Heart regeneration in salamanders depends on white blood cells

Date:
September 20, 2017

Source:
Mount Desert Island Biological Laboratory

Summary:
The answer to the question of why some organisms can regenerate major body parts while others, such as humans, cannot may lie with the body’s innate immune system, according to a new study of heart regeneration in the Mexican salamander.

 

The ability of the axolotl, or Mexican salamander, to regenerate the form and function of almost any body part makes it a popular model for the study of the genetic pathways for regeneration.
Credit: MDI Biological Laboratory

 

 

The answer to regenerative medicine’s most compelling question — why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot — may lie with the body’s innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander, an organism that takes the prize as nature’s champion of regeneration.

The study, which was conducted by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, found that the formation of new heart muscle tissue in the adult axolotl after an artificially induced heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The study has significant implications for human health. Since salamanders and humans have evolved from a common ancestor, it’s possible that the ability to regenerate is also built into our genetic code.

Godwin’s research demonstrates that scar formation plays a critical role in blocking the program for regeneration. “The scar shoots down the program for regeneration,” he said. “No macrophages means no cardiac regeneration.”

Godwin’s goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. His team is already looking at molecular targets for drug therapies to influence these genetic programs.

“If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken,” Godwin explained. “We don’t know yet if it’s only scarring that prevents regeneration or if other factors are involved. But if we’re really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate.”

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But Godwin found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. His findings suggest that research efforts should pay more attention to the genetic signals controlling scarring.

The extraordinary incidence of disability and death from heart disease, which is the world’s biggest killer, is directly attributable to scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart’s ability to pump, leading to disability and ultimately to terminal heart failure.

In addition to regenerating heart tissue following a heart attack, the ability to unlock dormant capabilities for regeneration through the suppression of scarring also has potential applications for the regeneration of tissues and organs lost to traumatic injury, surgery and other diseases, Godwin said.

Godwin’s findings are a validation of the MDI Biological Laboratory’s unique research approach, which is focused on studying regeneration in a diverse range of animal models with the goal of gaining insight into how to trigger dormant genetic pathways for regeneration in humans. In the past year and a half, laboratory scientists have discovered three drug candidates with the potential to activate regeneration in humans.

“Our focus on the study of animals with amazing capabilities for regenerating lost and damaged body parts has made us a global leader in the field of regenerative medicine,” said Kevin Strange, Ph.D., MDI Biological Laboratory president. “James Godwin’s discovery of the role of macrophages in heart regeneration demonstrates the value of this approach: we won’t be able to develop rational and effective therapies to enhance regeneration in humans until we first understand regeneration works in animals like salamanders.”

Godwin, who is an immunologist, originally chose to look at the function of the immune system in regeneration because its role as the equivalent of a first responder at the site of an injury means that it is responsible for preparing the ground for tissue repairs. The recent study was a follow-up to an earlier study which found that macrophages also play a critical role in limb regeneration.

The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, Godwin would like to understand why macrophages produced by adult mice and humans don’t suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

Godwin holds a dual appointment with The Jackson Laboratory, also located in Bar Harbor, which is focused on the mouse as a model animal. The dual appointment allows him to conduct experiments that compare genetic programming in the highly regenerative animals used as models at the MDI Biological Laboratory with genetic programming in neonatal and adult mice.

Story Source:

Materials provided by Mount Desert Island Biological LaboratoryNote: Content may be edited for style and length.


Journal Reference:

  1. J. W. Godwin, R. Debuque, E. Salimova, N. A. Rosenthal. Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscapenpj Regenerative Medicine, 2017; 2 (1) DOI: 10.1038/s41536-017-0027-y

 

Source: Mount Desert Island Biological Laboratory. “Immune system is critical to regeneration, study finds: Heart regeneration in salamanders depends on white blood cells.” ScienceDaily. ScienceDaily, 20 September 2017. <www.sciencedaily.com/releases/2017/09/170920154948.htm>.

Study challenges traditional presumptions of migratory behavior

Date:
September 20, 2017

Source:
University of Nebraska-Lincoln

Summary:
The onset of the last ice age may have forced some bird species to abandon their northerly migrations for thousands of years, says new research led by an ornithologist. The study challenges a long-held presumption that birds merely shortened their migratory flights when glaciers advanced south to cover much of North America and northern Europe about 21,000 years ago.

 

The University of Nebraska-Lincoln’s Robert Zink has authored a new study suggesting that the last ice age completely halted the northerly migrations of some bird species from about 21,000 to 12,000 years ago.
Credit: Craig Chandler, University of Nebraska-Lincoln

 

 

The onset of the last ice age may have forced some bird species to abandon their northerly migrations for thousands of years, says new research led by a University of Nebraska-Lincoln ornithologist.

Published Sept. 20 in the journal Science Advances, the study challenges a long-held presumption that birds merely shortened their migratory flights when glaciers advanced south to cover much of North America and northern Europe about 21,000 years ago.

The study concluded that the emergence of glaciers in those regions instead acted as an “adaptive switch” that turned off migratory behavior, transforming the tropics from a cold-weather resort into a long-term residence for certain bird species.

Of the 29 long-distance migrant species examined in the study, 20 likely saw their northern breeding grounds become uninhabitable, according to models developed by the researchers. When the climate again warmed and glaciers retreated back to the Arctic, those species presumably resumed their seasonal migrations.

Lead author Robert Zink said the conclusions could alter how scientists reconstruct the history of bird migration.

“It fundamentally changes the way we study the evolution of migration and think about the migratory behavior of birds,” said Zink, professor of natural resources and biological sciences at Nebraska.

Putting Migration On Ice

Researchers generally agree that, millions of years ago, many birds did not migrate from the tropics. But as the global climate began to warm, some species ventured beyond their native habitats to capitalize on better breeding and feeding opportunities afforded by the longer days and insect-rich environments of northern latitudes.

