Findings could lead to non-toxic drugs that block diseases’ chemistry

Date:
January 28, 2016

Source:
University of Iowa

Summary:
Chemists have revealed the chemistry behind how certain diseases, from anthrax to tuberculosis, replicate. The key lies in the function of a gene absent in humans, called thyX, and its ability to catalyze the DNA building block thymine. The finding could help drug companies target the chemical reaction, rather than testing millions of compounds, to stop these diseases.

 

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University of Iowa chemists have unraveled the chemistry underlying how some deadly diseases, such as tuberculosis, produce thymine, a DNA base critical for these diseases to survive and reproduce. The team found these diseases use a different chemical pathway that involves an enzymatic relay system called flavin. The finding could help drug companies target the chemical reaction, rather than testing millions of compounds, to stop these diseases.
Credit: Amnon Kohen lab, University of Iowa

 

 

Humans have been successful at treating a host of diseases. Yet some continue to elude medicine’s best attempts.

Tuberculosis killed 15 percent of the 9.6 million people who contracted it worldwide in 2014. Typhus has flared periodically throughout history, with deadly consequences. Rocky Mountain spotted fever is a tick-borne threat in North and South America. Pneumonia is common everywhere.

What unites these diseases is their ability to fend off antibiotics and continue to reproduce, through a mysterious molecular route that yields thymine, a DNA building block the bacteria need to survive and reproduce.

Now, researchers at the University of Iowa have revealed how these diseases replicate by tracing the precise steps through which they use a gene absent in humans, called thyX, to code an enzyme to produce thymine. In a paper published online Jan. 28 in the journal Science, the Iowa chemists break down each stage in a rapid-fire chain of chemical reactions showing how thyX and the enzyme it encodes are used in the diseases’ DNA-production cycle.

The discovery could lead to the creation of non-toxic antibiotics that block the chemical reaction involving thyX, rather than relying on the current method of testing millions of drug compounds in the hopes of finding one that would faithfully kill each disease.

“We know a lot about these pathogens, but we didn’t know how the enzyme with them is catalyzing the reactions for DNA synthesis–the chemistry behind it,” says Amnon Kohen, a chemistry professor at the UI and corresponding author on the paper. “Now, we’re showing at the molecular level, the principal steps by which the thyX-encoded enzyme catalyzes the production of thymine’s precursor, thymidylate.”

ThyX has lurked, undetected, for eons. Scientists first spotted the gene when they noticed that thermophilic bacteria–ancient organisms that live at very high temperatures and pressures around deep-ocean vents–were able to produce thymine even though they didn’t seem to have the genes to do it. In 2002, a research group in France pinpointed the heretofore mystery genes, and called them thyX. These new–or rather, ancient–genes seemed to produce thymine similar to the human gene thyA but had evolved separately.

No one knew why.

Kohen’s group dove deep into molecular chemistry to figure it out.

The team linked up with the UI’s Nuclear Magnetic Resonance facility to identify a critical intermediate of the reaction catalyzed by FDTS, an enzyme coded by thyX. When they compared that intermediate to those found in human enzymes, they found the paths to thymine were completely different. The human enzymes are encoded by folA and thyA genes, and their catalytic path involves a covalent bond activating one reactant, and direct chemistry between two reactants. The thyX-encoded FDTS, on the other hand, makes no bond with the reactant and conducts the chemistry through an enzymatic relay system (flavin).

“Actually, there are hardly any similarities between the classical mechanism found in humans and the newly discovered one,” Kohen says.

Several deadly diseases rely exclusively on thyX for survival and reproduction. Others, such as tuberculosis, can synthesize thymine with thyA or thyX, which makes them fiendishly difficult to eradicate because they can switch to another thymine pathway if one has been blocked. That explains why tuberculosis strains have become resistant to multiple drugs and thus difficult to contain.

Now that thyX’s role has been revealed, pharmaceutical companies can zero in on a product that gums up the cycle.

“Once it’s stuck, you’re dead in the water,” Kohen said.

Tatiana Mishanina, formerly with Kohen’s group and now at the University of Wisconsin-Madison, is the paper’s first author. Contributing authors are Liping Yu, director of the UI’s NMR facility, and members of Kohen’s group: Kalani Karunaratne, Dibyendu Mondal, John Corcoran, and Michael Choi.

