is considerably higher in protein and fat. Since protein and fat are digested primarily in the intestines, the food needs to move more rapidly from the stomach to the gut. The digestive system evolved to deal with these demands. For example, a large quantity of stomach acid is produced so that the stomach can process the food quickly; comparatively thicker stomach muscles then push it smoothly into the intestines.Plenty of enzymes and other fluids are secreted to aid the digestion of fat and protein inside the intestines.

It has long been known that the ability of adults to digest milk varies by ethnicity and region. The bodys capacity to digest the lactose in milk hinges on continued production of the enzyme lactase. The map in figure 2 shows the global distribution of lactose-intolerant adults in various parts of the world, with higher concentrations indicated by darker shades. While most people in the British Isles and Scandinavia digest milk easily, close to 90% of adults in Southeast Asia and East Asia (including Japan) have trouble with it.

Darker shades indicate regions with higher rates of adult lactose intolerance.

Such differences in physiology can translate into serious health problems when people adopt different diets and lifestyles. One example involves vitamin D, which is essential to bone health, among other things. Vitamin D is produced inside the body when the skin is exposed to the suns ultraviolet rays, but it can also be obtained from dietary sources like oily fish. It has been suggested that Africans, who evolved in a part of the world where year-round UV exposure is high, may be less well equipped to absorb vitamin D from dietary sources, and this may be why African Americans tend to have relatively low vitamin-D levels. Some experts have warned that African Americans need to adjust their diets to avoid health problems resulting from vitamin D insufficiency. The optimum diet for any person depends on genetic makeup, as well as lifestyle and environment.

Genetics also influences the way our bodies accumulate fat. One characteristic of the Japanese constitution is the tendency to accumulate visceral adipose tissue, or fat inside the abdominal cavity, as opposed to the subcutaneous fat that collects under the skin. Unfortunately, visceral fat is the more worrisome kind.

Cross-sections showing the distribution of abdominal fat in representative Japanese (left) and Westerners (right) subjects.

This is a fairly recent phenomenon, mind you. In earlier times, obesity was relatively rare in Japan, and the incidence of chronic diseases associated with visceral fatincluding type 2 diabetes, along with other diseases like breast cancer and colon cancerwas correspondingly low. That began to change in the 1960s to 1980s, as the Japanese diet became increasingly westernized, leading to higher fat consumption and lower intake of fiber. And with more people doing deskwork and leading sedentary lifestyles, lack of exercise contributed to the rise of obesity and the accumulation of visceral fat. The result has been a significant increase in disease, raising concerns for the future.

Extensive studies have revealed that a traditional Japanese dietlow in meat and dairy products, high in soybeans and fish, and high in fiber from grains, vegetables, and seaweedis tied to very low accumulation of visceral fat. In other words, washoku is ideally suited to the physiological traits of the Japanese people, protecting them from their innate tendency to accumulate visceral fat. Without knowing the science, our forebears managed to develop, preserve, and pass down a dietary culture perfectly adapted to our own metabolism.

Washoku has other health benefits as well. Soybeans, green and yellow vegetables, and small fish eaten whole all help to build strong bones. Lifelong consumption of soy foods also contributes to the relativelylow incidence in Japan of diabetes, breast cancer, and colon cancer, all ailments linked closely to visceral fat levels, as compared with the West

One notable weakness of the Japanese diet as it has developed in the past two or three centuries is the overwhelming preference for polished rice. For the health-conscious, I would recommend brown rice, which has seven times the dietary fiber of white rice and contains substances that help the body burn visceral fat.

In recent years, science has made considerable progress in identifying genetic differences among ethnic groups. In 2016, a Japanese team of researchers released the first Japanese reference genome panel (JRG v1), a whole-genome assembly representing the genes of a typical healthy Japanese. Comparison with the human reference genome has revealed millions of single-nucleotide differences, many of which doubtless reflect significant differences in nutrition physiology. We need to abandon the one-size-fits-all approach to nutrition and consider what diet works best for each ethnic group.

Nowadays, the Japanese people are able to enjoy delicious cooking from every part of the world. That is a splendid thing, as long as we keep in mind that washoku is the bedrock of our much-admired health and longevity.

(Originally written in Japanese. Banner photo: Dairy and meat products figure heavily in the Western diet, while the traditional Japanese diet has much to offer in the area of human health. Pixta.)