Those species eventually ventured farther and farther from their habitats, finally stopping when they reached environments that could not sustain them during the autumn and winter. They continued to migrate south when seasonal temperatures dropped and food sources waned.

In that context, Zink said his hypothesis suggests that the origin story of bird migration simply underwent multiple reboots, with the “migratory machinery” of birds halting for each of the 20 or so ice ages that have glazed Earth during the past 2.5 million years.

“Migrations are costly and risky,” said Zink, curator of zoology at the University of Nebraska State Museum. “They’re costly in terms of safety, energy — anything you can think of.”

Rather than paying those costs to reach breeding grounds that the encroaching glaciers had shrunk to tiny fractions of their former size, he said, birds instead resorted to their ancestral state: tropical homebodies.

“Some of them were forced so far south that it was no longer a fitness advantage to migrate, because the extra young they could produce south of the glacier wasn’t enough to compensate for the cost of migration,” Zink said, “and then coming back to the tropics and re-establishing their territory.

“To some people, that’s so completely off the wall that they may have trouble wrapping their heads around it — except that it’s the way they would explain to their classes the evolution of migration in the first place. So, in a sense, what I’m proposing is nothing novel. What’s novel about it is that (the advent of migration) probably occurred many times.”

Redrawing the Map

Zink and his co-author, the University of Minnesota’s Aubrey Gardner, conducted their study using a computer model that linked the modern-day distribution of bird species with climate variables — temperature, precipitation, seasonality — that characterize their habitats. By comparing those climates with conditions that existed during the last ice age, the model mapped the regions that likely could have supported each of those species from about 21,000 to 12,000 years ago.

In many cases, Zink said, the model either found no habitable regions beyond the tropics or located habitats so miniscule that they would have struggled to support sizable populations of the species.

“Some species were probably just forced (slightly) south of the glaciers, and their habitats were extensive enough that they would maybe maintain some migratory ability,” he said. “But for others, I think there was so little predicted habitat that they just ceased migration all together.

“This evolution of migration is a very (variable) thing. Normally, when we think of evolution, we think of singular, unique events in evolutionary history. But in this case, the ability to migrate is entrenched in birds. They have the ability to navigate using the sun, the stars, the (Earth’s) magnetic field. They have the ability to put on large amounts of fat and sustain trans-gulf migrations. Birds are (adaptive) enough in their behavior and physiology that this wasn’t a reinvention of some incredible phenomenon.”

And if some species did transition back and forth from sedentary to migratory states, researchers should consider pruning certain evolutionary trees accordingly, Zink said. Many evolutionary trees currently treat migration as an irreversible trait rather than a variable behavior, he said, and that assumption could be misinforming discussions of when and where it evolved.

“I wanted to point out that this was a real danger and fallacy that’s being committed: mapping something onto an evolutionary tree where the feature — migration or sedentariness — changes faster than new species evolved,” he said. “You would have constructed the history of migration totally differently.”

Story Source:

Materials provided by University of Nebraska-Lincoln. Original written by Scott Schrage. Note: Content may be edited for style and length.


Journal Reference:

  1. Robert M. Zink, Aubrey S. Gardner. Glaciation as a migratory switchScience Advances, 2017; DOI: 10.1126/sciadv.1603133

 

Source: University of Nebraska-Lincoln. “Fly away home? Ice age may have clipped bird migration: Study challenges traditional presumptions of migratory behavior.” ScienceDaily. ScienceDaily, 20 September 2017. <www.sciencedaily.com/releases/2017/09/170920144653.htm>.

Date:
September 19, 2017

Source:
NASA/Goddard Space Flight Center

Summary:
Arctic sea ice appeared to have reached its yearly lowest extent on Sept. 13, scientists have reported. Analysis of satellite data showed that at 1.79 million square miles (4.64 million square kilometers), this year’s Arctic sea ice minimum extent is the eighth lowest in the consistent long-term satellite record, which began in 1978.

 

 

Arctic sea ice appeared to have reached its yearly lowest extent on Sept. 13, NASA and the NASA-supported National Snow and Ice Data Center (NSIDC) at the University of Colorado Boulder have reported. Analysis of satellite data by NSIDC and NASA showed that at 1.79 million square miles (4.64 million square kilometers), this year’s Arctic sea ice minimum extent is the eighth lowest in the consistent long-term satellite record, which began in 1978.

 

Arctic sea ice, the layer of frozen seawater covering much of the Arctic Ocean and neighboring seas, is often referred to as the planet’s air conditioner: its white surface bounces solar energy back to space, cooling the globe. The sea ice cap changes with the season, growing in the autumn and winter and shrinking in the spring and summer. Its minimum summertime extent, which typically occurs in September, has been decreasing, overall, at a rapid pace since the late 1970s due to warming temperatures.

This year, temperatures in the Arctic have been relatively mild for such high latitudes, even cooler than average in some regions. Still, the 2017 minimum sea ice extent is 610,000 square miles (1.58 million square kilometers) below the 1981-2010 average minimum extent.

“How much ice is left at the end of summer in any given year depends on both the state of the ice cover earlier in the year and the weather conditions affecting the ice,” said Claire Parkinson, senior climate scientist at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. “The weather conditions have not been particularly noteworthy this summer. The fact that we still ended up with low sea ice extents is because the baseline ice conditions today are worse than the baseline 38 years ago.”

The three years with the lowest Arctic ice extents on record — 2012, 2016 and 2007 — experienced strong summer storms that hammered the ice cover and sped up its melt. “In all of those cases, the weather conditions contributed to the reduced ice coverage. But if the exact same weather system had occurred three decades ago, it is very unlikely that it would have caused as much damage to the sea ice cover, because back then the ice was thicker and it more completely covered the region, hence making it more able to withstand storms,” Parkinson said.