The National Institutes of Health (grants R01 GM1 10775 and T32 GM008365) funded the study.

Here is a list of bacteria that use the gene thyX to replicate, and their associated diseases and conditions. Some also have a second pathway, using a gene found in humans–thyA–to reproduce.

Bacillus anthracis–anthrax

Borrelia burgdorferi–Lyme disease

Campylobacter jejuni–diarrhea

Chlamydia trachomatis–trachoma

Chlamydia pneumonia–pneumonia

Clostridium botulinum–botulism

Helicobacter pylori–stomach ulcer, gastric cancer

Mycobacterium leprae–leprosy

Mycobacterium tuberculosis–tuberculosis

Rickettsia prowazeki–typhus

Rickettsia rickettsii–Rocky Mountain spotted fever

Treponema pallidum–syphillis


Story Source:

The above post is reprinted from materials provided by University of Iowa. The original item was written by Richard C. Lewis. Note: Materials may be edited for content and length.


Journal Reference:

  1. T. V. Mishanina, L. Yu, K. Karunaratne, D. Mondal, J. M. Corcoran, M. A. Choi, A. Kohen. An unprecedented mechanism of nucleotide methylation in organisms containing thyX. Science, 2016; 351 (6272): 507 DOI: 10.1126/science.aad0300

 

Source: University of Iowa. “Chemists uncover how key agent allows diseases to reproduce: Findings could lead to non-toxic drugs that block diseases’ chemistry.” ScienceDaily. ScienceDaily, 28 January 2016. <www.sciencedaily.com/releases/2016/01/160128151942.htm>.

Date:
January 28, 2016

Source:
Space Telescope Science Institute (STScI)

Summary:
New Hubble telescope observations suggest that a high-velocity gas cloud was launched from the outer regions of our own galaxy around 70 million years ago. Now, the cloud is on a return collision course and is expected to plow into the Milky Way’s disk in about 30 million years. Astronomers believe it will ignite a spectacular burst of star formation then.

 

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This composite image shows the size and location of the Smith Cloud on the sky. The cloud appears in false-color, radio wavelengths as observed by the Robert C. Byrd Green Bank Telescope in West Virginia. The visible-light image of the background star field shows the cloud’s location in the direction of the summer constellation Aquila. The cloud is 15 degrees across in angular size — the width of an outstretched hand at arm’s length. The apparent size of the full moon is added for comparison.
Credit: B. Saxton and F. Lockman (NRAO/AUI/NSF), and A. Mellinger

 

 

Hubble Space Telescope astronomers are finding that the old adage “what goes up must come down” even applies to an immense cloud of hydrogen gas outside our Milky Way galaxy. The invisible cloud is plummeting toward our galaxy at nearly 700,000 miles per hour.

Though hundreds of enormous, high-velocity gas clouds whiz around the outskirts of our galaxy, this so-called “Smith Cloud” is unique because its trajectory is well known. New Hubble observations suggest it was launched from the outer regions of the galactic disk, around 70 million years ago. The cloud was discovered in the early 1960s by doctoral astronomy student Gail Smith, who detected the radio waves emitted by its hydrogen.

The cloud is on a return collision course and is expected to plow into the Milky Way’s disk in about 30 million years. When it does, astronomers believe it will ignite a spectacular burst of star formation, perhaps providing enough gas to make 2 million suns.

“The cloud is an example of how the galaxy is changing with time,” explained team leader Andrew Fox of the Space Telescope Science Institute in Baltimore, Maryland. “It’s telling us that the Milky Way is a bubbling, very active place where gas can be thrown out of one part of the disk and then return back down into another.”

“Our galaxy is recycling its gas through clouds, the Smith Cloud being one example, and will form stars in different places than before. Hubble’s measurements of the Smith Cloud are helping us to visualize how active the disks of galaxies are,” Fox said.

Astronomers have measured this comet-shaped region of gas to be 11,000 light-years long and 2,500 light-years across. If the cloud could be seen in visible light, it would span the sky with an apparent diameter 30 times greater than the size of the full moon.

Astronomers long thought that the Smith Cloud might be a failed, starless galaxy, or gas falling into the Milky Way from intergalactic space. If either of these scenarios proved true, the cloud would contain mainly hydrogen and helium, not the heavier elements made by stars. But if it came from within the galaxy, it would contain more of the elements found within our sun.