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Physiology

O’Brien named EHS Teacher of the Month – The Review

RICHMOND Shane OBrien has been named August Teacher of the Month at Edison High School. Coach OBrien has roots in Edison as a 2012 graduate and continued his football career at Mount Union University. He graduated from West Liberty University in 2016 with a bachelors degree in exercise physiology and currently teaches weightlifting and serves as head football coach at EHS. This is his third season at the helm for the Wildcats after serving as an assistant coach for four years under coaches Derrick Stickles and Nate Moses. He managed to lead the Wildcats to a 31-29 victory over Toronto during this years season opener and has also coached track and wrestling while at Edison.

He is the son of Dave and Jenney OBrien and is currently dating head cheerleading coach Madison Brown. OBrien also enjoys health and fitness.

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Physiology

Cell-autonomous immunity shaped human evolution | Illinois – University of Illinois News

CHAMPAIGN, Ill. Every human cell harbors its own defenses against microbial invaders, relying on strategies that date back to some of the earliest events in the history of life, researchers report in The Quarterly Review of Biology. Because this cell-autonomous immunity is so ancient and persistent, understanding it is essential to understanding human evolution and human medicine, the researchers said.

Like amoebae, most human cells can transform themselves to engulf and degrade foreign agents in a process known as phagocytosis, said Jessica Brinkworth, a professor of anthropology at the University of Illinois, Urbana-Champaign who wrote the new report with former undergraduate student Alexander Alvarado. And the methods that human cells use to detect, pierce or hack up invading microbes are inherited from and shared by bacteria and viruses, she said.

Every cell has these things and they have this deep evolutionary history, Brinkworth said. This means that if youre going to study humans, you need to accept that immunity is always going to be part of what youre looking at. And youre going to have to go deep into evolutionary time.

The authors reject the notion that the immune system is distinct from other bodily systems.

Immunity is literally everywhere, Brinkworth said. The whole of the organism, from the skin down to the level of the last enzyme floating anywhere in the body, almost all of it is engaged in protection in one form or another.

For that reason, she suggests that medical approaches to fighting infection that try to tamp down evolutionarily conserved immune responses such as pro-inflammatory pathways are misguided. While it can be useful or necessary to use immune-suppressing drugs against autoimmune conditions or in the case of organ transplants, such drugs do not appear to work against severe microbial infections.

In the context of severe infections, there have been many attempts to come up with ways of reducing the immune response by throwing a bunch of steroids at it or blocking the bodys ability to detect the pathogen, Brinkworth said. But targeting these immune mechanisms that have been around for millions of years is potentially counterproductive.

In the case of sepsis, which Brinkworth studies, this approach has not been fruitful.

More than 100 trials of immunomodulatory approaches to sepsis have failed, she said. And the one drug that made it to market then failed. Most of these drugs tried to block highly evolutionarily conserved defenses, like mechanisms of cell-autonomous immunity.

Many immunomodulatory drugs now being tested against the new coronavirus are failed sepsis drugs, she said.

Similarly, anthropologists often fail to consider how millions of years of battle against infections at the cellular level have shaped human genetics, physiology and even behavior, Brinkworth said.

If youre talking about human evolution, if youre in any physiological system, youre going to have to address at some point how pathogens have shaped it, she said.

Brinkworth also is an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

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Physiology

Researchers Discovers Cell in Zebrafish Critical to Brain Assembly and Function – Technology Networks

New research from Oregon Health & Science University for the first time documents the presence of astrocytes in zebrafish, a milestone that will open new avenues of research into a star-shaped type of glial cell in the brain that is critical for nearly every aspect of brain assembly and function.

The research was published this week in the journal Nature Neuroscience.

With their transparent bodies, zebrafish larvae provide a unique opportunity to gaze into the inner workings of the central nervous system, including the brain, even in living animals. The identification of astrocytes and the generation of tools to work with them in zebrafish will enable researchers around the world to open new lines of research to advance scientific understanding of how astrocytes function.

Astrocytes, it turns out, are the most abundant and mysterious cell type in the human brain, and OHSU is becoming a hub for research into their roles in development, brain function and disease.