On the other side of the planet, Antarctica is heading to its maximum yearly sea ice extent, which typically occurs in September or early October. This year’s maximum extent is likely to be among the eight lowest in the satellite record — a dramatic turn of events considering that 2012, 2013 and 2014 all saw consecutive record high maximum extents, followed by a sudden large drop in 2015 and a further although smaller decrease in 2016. So far, the September Antarctic ice extents this year are comparable to those of a year ago.

“What had been most surprising about the changing sea ice coverage in the past three decades was the fact that the Antarctic sea ice was increasing instead of decreasing,” Parkinson said. “The fact of Arctic sea ice decreases was not as shocking because this was expected with a warming climate, although the overall rate of the decreases was greater than most models had forecast.”

Parkinson said that although it is still too early to talk about a long-term reversal in the behavior of Antarctic sea ice, the decreases witnessed in the past two years provide important data to test the various hypotheses that scientists have put forward to explain why Antarctic sea ice coverage had been increasing, overall, between 1979 and 2015.

Adding the Antarctic and Arctic sea ice extents month by month through the satellite record shows that globally the Earth has been losing sea ice since the late 1970s in each portion of the annual cycle of ice growth and decay. “In fact, this year, every single month from January through August experienced a new monthly record low in global sea ice extents,” Parkinson said.

Story Source:

Materials provided by NASA/Goddard Space Flight CenterNote: Content may be edited for style and length.

 

Source: NASA/Goddard Space Flight Center. “End-of-summer Arctic sea ice extent is eighth lowest on record.” ScienceDaily. ScienceDaily, 19 September 2017. <www.sciencedaily.com/releases/2017/09/170919160152.htm>.

Animals in the Goldilocks zone — neither too big, nor too small, but just the right size — face a lower risk of extinction than do those on both ends of the scale

Date:
September 18, 2017

Source:
Oregon State University

Summary:
Animals in the Goldilocks zone — neither too big, nor too small, but just the right size — face a lower risk of extinction than do those on both ends of the scale, according to an extensive global analysis.

 

Extinction risks are greater for animals at the small and large ends of the scale.
Credit: Illustration: Oliver Day, Oregon State University

 

 

Animals in the Goldilocks zone — neither too big, nor too small, but just the right size — face a lower risk of extinction than do those on both ends of the scale, according to an extensive global analysis.

Reporting today in the Proceedings of the National Academy of Sciences, researchers who determined body masses for thousands of vertebrate animal species showed that the largest and smallest species face a greater risk of extinction than do mid-sized animals.

Disproportionate losses at the large and small ends of the scale raise the likelihood of significant changes to the way natural ecosystems function in forests, grasslands, oceans and even rivers and streams — “the living architecture of the planet,” the researchers wrote.

“Knowing how animal body size correlates with the likelihood of a species being threatened provides us with a tool to assess extinction risk for the many species we know very little about,” said William Ripple, a distinguished professor of ecology at Oregon State University and lead author of the study.

Ripple and colleagues from the United States, Australia and Switzerland looked at the more than 27,000 vertebrate animal species assessed by the International Union for the Conservation of Nature in the so-called Red List. About 4,400 are threatened with extinction.

Among the groups of animals evaluated were birds, reptiles, amphibians, bony fishes, cartilaginous fishes (mostly sharks and rays) and mammals.

The largest animals are threatened principally with harvesting by humans. “Many of the larger species are being killed and consumed by humans, and about 90 percent of all threatened species larger than 2.2 pounds (1 kilogram) in size are being threatened by harvesting,” said Ripple.

“Harvesting of these larger animals takes a variety of forms including regulated and unregulated fishing, hunting and trapping for meat consumption, the use of body parts as medicine and killing due to unintentional bycatch,” the authors wrote.

Meanwhile, threats to the smallest animals may be grossly underestimated. The smallest species with high extinction risk consist of tiny vertebrate animals generally less than about 3 ounces (77 grams) in body weight. These diminutive species are mostly threatened by loss or modification of habitat. Examples include the Clarke’s banana frog, sapphire-bellied hummingbird, gray gecko, hog-nosed bat and the waterfall climbing cave fish. Small species that require freshwater habitats are especially imperiled.

Different conservation strategies will be needed to address threats to the largest and smallest animals, the scientists said. Well known mammals at the large end of the scale — whales, elephants, rhinos, lions — have been the target of protection programs, but conservation attention is also needed for large-bodied species that are not mammals. They include large fish, birds, amphibians and reptiles such as the whale shark, Atlantic sturgeon, Somali ostrich, Chinese giant salamander and the Komodo dragon.

Human activity seems poised to chop off both the head and tail of the size distribution of life, the authors added, which will fundamentally restructure many ecological communities.

Story Source:

Materials provided by Oregon State UniversityNote: Content may be edited for style and length.


Journal Reference:

  1. William J. Ripple, Christopher Wolf, Thomas M. Newsome, Michael Hoffmann, Aaron J. Wirsing, and Douglas J. McCauley. Extinction risk is most acute for the world’s largest and smallest vertebratesPNAS, September 18, 2017 DOI: 10.1073/pnas.1702078114

 

Source: Oregon State University. “When it comes to the threat of extinction, size matters: Animals in the Goldilocks zone — neither too big, nor too small, but just the right size — face a lower risk of extinction than do those on both ends of the scale.” ScienceDaily. ScienceDaily, 18 September 2017. <www.sciencedaily.com/releases/2017/09/170918132732.htm>.

Jules Mitchel Receives PharmaVOICE Red Jacket Award

 

This past week, PharmaVOICE honored their PharmVOICE 100 and Red Jacket awards at the Alexandria Center in NYC. Target Health is pleased to announce that Jules Mitchel, President of Target Health Inc. received the coveted Red Jacket Award, together with Jim Curtis, Remedy Health Media; Cameron Durrant, M.D., Humanigen Inc.; Terry Herring Mission Pharmacal; Brian Loew, Inspire; Matt McNally, Publicis Health; and Wendy White, Wendy White Consulting.