The team used Hubble to measure the Smith Cloud’s chemical composition for the first time, to determine where it came from. They observed the ultraviolet light from the bright cores of three active galaxies that reside billions of light-years beyond the cloud. Using Hubble’s Cosmic Origins Spectrograph, they measured how this light filters through the cloud.

In particular, they looked for sulfur in the cloud which can absorb ultraviolet light. “By measuring sulfur, you can learn how enriched in sulfur atoms the cloud is compared to the sun,” Fox explained. Sulfur is a good gauge of how many heavier elements reside in the cloud.

The astronomers found that the Smith Cloud is as rich in sulfur as the Milky Way’s outer disk, a region about 40,000 light-years from the galaxy’s center (about 15,000 light-years farther out than our sun and solar system). This means that the Smith Cloud was enriched by material from stars. This would not happen if it were pristine hydrogen from outside the galaxy, or if it were the remnant of a failed galaxy devoid of stars. Instead, the cloud appears to have been ejected from within the Milky Way and is now boomeranging back.

Though this settles the mystery of the Smith Cloud’s origin, it raises new questions: How did the cloud get to where it is now? What calamitous event could have catapulted it from the Milky Way’s disk, and how did it remain intact? Could it be a region of dark matter — an invisible form of matter — that passed through the disk and captured Milky Way gas? The answers may be found in future research.


Story Source:

The above post is reprinted from materials provided by Space Telescope Science Institute (STScI). Note: Materials may be edited for content and length.


Journal Reference:

  1. Andrew J. Fox, Nicolas Lehner, Felix J. Lockman, Bart P. Wakker, Alex S. Hill, Fabian Heitsch, David V. Stark, Kathleen A. Barger, Kenneth R. Sembach, Mubdi Rahman. ON THE METALLICITY AND ORIGIN OF THE SMITH HIGH-VELOCITY CLOUD. The Astrophysical Journal, 2015; 816 (1): L11 DOI: 10.3847/2041-8205/816/1/L11

 

Source: Space Telescope Science Institute (STScI). “Monstrous cloud boomerangs back to our galaxy.” ScienceDaily. ScienceDaily, 28 January 2016. <www.sciencedaily.com/releases/2016/01/160128155751.htm>.

First observational evidence for assembly bias could impact understanding of the universe

Date:
January 25, 2016

Source:
Carnegie Mellon University

Summary:
An international team of researchers has shown that the relationship between galaxy clusters and their surrounding dark matter halo is more complex than previously thought. The researchers’ findings are the first to use observational data to show that, in addition to mass, a galaxy cluster’s formation history plays a role in how it interacts with its environment.

 

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These are density maps of galaxy cluster distribution.
Credit: Kavli IPMU

 

 

An international team of researchers, including Carnegie Mellon University’s Rachel Mandelbaum, has shown that the relationship between galaxy clusters and their surrounding dark matter halo is more complex than previously thought. The researchers’ findings, published in Physical Review Letters today (Jan. 25), are the first to use observational data to show that, in addition to mass, a galaxy cluster’s formation history plays a role in how it interacts with its environment.

There is a connection between galaxy clusters and their dark matter halos that holds a great deal of information about the universe’s content of dark matter and accelerating expansion due to dark energy. Galaxy clusters are groupings of hundreds to thousands of galaxies bound together by gravity, and are the most massive structures found in the universe. These clusters are embedded in a halo of invisible dark matter. Traditionally, cosmologists have predicted and interpreted clustering by calculating just the masses of the clusters and their halos. However, theoretical studies and cosmological simulations suggested that mass is not the only element at play — something called assembly bias, which takes into account when and how a galaxy cluster formed, also could impact clustering.

“Simulations have shown us that assembly bias should be part of our picture,” said Mandelbaum, a member of Carnegie Mellon’s McWilliams Center for Cosmology. “Confirming this observationally is an important piece of understanding galaxy and galaxy cluster formation and evolution.”

In the current study, the research team, led by Hironao Miyatake, Surhud More and Masahiro Takada of the Kavli Institute for the Physics and Mathematics of the Universe, analyzed observational data from the Sloan Digital Sky Survey’s DR8 galaxy catalog. Using this data, they demonstrated that when and where galaxies group together within a cluster impacts the cluster’s relationship with its dark matter environment.