"There is no neurodegenerative disease that I know of where astrocytes are not profoundly affected in some way," said senior author Kelly Monk, Ph.D., professor and co-director of the Vollum Institute at OHSU. "This gives us a powerful tool to get a handle on what these cells do and how they do it."

Monk and co-author Marc Freeman, Ph.D., credit lead author Jiakun Chen, Ph.D., a post-doctoral researcher in the Monk and Freeman labs, with developing a panoply of tools, including a cell-specific approach using the gene editing tool CRISPR to label and manipulate astrocyte precursors and incisively study their development and functions.

"He was able to capture the birth of an astrocyte from a stem cell and its entire development, which has never been visualized before in a vertebrate animal," Monk said.

Freeman said the discovery will dramatically enhance the study of how glia regulate brain development and physiology.

"This opens the door to experiments that you can't do in any other organism," Freeman said. "Zebrafish is the only animal in which you can now live-image all types of vertebrate glial cellsastrocytes, microglia, oligodendrocytes and OPCsalong with any neuron in intact neural circuits, from the earliest stages of development. Zebrafish is also the only vertebrate in which you can image the entire brain in live, behaving animals to figure out how it works. Understanding the role of these cells (astrocytes) in brain development will be key to understanding devastating neurodevelopmental disorders like autism spectrum disorder and schizophrenia.

"It's a major step forward and should power a lot of exciting work in the coming years."

Reference:Jiakun Chen, Kira E. Poskanzer, Marc R. Freeman & Kelly R. Monk. Live-imaging of astrocyte morphogenesis and function in zebrafish neural circuits, Nature Neuroscience,2020. DOI: 10.1038/s41593-020-0703-x

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Physiology

University of Pittsburgh Selected to Lead International Trials in COVID-19 Care – UPJ Athletics

The National Institutes of Health (NIH) has selected the University of Pittsburgh to lead a trio of Phase 3 clinical trials involving COVID-19 patients. Collectively known as ACTIV-4 Antithrombotics, these trials will explore the use of blood thinners in saving lives and improving care, particularly among adult COVID-19 patients who are at risk of developing life-threatening blood clots.

As the coordinating center for these trials, Pitt is occupying a leading role in the National Institutes of Healths Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, funded through Operation Warp Speed. Sixother universitiesHarvard University, New York University, the University of Illinois at Chicago, the University of Michigan, the University of North Carolina at Chapel Hill and the University of Vermontare also participating in the initiative, which will continue to add qualifying institutions.

This is a massive undertaking supported by the NIHone that is leveraging a global network to help improve patient outcomes for COVID-19, said Anantha Shekhar, who serves as Pitts senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of the School of Medicine. It is also a challenge that the University of Pittsburgh, a longtime leader in health care innovation, is perfectly positioned to tackle.

Researchers and clinicians have noted that many patients who have died from COVID-19 formed blood clots throughout their bodies, including in their smallest blood vessels. This unusual clottingone of many life-threatening effects of the diseasecauses multiple health complications, from lung and other organ damage to heart attacks, pulmonary embolisms and strokes.

Antithrombotics, also known as blood thinners or anticoagulants, keep blood protein and plateletsfrom turning into clumps or sticking to each other, but doctors have not yet figured out ifand at what point in the course of COVID-19blood thinners might be effective at treating patients with this condition.

Stephen Wisniewski, vice provost for budget and analytics, and two physician scientists from PittMatthew D. Neal, the Roberta G. Simmons Associate Professor of Surgery; and Frank Sciurba, a professor of medicine and education who directs the Pulmonary Function Exercise Physiology Laboratoryare leading this effort.

Understanding how to treat coagulation risk in COVID-19 patients is critical to lessening the impact of this pandemic, said Wisniewski. Pitts ability to innovate and collaborate enables us to help ensure that these trials will be completed with the rigor and speed necessary to make an impact at this critical moment. In collaboration with the National Institutes of Health and our peer institutions, we will use the combined tools of biology and statistics to advance the treatments of this deadly virus.

ACTIV-4 consists of three platforms: an inpatient platform launching now, an outpatient platformthat will focus on patients who do not need hospitalizationand a post-hospitalization outpatient platform that will focus onpatients who have already been discharged from care.