 

RBM 2017 Meeting: Risk-Based Trial Management and Monitoring

 

On November 2-3, 2017, Dr. Mitchel will be presenting at CBI’s “RBM 2017 Meeting: Risk-Based Trial Management and Monitoring,“ being held at the Warwick Rittenhouse Square | Philadelphia, PA. The conference theme is: Enhance Process and System Interoperability to Optimize Data Quality, Improve Trial Efficiency and Ensure Compliance.

 

Dr. Mitchel’s topic is “RBM Risk Assessment – What Risks Are We Assessing from the Patient, Study, Site and Sponsor Perspectives?“ In summary, assessing risk is an ongoing process for any industry, and clearly the impact of all risks are not equal. In the clinical research environment, the primary concern is the safety risk to the patient when taking an experimental medicinal product or using an unapproved medical device. Other risks include the impact of not following the protocol and not being complaint with rules and regulations.

 

This session will present a model for risk assessment and will provide concrete examples of risk factors such as:

 

1. the severity of the event, should it happen

2. the likelihood that the event would happen

3. the likelihood of detecting the event

4. risk mitigation strategies for each risk

5. Assessment of unique risks associated with specific studies

 

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

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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Substance in Coffee Delays Onset of Diabetes in Laboratory Mice

The blue circle is the global symbol for diabetes, introduced by the International Diabetes Federation with the aim of giving diabetes a common identity, supporting existing efforts to raise awareness of diabetes and placing the diabetes epidemic firmly in the public spotlight.  Credit: IntDiabetesFed – International Diabetes Federation (IDF). IDF holds all rights to the use of the blue circle for diabetes., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2983689

 

Diabetes mellitus type 2, is also called, 1) ___-onset diabetes. Symptoms include, increased thirst, frequent urination, unexplained weight loss, increased hunger. Complications can include, hyperosmolar hyperglycemic state, diabetic ketoacidosis, heart disease, strokes, diabetic retinopathy, kidney failure. The usual age of onset is middle or older age, and the duration is usually long term. The causes are obesity, lack of exercise and genetic predisposition. 2) ___ tests determine the diagnosis. Prevention consists of,            maintaining normal weight, exercising, eating properly. Treatments include, dietary changes, metformin, insulin, bariatric surgery. The prognosis is a10 year shorter life expectancy.

 

Diabetes mellitus type 2 is a long-term metabolic disorder that is characterized by high blood 3) ___, insulin resistance, and relative lack of insulin. Symptoms may also include feeling tired, and sores that do not 4) ___. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. Some people are more genetically at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. In diabetes mellitus type 1, there is a lower total level of insulin to control blood glucose, due to an autoimmune induced loss of insulin-producing beta cells in the pancreas. Diagnosis of diabetes is by blood tests such as fasting plasma glucose, oral glucose tolerance test, or glycated hemoglobin (A1C).

 

Type 2 diabetes is partly preventable by maintaining a normal 5) ___, exercising regularly, and eating properly. Treatment involves exercise and dietary changes. If blood sugar levels are not adequately lowered, the medication metformin is typically recommended. Many people may eventually also require insulin injections. In those on insulin, routinely checking blood sugar levels is advised; however, this may not be needed in those taking pills. Bariatric surgery often improves diabetes in those who are obese. Rates of type 2 diabetes have increased markedly since 1960 in parallel with 6) ___. As of 2015, there were approximately 392 million people diagnosed with the disease compared to around 30 million in 1985. Typically it begins in middle or older age, although rates of type 2 diabetes are increasing in young people. Type 2 diabetes is associated with a ten-year-shorter life expectancy. Historically, diabetes was one of the first diseases described. The importance of insulin in the disease was determined in the 1920s.

 

In September 2017, researchers identified substances in coffee that could help quash the risk of developing Type 2 diabetes. But few of these have been tested in animals. Now in a study appearing in the Journal of Natural Products, it was reported that one of these previously untested compounds appears to improve cell function and insulin sensitivity in laboratory 7) ___. The finding could spur the development of new drugs to treat or even prevent the disease. Some studies suggest that drinking three to four cups of 8) ___ a day can reduce the risk of developing Type 2 diabetes. Initially, it was suspected that caffeine was responsible for this effect. But other findings, suggested that other substances in coffee may have had a more important role. In a previous laboratory study, it was found that a compound in coffee called cafestol, increased insulin secretion in pancreatic cells when they were exposed to 9) ___. Cafestol also increased glucose uptake in muscle cells just as effectively as a commonly prescribed antidiabetic drug. In this new study, the researchers wanted to see if cafestol would help prevent or delay the onset of Type 2 diabetes in mice. The researchers divided mice that are prone to develop Type 2 diabetes into three groups. Two of the groups were fed differing doses of cafestol. After 10 weeks, both sets of cafestol-fed mice had lower blood glucose levels and improved insulin secretory capacity compared to a control group, which was not given the compound. Cafestol also didn’t result in hypoglycemia, or low blood sugar, a possible side effect of some antidiabetic medications. The study conclude that daily consumption of 10) ___ can delay the onset of Type 2 diabetes in these mice, and that it is a good candidate for drug development to treat or prevent the disease in humans.

 

Sources: American Chemical Society; Fredrik Brustad Mellbye, Per Bendix Jeppesen, Pedram Shokouh, Christoffer Laustsen, Kjeld Hermansen, S?ren Gregersen. Cafestol, a Bioactive Substance in Coffee, Has Antidiabetic Properties in KKAy Mice. Journal of Natural Products, 2017; 80 (8): 2353 DOI: 10.1021/acs.jnatprod.7b00395

 

The darker the orange, the more prevalent the diabetes cases.