The researchers divided close to 9,000 galaxy clusters into two groups based on the spatial distribution of the galaxies in each cluster. One group consisted of clusters with galaxies aggregated at the center and the other consisted of clusters in which the galaxies were more diffuse. They then used a technique called gravitational lensing to show that, while the two groups of clusters had the same mass, they interacted with their environment much differently. The group of clusters with diffuse galaxies were much more clumpy than the group of clusters that had their galaxies close to the center.

“Measuring the way galaxy clusters clump together on large scales is a linchpin of modern cosmology. We can go forward knowing that mass might not be the only factor in clustering,” Mandelbaum said.


Story Source:

The above post is reprinted from materials provided by Carnegie Mellon University. The original item was written by Jocelyn Duffy. Note: Materials may be edited for content and length.


Journal Reference:

  1. Hironao Miyatake, Surhud More, Masahiro Takada, David N. Spergel, Rachel Mandelbaum, Eli S. Rykoff, and Eduardo Rozo. Evidence of Halo Assembly Bias in Massive Clusters. Phys. Rev. Lett., 25 January 2016 DOI: 10.1103/PhysRevLett.116.041301

 

Source: Carnegie Mellon University. “In galaxy clustering, mass may not be the only thing that matters: First observational evidence for assembly bias could impact understanding of the universe.” ScienceDaily. ScienceDaily, 25 January 2016. <www.sciencedaily.com/releases/2016/01/160125114233.htm>.

Date:
January 22, 2016

Source:
University of Notre Dame

Summary:
A team of researchers has observed the brightest ultra metal-poor star ever discovered. The star is a rare relic from the Milky Way’s formative years. As such, it offers astronomers a precious opportunity to explore the origin of the first stars that sprung to life within our galaxy and the universe.

 

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A team of researchers has observed the brightest ultra metal-poor star ever discovered.
Credit: ESO/Beletsky/DSS1 + DSS2 + 2MASS

 

 

A team of researchers has observed the brightest ultra metal-poor star ever discovered.

The star is a rare relic from the Milky Way’s formative years. As such, it offers astronomers a precious opportunity to explore the origin of the first stars that sprung to life within our galaxy and the universe.

A Brazilian-American team including Vinicius Placco, a research assistant professor at the University of Notre Dame and a member of JINA-CEE (Joint Institute for Nuclear Astrophysics — Center for the Evolution of the Elements), and led by Jorge Meléndez from the University of São Paulo used two of European Southern Observatory’s telescopes in Chile to discover this star, named 2MASS J18082002-5104378.

The star was spotted in 2014 using ESO’s New Technology Telescope. Follow-up observations using ESO’s Very Large Telescope discovered that, unlike younger stars such as the sun, this star shows an unusually low abundance of what astronomers call metals — elements heavier than hydrogen and helium. It is so devoid of these elements that it is known as an ultra metal-poor star.

Although thought to be ubiquitous in the early universe, metal-poor stars are now a rare sight within both the Milky Way and other nearby galaxies. Metals are formed during nuclear fusion within stars, and are spread throughout the interstellar medium when some of these stars grow old and explode. Subsequent generations of stars therefore form from increasingly metal-rich material. Metal-poor stars, however, formed from the unpolluted environment that existed shortly after the Big Bang. Exploring stars such as 2MASS J18082002-5104378 may unlock secrets about their formation, and show what the universe was like at its very beginning.


Story Source:

The above post is reprinted from materials provided by University of Notre Dame. Note: Materials may be edited for content and length.


Journal Reference:

  1. Jorge Meléndez, Vinicius M. Placco, Marcelo Tucci-Maia, Iván Ramírez, Ting S. Li, Gabriel Perez. 2MASS J18082002−5104378: The brightest (V= 11.9) ultra metal-poor star. Astronomy & Astrophysics, 2016; 585: L5 DOI: 10.1051/0004-6361/201527456

 

Source: University of Notre Dame. “Newly discovered star offers opportunity to explore origins of first stars sprung to life in early universe.” ScienceDaily. ScienceDaily, 22 January 2016. <www.sciencedaily.com/releases/2016/01/160122144733.htm>.