There is currently no standard of care for anticoagulation in hospitalized COVID-19 patients, and there is a desperate need for clinical evidence to guide practice, said Francis S. Collins, director of NIH. Conductingtrials using multiple existing networks of research sites provides the scale and speed that will get us answers faster.

The first trial, ACTIV-4 Antithrombotics Inpatient, is a master platform for collaboration among several randomized clinical trial platforms, including PROTECT COVID-19 at NYU Langone Health; the international REMAP-CAP, including leadership from Pitt and UPMC; and ATTACC from Canada. It will evaluate the safety and effectiveness of varying doses of the blood thinner heparin.

The trial will assign patients to either a low or high dose of heparin and, as the trial progresses, additional anticoagulants may be tested, depending on early results. Throughout the study, all participants will receive clinical care as indicated for their condition.

This has been an amazingly cooperative endeavorunequivocally the most rapidly moving, complex but also highly collaborative experience of my life, said Neal. By harmonizing these platforms, well be able to arrive at an answer as to whether antithrombotics can improve outcomes in COVID-19and at what dosesfar faster than we would otherwise.

Neal is co-chair of the protocol development committee and a lead investigator for the ACTIV-4 Antithrombotics Inpatient platform. Sciurba, who also serves as director of UPMCs Pulmonary Physiology Center, is co-chair of the protocol development committee and a lead investigator of the outpatient platform.

While the greatest focus on blood clotting complications has been in the inpatient setting, earlier attention in more stable patients prior to hospitalization may have an important impact on progression to the more serious consequences of COVID-19, said Sciurba.

Other investigators from Pitt include Maria Mori Brooks, professor of epidemiology and biostatistics and co-director of Pitts Epidemiology Data Center, who is leading the statistical design of the outpatient platform; Alison Morris, chief of the Division of Pulmonary, Allergy and Critical Care Medicine, who is the co-chair of the protocol development committee of the post-hospitalization outpatient platform; and Abdus S. Wahed, director of PhD Graduate Programs in Pitts Department of Biostatistics, who is leading the statistical design of the post-hospitalization outpatient platform.

Given the unpredictable geographic variability of COVID-19, the ACTIV-4 team is actively recruiting sites with clinical trial experience that have significant COVID-19 burden. To inquire, email ACTIV4siteenroll@pitt.edu.

Scientists and clinicians across Pitts six health sciences schools, along with colleagues from other academic departments, have taken a prominent role in responding to the pandemic. In all, Pitt is home to more than 400 ongoing studies related to COVID-19 and the coronavirus.

Earlier this month, a study led by Derek Angus, distinguished professor and the Mitchell P. Fink Endowed Chair of Pitts Department of Critical Care Medicine, appeared in the Journal of the American Medical Association and informed the World Health Organizations recommendation to use steroids to treat critically ill COVID-19 patients.

Additional efforts at Pitt to fight COVID-19 include work led by Paul Duprex, in Pitts Center for Vaccine Research to harness a measles vaccine engineered to express SARS-CoV-2 proteins on its surface to generate immunity to the virus that causes COVID-19.

Also in the Center for Vaccine Research: William Klimstra, an associate professor of immunology, is investigating an antibody therapy called SAB-185 that could be used to both treat COVID-19 and prevent it in front-line workers and military personnel. Last month, clinical staff began injecting SAB-185 into healthy volunteers for a phase I safety study.

Pitts Clinical and Translational Science Institute has awarded nearly $1 million to 17 studies that are exploring different aspects of the pandemic, from modeling the virus to examining how the lungs microbiome may impact infection.

Two pharmaceutical companies, Moderna and AstraZeneca, are also partnering with Pitt and UPMC on vaccine trials. The phase III trials, led by Judy Martin, director of the Pittsburgh Vaccine Clinical Trials Unit and professor of pediatrics, and Sharon Riddler, director of clinical research in Pitts Division of Infectious Diseases, seek to determine if the vaccines can prevent COVID-19 and for how long.

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University of Pittsburgh Selected to Lead International Trials in COVID-19 Care - UPJ Athletics

Physiology

Rodents in space: Keeping bone and muscle strong on the ISS – Astronomy Magazine

The decoy has another effect: It traps a second protein, called activin A, which also prevents growth of muscle as well as bone. Sure enough, space mice injected with the decoy receptor gained a double benefit: They kept their muscles buff and their bone density high. Bone and muscle even grew, so that the treated mice touched down with more of those tissues than untreated mice that were left on the ground.