Graphic credit: Lokal_Profil, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=8351261

 

ANSWERS: 1) adult; 2) Blood; 3) sugar; 4) heal; 5) weight; 6) obesity; 7) mice; 8) coffee; 9) glucose; 10) cafestol

 

Diabetes

From ancient Egyptian medical papyruses, like the Edwin Smith Papyrus, above, we know that the symptoms of diabetes were known in 1552 BC, including the understanding that ants were attracted to people with this disease. Source: Wikipedia

 

 

Diabetes mellitus is one of the oldest known human diseases.

 

The first known mention of diabetes symptoms was in 1552 BCE, when Hesy-Ra, an Egyptian physician, documented, in an Egyptian papyrus, frequent urination as a symptom of a mysterious disease that also caused emaciation. Also around this time, ancient healers noted that ants seemed to be attracted to the urine of people who had this disease. Type 1 and type 2 diabetes were also identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400-500 CE with type 1 associated with youth and type 2 with being overweight. The term “mellitus“ or “from honey“ was added by the Briton John Rolle in the late 1700’s to separate the condition from diabetes insipidus which is also associated with frequent urination. The term “diabetes“ or “to pass through“ was first used in 230 BCE by the Greek Apollonius of Memphis. The disease was rare during the time of the Roman empire with Galen commenting that he had only seen two cases during his career. In 150 CE, the Greek physician Arateus described what we now call diabetes as “the melting down of flesh and limbs into urine.“ From then on, physicians began to gain a better understanding of diabetes.

 

Centuries later, people known as “water tasters“ diagnosed diabetes by tasting the urine of people suspected to have it. If urine tasted sweet, diabetes was diagnosed. To acknowledge this feature, in 1675 the word “mellitus,“ meaning honey, was added to the name “diabetes,“ meaning siphon. It wasn’t until the 1800’s that scientists developed chemical tests to detect the presence of sugar in the urine. As physicians learned more about diabetes, they began to understand how it could be managed. The first diabetes treatment involved prescribed exercise, often horseback riding, which was thought to relieve excessive urination. In the 1700’s and 1800’s, physicians began to realize that dietary changes could help manage diabetes, and they advised their patients to do things like eat only the fat and meat of animals or not consume large amounts of sugar. During the Franco-Prussian War of the early 1870’s, the French physician Apollinaire Bouchardat noted that his diabetic patients’ symptoms improved due to war-related food rationing, and he developed individualized diets as diabetes treatments. This led to the fad diets of the early 1900s, which included the “oat-cure,“ “potato therapy,“ and the “starvation diet.“

 

In 1916, Boston scientist Elliott Joslin established himself as one of the world’s leading diabetes experts by creating the textbook “The Treatment of Diabetes Mellitus,“ which reported that a fasting diet combined with regular exercise could significantly reduce the risk of death in diabetes patients. Today, doctors and diabetes educators still use these principles when teaching their patients about lifestyle changes for the management of diabetes. Despite these advances, before the discovery of insulin, diabetes inevitably led to premature death. The first big breakthrough that eventually led to the use of insulin to treat diabetes was in 1889, when Oskar Minkowski and Joseph von Mering, researchers at the University of Strasbourg in France, showed that the removal of a dog’s pancreas could induce diabetes. In the early 1900s, Georg Zuelzer, a German scientist, found that injecting pancreatic extract into patients could help control diabetes. Frederick Banting, a physician in Ontario, Canada, first had the idea to use insulin to treat diabetes in 1920, and he and his colleagues began trying out his theory in animal experiments. Banting and his team finally used insulin to successfully treat a diabetic patient in 1922 and were awarded the Nobel Prize in Medicine the following year.

 

Frederick Banting in 1938: Photo credit: Arthur Goss – Library and Archives of Canada – PA-123481, Public Domain, https://commons.wikimedia.org/w/index.php?curid=468141

 

A “Flame of Hope” was lit by Her Majesty Queen Elizabeth the Queen Mother in 1989 as a tribute to Dr. Frederick Banting and all the people that have lost their lives to diabetes. The flame will remain lit until there is a cure for diabetes. When a cure is found, the flame will be extinguished by the researchers who discover the cure. The flame is located at Sir Frederick Banting Square in London, Ontario, Canada beside the Banting House National Historic Site of Canada.

 

Best and Banting in 1924.  Photo credit: University of Toronto, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5956010

 

A time capsule was buried in the Sir Frederick Banting Square in 1991 to honor the 100th anniversary of Sir Frederick Banting’s birth. It was buried by the International Diabetes Federation Youth Representatives and Governor General of Canada Ray Hnatyshyn. It will be exhumed if a cure for diabetes is found. Prior to the award of the Nobel Prize in Physiology or Medicine for 1923, which Banting shared with Macleod, he received the Reeve Prize of the University of Toronto (1922). In 1928 Banting gave the Cameron Lecture in Edinburgh. He was a member of numerous medical academies and societies in Canada and abroad, including the British and American Physiological Societies, and the American Pharmacological Society. In 1934 he was knighted as a Knight Commander of the Order of the British Empire (KBE) and became an active Vice-President of the Diabetic Association (now Diabetes UK). In May, 1935 he was elected a Fellow of the Royal Society. In 2004, Banting was inducted into the National Inventors Hall of Fame.

 

Sir Frederick Grant Banting

 

Sir Frederick Grant Banting, KBE MC FRS FRSC (November 14, 1891 – February 21, 1941) was a Canadian medical scientist, physician, painter, and Nobel laureate noted as the co-discoverer of insulin and its therapeutic potential. In 1923 Banting and John James Rickard Macleod received the Nobel Prize in Medicine. Banting shared the award money with his colleague, Dr. Charles Best. As of November 2016, Banting, who received the Nobel Prize at age 32, remains the youngest Nobel laureate in the area of Physiology/Medicine. In 1923 the Government of Canada granted Banting a lifetime annuity to continue his work. In 1934 he was knighted by King George V.