Cultural Liaison at Target Health

 

One way Target Health gives back to New York City for being one of the greatest city in the world is to sponsor many theatre clubs, the Metropolitan Opera and membership in the Nippon Club. CEO Joyce Hays has assigned Mui Ying Kwan as Cultural Liaison at Target Health. Mui Ying has been at Target Health for over 10 years and is a member of our clinical research department. In the capacity of, Cultural Liaison, Mui Ying will work closely with Joyce Hays to represent Target Health at cultural events. Mui Ying had a similar position when attending the New School. She was in a fellowship that collaborated with IDEO where she worked on cultural and educational design innovation projects for two semesters. IDEO is an award-winning global design firm that takes a human-centered, design-based approach to helping organizations in the public and private sectors innovate and grow..

 

View From the Upper East Side – Snow Storm Paralyzes the East Coast

 

With climate change, tornados hit Florida last week and this week the snow blanketed the East Coast of the US. This is a view of the Upper East Side of Manhattan the morning after. The drift below is at least 10 feet high.

 

 

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View From the Upper East Side. ©Jules Mitchel, Target Health Inc.

 

ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212 – 681 – 2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. 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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Triglyceride/HDL Ratio Predicts Heart Attacks, Diabetes

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The American Heart Association recommends all adults over age 20 should have their cholesterol levels checked every four to six years. Cholesterol screening is done with a blood test that measures your levels of high-density lipoprotein (HDL) cholesterol (“good“ cholesterol), low-density lipoprotein (LDL) cholesterol (“bad“ cholesterol), and triglycerides. Most of the cholesterol in our bloodstream (75%) is produced by the liver, and the remaining 25% comes from the foods we eat. We all know that elevated blood cholesterol levels are not good for your health, but the right levels of cholesterol actually play a vital role in maintaining cell membranes and synthesizing hormones. The Centers for Disease Control reports that one-third of adults have high cholesterol levels.

 

A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituent of body 1) ___ in humans and animals, as well as vegetable fat. They are also present in the blood to enable the bidirectional transference of adipose fat and blood glucose from the liver, and are a major component of human skin oils. There are many different types of triglyceride, with the main division being between saturated and unsaturated types. Saturated fats are “saturated“ with hydrogen – all available places where hydrogen atoms could be bonded to carbon atoms are occupied. These have a higher melting point and are more likely to be solid at room temperature. 2) ___ fats have a lower melting point and are more likely to be liquid at room temperature.

 

Triglycerides cannot pass through cell membranes freely. Special enzymes on the walls of blood vessels called lipoprotein lipases must break down triglycerides into free fatty acids and glycerol. Fatty acids can then be taken up by cells via the fatty acid transporter (FAT). Triglycerides, play an important role in metabolism as energy sources and transporters of dietary fat. They contain more than twice as much 3) ___ as carbohydrates. In the human body, high levels of triglycerides in the bloodstream have been linked to atherosclerosis and, by extension, the risk of heart disease and 4) ___. However, the relative negative impact of raised levels of triglycerides compared to that of LDL:HDL ratios is as yet unknown. The risk can be partly accounted for by a strong inverse relationship between triglyceride level and HDL-cholesterol level.

 

Two blood tests that are done during routine physical exams can be used to predict whether you are at increased risk for a heart 5) ___(The Journal of Clinical Hypertension, Jan 13, 2016). It’s called the triglyceride/HDL ratio, calculated by dividing your triglycerides number by your HDL number.

 

Your triglycerides should be below 150 mg/dL (in Canada less than 1.7 mmol/L)

Your HDL cholesterol should be above 40 (in Canada, greater than 1.00 mmol/L)

Thus your Triglycerides/HDL ratio should be under 3.75

 

The triglycerides/HDL ratio also predicts risk for diabetes and pre-diabetes (J Investig Med, Feb 2014;62(2):345-9). Almost 50% of North American adults already have diabetes or 6) ___ (JAMA, September 8, 2015), diseases that damage every cell in your body to cause heart attacks, strokes, dementia, impotence, many cancers, blindness, deafness, and premature death. If your triglyceride/HDL ratio is above 3.75, you are at increased risk for pre-diabetes or diabetes. Check with your doctor. Since the majority of cases of diabetes are caused by a faulty lifestyle, not just by 7) ___, diabetes is both a preventable and curable disease with lifestyle changes. Many people with pre-diabetes and early diabetes can return to normal by changing their lifestyles long before they develop any symptoms of the disease.