The team also tested whether the treatments could reverse muscle wasting and bone loss that had already happened. To do this, they gave the decoy receptor to regular mice that had lost muscle and bone mass on the ISS, after theyd splashed down in the Pacific on January 7, 2020, and been taken to land in San Diego. These animals quickly recovered both bone and muscle; their muscles even grew bigger than theyd been before takeoff.

The results suggest that there could be a way to use a drug to protect astronauts from muscle and bone loss, says David Glass, vice president for research on aging and age-related disorders at Regeneron Pharmaceuticals in Tarrytown, New York. He cautioned, however, that space atrophy is different from Earth-based forms.

Nonetheless, Lees hope is that blockers for myostatin and activin A could preserve or restore muscle on the ground. Physiologist Christoph Handschin of the University of Basel in Switzerland agrees, but he adds a caveat: This looks super-promising if this can be translated into humans. Handschin, wholaid out the landscape of therapies for muscle wastingin theAnnual Review of Physiology, notes that several drug companies have tried to treat people with compounds that interfere with myostatin, without much success.

Lee is optimistic, though. He suspects that blocking myostatin in people is not sufficient, so he hopes that compounds like the decoy receptor that engage activin A might prove more effective than earlier compounds did. Glass says that to avoid side effects, it would be important to design a medication that is unlikely to interact with molecules other than myostatin and activin A, as the decoy can.

And while supporting human space travel isnt Lees main goal, such a molecule could, perhaps, catch NASAs interest as the agencyplans for longer space missionsthat will probably not have room for extensive gym equipment.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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Rodents in space: Keeping bone and muscle strong on the ISS - Astronomy Magazine

Physiology

News of the Weird | National | lagrandeobserver.com – La Grande Observer

Youre going to need a bigger boat a much bigger boat

BRISTOL, England Paleontologists with the University of Bristol, England, have unveiled the true size of the prehistoric mega-shark megalodon.

Today, the most fearsome living shark is the Great White. Adults can exceed 20 feet in length and bite with a force of two tons.

The University of Bristol in a press release Sept. 3 announced new research estimating the Great Whites fossil relative was more than twice that long and could bite with a force of 10 tons.

The massive predator and star of a share of B movies lived from 23 million to around three million years ago. The fossils of megalodon are mostly huge triangular cutting teeth bigger than a human hand.

Jack Cooper, who completed his masters courses in palaeobiology at the University of Bristols School of Earth Sciences, and colleagues made close comparisons to a diversity of living relatives with ecological and physiological similarities to megalodon, according to the press release, and used a number of mathematical methods to pin down the size and proportions of this monster.

Shark expert Dr. Catalina Pimiento from Swansea University and professor Mike Benton, a palaeontologist at Bristol, supervised the project. Professor Humberto Ferrn of Bristol also collaborated.

The journal Scientific Reports published the research.

I have always been mad about sharks, Cooper said in the press release. As an undergraduate, I have worked and dived with Great whites in South Africa protected by a steel cage of course. Its that sense of danger, but also that sharks are such beautiful and well-adapted animals, that makes them so attractive to study.

Megalodon, he continued, was actually the very animal that inspired me to pursue paleontology in the first place at just 6 years old.

Previously the fossil shark, known formally as Otodus megalodon, was compared with the Great White.

Cooper and his colleagues, for the first time, expanded this analysis to include five modern sharks. Pimiento said in the press release that megalodon is not a direct ancestor of the Great White but is equally related to makos, the salmon shark and porbeagle shark.

We pooled detailed measurements of all five to make predictions about megalodon, he said.

Benton explained the team first had to test whether these five modern sharks changed proportions as they grew to adulthood.

If, for example, they had been like humans, where babies have big heads and short legs, he said according to the press release, we would have had some difficulties in projecting the adult proportions for such a huge extinct shark.

He said they were surprised and relieved to discover the babies of all these modern predatory sharks start out as little adults and dont change in proportion as they get larger.

Cooper added this meant they could take the growth curves of the five modern forms and project the overall shape as they get larger and larger.

Right up to a body more than 52 feet long.