 

Frederick Banting was born on November 14, 1891, in a farm house near Alliston, Ontario. The youngest of five children of William Thompson Banting and Margaret Grant, Banting attended public high schools in Alliston. In 1910, he started at Victoria College, part of the University of Toronto, in the General Arts program. After failing his first year, he petitioned to join the medical program in 1912 and was accepted. He began medical school in September 1912. In 1914, he attempted to enter the army on August 5, and then again in October, but was refused due to poor eyesight. Banting successfully joined the army in 1915, and spent the summer training before returning to school. His class was fast-tracked to get more doctors into the war and so he graduated in December 1916 and reported for military duty the next day. He was wounded at the Battle of Cambrai in 1918. Despite his injuries, he helped other wounded men for sixteen hours, until another doctor told him to stop. He was awarded the Military Cross in 1919, for heroism.

 

Banting returned to Canada after the war and went to Toronto to complete his surgical training. He studied orthopedic medicine and, in 1919-1920, was Resident Surgeon at The Hospital for Sick Children. Banting was unable to gain a place on the hospital staff and so he decided to move to London, Ontario to set up a medical practice. From July 1920 to May 1921, he continued his general practice, while teaching orthopedics and anthropology part-time at the University of Western Ontario in London because his medical practice had not been particularly successful. From 1921 to 1922 he lectured in pharmacology at the University of Toronto. He received his M.D. degree in 1922, and was also awarded a gold medal. An article he read about the pancreas piqued Banting’s interest in diabetes. Banting had to give a talk on the pancreas to one of his classes at the University of Western Ontario on November 1, 1920, and as a result, read reports that other scientists had written. Research by German pathologist Bernhard Naunyn, Oskar Minkowski, American physician and pathologist Eugene Lindsay Opie, English physiologist Edward Albert Sharpey-Schafer, and others suggested that diabetes resulted from a lack of a protein hormone secreted by the islets of Langerhans in the pancreas. Schafer had named this putative hormone “insulin“. Insulin was thought to control the metabolism of sugar; its lack led to an increase of sugar in the blood which was then excreted in urine. Attempts to extract insulin from ground-up pancreas cells were unsuccessful, likely because of the destruction of the insulin by the proteolysis enzyme of the pancreas. The challenge was to find a way to extract insulin from the pancreas prior to it being destroyed.

 

Moses Barron published an article in 1920 which described experimental closure of the pancreatic duct by ligature; this further influenced Banting’s thinking. The procedure caused deterioration of the cells of the pancreas that secrete trypsin which breaks down insulin, but it left the islets of Langerhans intact. Banting realized that this procedure would destroy the trypsin-secreting cells but not the insulin. Once the trypsin-secreting cells had died, insulin could be extracted from the islets of Langerhans. Banting discussed this approach with J. J. R. Macleod, Professor of Physiology at the University of Toronto. Macleod provided experimental facilities and the assistance of one of his students, Dr. Charles Best. Banting and Best, with the assistance of biochemist James Collip, began the production of insulin by this means. As the experiments proceeded, the required quantities could no longer be obtained by performing surgery on living dogs. On November 16, 1921, Banting hit upon the idea of obtaining insulin from the fetal pancreas. He removed the pancreases from fetal calves at a William Davies slaughterhouse and found the extracts to be just as potent as those extracted from the dog pancreases. Pork and beef would remain the primary commercial sources of insulin until they were replaced by genetically-engineered bacteria in the late 20th century. In spring of 1922, Banting established a private practice in Toronto and began to treat diabetic patients, including Elizabeth Hughes Gossett, daughter of then U.S. Secretary of State Charles Evans Hughes.

 

Banting and Macleod were jointly awarded the 1923 Nobel Prize in Physiology or Medicine. Banting split his half of the Prize money with Best, and Macleod split the other half of the Prize money with James Collip. Banting was appointed Senior Demonstrator in Medicine at the University of Toronto in 1922. The following year he was elected to the new Banting and Best Chair of Medical Research, endowed by the Legislature of the Province of Ontario. He also served as Honorary Consulting Physician to the Toronto General, the Hospital for Sick Children, and the Toronto Western Hospital. At the Banting and Best Institute, he focused his research on silicosis, cancer, and the mechanisms of drowning. In 1938, Banting’s interest in aviation medicine resulted in his participation with the Royal Canadian Air Force (RCAF) in research concerning the physiological problems encountered by pilots operating high-altitude combat aircraft. Banting headed the RCAF’s Number 1 Clinical Investigation Unit (CIU), which was housed in a secret facility on the grounds of the former Eglington Hunt Club in Toronto. During the Second World War he investigated the problems of aviators, such as “blackout“ (syncope). He also helped Wilbur Franks with the invention of the G-suit to stop pilots from blacking out when they were subjected to g-forces while turning or diving. Another of Banting’s projects during the Second World War involved using and treating mustard gas burns. Banting even tested the gas and antidotes on himself to see if they were effective.

 

Banting developed an interest in painting beginning around 1921 while he was in London, Ontario. Some of his first pieces were done on the back of the cardboard in which his shirts were packed by the dry-cleaners. He became friends with The Group of Seven artists A. Y. Jackson and Lawren Harris, sharing their love of the rugged Canadian landscape. In 1927 he made a sketching trip with Jackson to the St. Lawrence River in Quebec. Later that year they traveled to RCMP outposts in the Arctic on the Canadian Government supply ship Beothic. The sketches, done both in oils on birch panels and in pen and ink, were named after the places he visited: Craig Harbor, Ellesmere Island; Pond Inlet, Baylot Island; Eskimo tents at Etach; others were untitled. Jackson and Banting also made painting expeditions to Great Slave Lake, Walsh Lake (Northwest Territories), Georgian Bay, French River and the Sudbury District.