The results suggest at that size, Otodus megalodon likely had a head about 15 feet long, a dorsal fin approximately 5.3 feet tall and a tail almost 13 feet tall.

The reconstruction of the size of megalodon body parts represents a fundamental step towards a better understanding of the physiology of this giant, according to the press release, and the intrinsic factors that may have made it prone to extinction.

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News of the Weird | National | lagrandeobserver.com - La Grande Observer

Physiology

Suicide Prevention: What Are the Warning Signs, Prevention measures? – Newsd.in

By Dr. Riddhish K. Maru

On World Suicide Prevention Day we look at the tell tale signs and symptoms you can watch out for in case you feel a friend, colleague or a loved one may be contemplating suicide.

The act of killing or trying to harm oneself is called suicide. It is an action against a humans basic survival instinct or against ones nature of procreation, this makes it an interesting subject interesting. Suicide is exclusively almost seen only in the human species and its been known off since immemorial time.

Suicide is the outcome of neurobiological breakdown. The process begins in severe stress and pain which has been generated by due to a serious life crisis. Suicide occurs when the stress induces unbearable pain that feelings of self-control and self-esteem are weakened & death is seen as the only relief.

Suicidal entails changes in the brains chemistry and physiology, an imbalance in serotonin levels. Para suicidal behaviour is seen when there are attempts to deliberately harm self to gain attention.

Incidence:

Suicide is on the rise in this century, 258,075 people committed suicide in India in 2012. Indias suicide rate was 21.1 per 100,000 people, according to WHO.

Psychology of Suicide:

Menninger believed that suicide is inverted homicide. Generally aggression is directed outward, at a person or an object. But when it is directed inwards, it becomes suicide. Freud beliefs were on similar lines but with the parameters of life force (Eros) and death force (Thanatos).

Suicide Warning Signs: F.A.C.T.

F for Feelings:

Hopelessness It will never get any better/Theres nothing anyone can do.

Fear of losing control, fear of going crazy, fear of harming oneself or others.

Helplessness, a feeling that no one cares, everyone would be better off without me.

Overwhelming guilt, shame, and self-hatred.

Pervasive sadness

A for Actions or Events

Drug or alcohol abuse

Themes of death or destruction in talk or written materials (letters, notes)

Nightmares

Recent losses through death, divorce, end of a relationship, separation, loss of job, money, status, pride, self-esteem.

Loss of religious faith or spirituality

Agitation, restlessness

Aggression, recklessness

C for Change

In personality more withdrawn, tired, apathetic, indecisive or more boisterous, talkative, outgoing.

Different temperament than usual.

In thoughts cant concentrate on schoolwork, routine tasks, etc.

In sleep patterns oversleeping, excessive sleeping, insomnia

In eating habits loss of appetite, weight gain/loss, overeating, change in eating rituals

In activities loss of interest in friends, hobbies, personal grooming, or other activities

Sudden improvement after a period of being down or withdrawn, too euphoric

T for Threats

Statements, e.g., How long does it take to bleed to death?

Threats, e.g., I wont be around much longer.

Plans, e.g., putting affairs in order, giving away favourite things, obtaining a weapon.

Gestures, or attempts, e.g., overdose, wrist cutting.

In India, suicide was illegal and a survivor would face jail term of up to one year and fine under Section 309 of the Indian Penal Code but Government of India decided to repeal the law in 2014.

Solution:

If you have ever had suicidal thoughts or you know someone who has, the first thing you need to do is accept that it is possible to feel that way. Denial can only lead to more repression and a bigger outburst of events. Secondly, talk to someone about it. It could be your family, friends, colleague or a psychiatrist. And always when you feel things are going out of your control, dont be ashamed to ask for help. These are few ways that suicidal ideas can be identified early and can be addressed. Electro convulsive therapy is the gold standard treatment of suicide.

Supportive psychotherapy is required in each case.

Reducing social isolation,

Preventing social disintegration,

Treating mental disorders by Psychiatrist

Banning of pesticides & ropes

Additionally, a set of state led policies are being enforced to decrease the high suicide rate among farmers of Karnataka and Maharashtra.

(The author is a Psychiatrist, consultant at Practo)

(IANSlife can be contacted at [emailprotected])

IANS

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Suicide Prevention: What Are the Warning Signs, Prevention measures? - Newsd.in