 

Banting married twice. His first marriage was to Marion Robertson in 1924; they had one child, William (born 1928). They divorced in 1932 and Banting married Henrietta Ball in 1937. Four years later, In February 1941, Banting died of wounds and exposure following the crash of a Lockheed L-14 Super Electra/Hudson in which he was a passenger, in Musgrave Harbor, Newfoundland. After departing from Gander, Newfoundland, both of the plane’s engines failed. The navigator and co-pilot died instantly, but Banting and the pilot, Captain Joseph Mackey, survived the initial impact. According to Mackey, the sole survivor, Banting died from his injuries the next day. Banting was en route to England to conduct operational tests on the Franks flying suit developed by his colleague Wilbur Franks. Banting and his wife are buried at Mount Pleasant Cemetery in Toronto.

 

In 1994 Banting was inducted into the Canadian Medical Hall of Fame. In 2004, he was nominated as one of the top 10 “Greatest Canadians“ by viewers of the Canadian Broadcasting Corporation. When the final votes were counted, Banting finished fourth behind Tommy Douglas, Terry Fox and Pierre Trudeau.

 

Banting’s namesake, the Banting Research Foundation, was created in 1925 and provides funding to support health and biomedical research in Canada. Banting’s name is immortalized in the yearly Banting Lectures, given by an expert in diabetes, and by the creation of the Banting and Best Department of Medical Research of the University of Toronto; Sir Frederick G Banting Research Centre located on Sir Frederick Banting Driveway in the Tunney’s Pasture complex, Ottawa, ON; Banting Memorial High School in Alliston, ON; Sir Frederick Banting Secondary School in London, ON; Sir Frederick Banting Alternative Program Site in Ottawa, ON; Frederick Banting Elementary School in Montr?al-Nord QC and ?cole Banting Middle School in Coquitlam, BC. The “Major Sir Frederick Banting, MC, RCAMC Award for Military Health Research“, sponsored by the True Patriot Love Foundation, is awarded annually by the Surgeon General to the researcher whose work presented at the annual Military and Veterans Health Research Forum is deemed to contribute most to military health. It was first awarded in 2011 in the presence of several Banting descendants. The “Canadian Forces Major Sir Frederick Banting Term Chair in Military Trauma Research“ at Sunnybrook Health Sciences Centre was established in 2012. The first Chair holder is Colonel Homer Tien, Medical Director of Sunnybrook’s Tory Regional Trauma Centre and Senior Specialist and Trauma Adviser to the Surgeon General. The Banting Postdoctoral Fellowship Program is administered by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council of Canada. The fellowship provided up to two years of funding at $70,000 per year to researchers in health, natural sciences, engineering, social sciences and humanities.

 

Banting House, his former home located in London, Ontario, was declared a National Historic Site of Canada in 1997. The Banting Interpretation Centre in Musgrave Harbor, Newfoundland and Labrador is a museum named after him which focuses on the circumstances surrounding the 1941 plane crash which claimed his life. The crater Banting on the Moon is also named after him for his contributions to medicine. During the voting for “Greatest Canadians“ in late 2003, controversy arose over the future use of the Banting family farm in New Tecumseth which had been left to the Ontario Historical Society by Banting’s late nephew, Edward, in 1998. The dispute centered on the future use of the 40 ha (100 acre) property and its buildings. In a year-long negotiation, assisted by a provincially appointed facilitator, the Town of New Tecumseth offered $1 million to the Ontario Historical Society (OHS). The town intended to turn the property over to the Sir Frederick Banting Legacy Foundation for preservation of the property and buildings, and the Legacy Foundation planned to erect a Camp for Diabetic Youths. The day after the November 22, 2006, deadline for the OHS to sign the agreement, the OHS announced that it had sold the property for housing development to Solmar Development for more than $2 million. The Town of New Tecumseth announced it would designate the property under the Ontario Heritage Act. This would prevent its commercial development and obligate the owner to maintain it properly. OHS objected. The Ontario Conservation Review Board heard arguments for and against designation in September 2007 and recommended designation of the entire property in October. The Town officially passed the designation by-law on November 12, 2007.

 

Banting’s artwork has gained attention in the art community; A painting of his called “St. T?te des Cap“ sold for $30,000 including buyer’s premium at a Canadian art auction in Toronto.

 

He and his insulin discovery have also been depicted in various media formats, including comic books, the biography by Michael Bliss, and on television. The National Film Board of Canada produced a short film in 1958, The Quest, about his initial insulin experiments on dogs. The 1988 television movie Glory Enough for All depicted the search for insulin by Banting and Best, with R. H. Thomson starring as Banting. Banting is also portrayed by Jason Priestley boarding his fatal flight in the 2006 historical drama Above and Beyond.

 

Zika Virus Selectively Infects and Kills Glioblastoma Cells in Mice

 

Even with current treatments, patients with glioblastomas – a highly malignant type of brain tumor – tend to have poor survival rates. Glioblastomas grow aggressively from a mass of unspecialized cells and ZIKV is known to infect similar cells in the nervous systems of developing fetuses. According to an article published online in The Journal of Experimental Medicine (5 September 2017), the Zika virus (ZIKV) may infect and kill a specific type of brain cancer cell, while leaving normal adult brain tissue minimally affected. In the paper, the authors describe the impact of ZIKV on glioblastoma cells in both human tissue samples and mice.

 

In this laboratory study, the authors introduced ZIKV to glioblastoma tissue samples removed from cancer patients as part of their treatment, as well as to healthy human neural tissue cultures. After seven days, ZIKV had replicated in certain glioblastoma cells and prevented them from multiplying, while the ordinary neural tissue cultures remained largely uninfected. The authors also tested mice with glioblastomas, treating an experimental group with a mouse-adapted strain of ZIKV. Mice who received ZIKV survived longer than mice in the control group, and their tumors were significantly smaller than those in the control mice after one week.

 

The authors caution that ZIKV may behave differently when introduced to an active glioblastoma in a living person, and that even if further studies continue to yield promising results, any potential treatment derived from ZIKV would need many years of rigorous testing for safety and efficacy.

 

Robotic Exoskeleton Offers Potential New Approach to Alleviating Crouch Gait in Children with Cerebral Palsy

 

Cerebral palsy is the most prevalent childhood movement disorder in the U.S. with approximately 10,000 new cases diagnosed each year. It is caused by a brain injury or abnormality in infancy or early childhood that disrupts the control of movement, posture, and balance. According to an article published in Science Translational Medicine (23 August 2017) , researchers from the NIH Clinical Center Rehabilitation Medicine Department have created the first robotic exoskeleton specifically designed to treat crouch (or flexed-knee) gait in children with cerebral palsy by providing powered knee extension assistance at key points during the walking cycle. Crouch gait, the excessive bending of the knees while walking, is a common and debilitating condition in children with cerebral palsy. Despite conventional treatments (including muscle injections, surgery, physical therapy, and orthotics), crouch gait can lead to a progressive degeneration of the walking function, ultimately resulting in the loss of walking ability in roughly half of adults with the disorder.

 

The authors tested their prototype powered knee exoskeleton in a cohort study to:

 

–Determine if motorized knee extension assistance safely and effectively reduced crouch gait during walking in ambulatory children with cerebral palsy.

 

–Evaluate its effect on voluntary muscle activity to determine whether children continued to use their own muscles during walking with motorized assistance.

 

–Quantify short term alterations in lower limb gait biomechanics in response to robotic knee extension assistance.

 

The study followed seven individuals between the ages of 5 and 19 who were diagnosed with crouch gait from cerebral palsy and had Gross Motor Function Classification System levels I-II, meaning each could walk at least 30 feet without use of a walking aid. Results showed that walking with the exoskeleton was well-tolerated with all participants able to walk independently without a mobility aids or therapist assistance with six doing so in the first practice session. Improvements in knee extension were observed in six participants with gains (8-37?) similar to or greater than average improvements reported from invasive surgical interventions. Importantly, the gains in knee extension occurred without a reduction in knee extensor muscle activity, indicating that these participants worked with the exoskeleton rather than offloading the task of straightening the leg during walking to the robot.

 

According to the authors, this study paves the way for the exoskeleton’s use outside the clinic setting, greatly increasing the amount and intensity of gait training, which they believe is key to successful long-term outcomes in this population. This study is also the first step toward the long-term goal of implementing a novel device-based approach to treating crouch gait, and suggests that powered knee exoskeletons should be investigated as an alternative to or in conjunction with conventional treatments. The results of this study provide evidence to support further device development and larger controlled intervention studies of pediatric exoskeleton efficacy for gait rehabilitation in cerebral palsy and other disorders.

 

“Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress

 

According to the FDA BLOG, authored by Michael Kopcha, Ph.D., R.Ph., FDA’s Director, Office of Pharmaceutical Quality, CDER, a new and exciting technology – continuous manufacturing (CM) – can transform the drug manufacturing process so that it is more reliable and efficient. A previous blog discussed how CM enables a much faster and more reliable manufacturing process. In some cases, manufacturing that takes a month to complete with older technology – often called batch technology – might only take days using CM. FDA is seeking input, through a public docket open until September 21, from experts in the field about the science, technology, and best practices concerning CM.

 

As with any new technology, implementing CM presents challenges, such as the initial cost of investing in new equipment. However, the CM production method offers clear benefits for both patients and industry. CM can shorten production times and improve the efficiency of the manufacturing process. CM also allows for more nimble testing and control that can help reduce the likelihood of manufacturing failures. These control strategies could potentially contribute to the prevention of drug shortages. CM technology can be implemented for an entire production process, or for specific operations within the process. Manufacturers can tailor their use of CM based on their particular product and business needs.

 

Congress has recognized the potential benefits CM can offer for drug manufacturing as well. The 21st Century Cures Act, enacted in December 2016, authorized grants to support studying CM and recommending improvements to the process of continuous manufacturing of drugs and biological products. FDA is encouraging adoption of this technology by engaging with firms interested in using CM. FDA’s Emerging Technology Team (ETT) assists companies that want to implement innovative technology, including CM, for manufacturing both new and existing drugs. FDA has already seen two companies that have implemented CM and benefited from early engagement with the ETT. Vertex has been using a CM process for their cystic fibrosis drug, Orkambi (lumacaftor/ivacaftor), since its approval in July 2015. In 2016, FDA approved a change in production from batch to continuous manufacturing for Janssen Products’ medication to treat HIV-1 infection, Prezista (darunavir).

 

With many companies now evaluating their operations for potential uses of CM, some have found specific ways to utilize CM techniques in their own production processes. As a result of these individual efforts, there are now a variety of different approaches for implementing CM technology throughout industry. Given these emerging variations, FDA’s goal is to provide a framework of principles that clarify our expectations, while still encouraging companies to innovate and implement CM. FDA is are talking with industry and are also helping lead this conversation on a global level by engaging our foreign regulatory counterparts regarding the development of clear regulatory standards. To further this effort and gather more input from experts, FDA has opened the public docketfor comment until September 21. FDA is interested in getting public feedback on published documents on this topic, including an industry-coordinated best practices document issued by the public-private consortium Center for Structured Organic Particulate Systems (C-SOPS), and white papers from a 2014 symposium published in the Journal of Pharmaceutical Sciences.

 

Assuring the availability of quality, safe and effective medications to the American public is a priority for FDA. CM, and other innovative manufacturing and control strategies, offer ways for the pharmaceutical industry to continue to help support this goal. By drawing upon the experience of FDA, industry, and academia, together, common guiding principles will be developed to support implementation of CM, building on the great progress made by industry to date.

 

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