 

Why Triglyceride/HDL Ratio Predicts Diabetes

 

Doctors screen for diabetes by ordering a fasting blood sugar. However, some people with pre-diabetes have normal fasting blood sugar levels. The first thing that happens when you start to become diabetic is that your blood sugar rises too high after you eat, even if your fasting blood sugar is normal. If your blood sugar is greater than 140 two hours after you eat, you are at least pre-diabetic, even if all your other tests are normal.

 

High Triglycerides: When your blood sugar rises too high, your liver converts the extra sugar into a fat called 8) ___, so an early sign of diabetes is a triglyceride level above 150 mg/dL (above 1.7 mmol/L in Canada).

 

Low HDL Cholesterol: High blood fat levels can cause clots and heart attacks, so you use your good HDL cholesterol to carry triglycerides from your bloodstream to your liver. A low HDL cholesterol is another early sign of diabetes.

 

Fatty Liver: Your HDL cholesterol carries extra fat from your bloodstream to your liver. Too much fat stored in your liver is called a fatty 9)___. Your liver is supposed to prevent blood sugar levels from rising too high. When blood sugar levels rise, the pancreas releases insulin which lowers high blood sugar levels by driving sugar from the bloodstream into the liver. However, if you have a fatty liver, it does not accept the 10) ___, so blood sugar levels remain high to cause diabetes.

 

You Can Check Your Own Triglyceride/HDL Ratio

Look at your most recent blood tests for your triglyceride and HDL cholesterol numbers. If your triglyceride/HDL ratio is greater than 3.75, you are likely to be at least pre-diabetic. If you can also pinch more than three inches of fat under the skin on your belly, you may already be diabetic. Check with your doctor. Realize that you cannot cure diabetes with drugs alone; you must change your lifestyle to prevent or cure diabetes:

 

1. Exercise

2. Lose weight if overweight

3. Restrict foods and drinks with added sugars, fried foods, red meat and processed meats

4. Eat more fruits and vegetables

5. Get blood levels of hydroxy vitamin D above 50 nmol/L

 

Several nutritional supplements have been shown to be beneficial in improving cholesterol levels.

 

1. Fish oil can reduce triglycerides, and soy protein can slightly lower levels of LDL (“bad“) cholesterol and triglycerides and raise HDL (“good“) cholesterol.

2. Plant stanols and sterols naturally found in some fruits, vegetables, nuts, seeds, and legumes may help block absorption of cholesterol in the intestine.

3. Prescription nicotinic acid (niacin or vitamin B3) is often prescribed to improve cholesterol. Doses found in over-the-counter vitamin supplements are not sufficient to treat high cholesterol, and because of the potential for side effects, high doses should only be taken under a doctor’s supervision.

Note: Pre-diabetics and diabetics can have triglyceride/HDL ratios under 3.75. Your doctor will probably do additional tests for your diagnosis and treatment. A more dependable test is blood sugar taken two hours after you eat. If this is above 140, you are at least pre-diabetic. Sources: Gabe Mirkin MD; Wikipedia

 

ANSWERS: 1) fat; 2) Unsaturated; 3) energy; 4) stroke; 5) attack; 6) pre-diabetes; 7) genetics; 8) triglycerides; 9) liver; 10) sugar

 

Diabetes and Edward Albert Sharpey-Schafer MD (1850-1935)

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Sir Edward Albert Sharpey-Shafer MD

 

Sir Edward Albert Sharpey-Schafer, an English physiologist and physician, is regarded as a founder of endocrinology. In 1894, together with George Oliver, he discovered and demonstrated the existence of adrenaline. He also coined the term “endocrine“ for the secretions of the ductless glands. Schafer’s method of artificial respiration is named after him. Schafer also coined the word “insulin“ after theorizing that a single substance from the pancreas was responsible for diabetes mellitus.

 

Sharpey-Schafer contributed greatly to the understanding diabetes, which has been affecting lives for thousands of years. An ailment suspected to be diabetes was recognized by the Egyptians in manuscripts dating to 1550 BCE. According to The National Medical Journal of India, ancient Indians (circa 600 BCE) were well aware of the condition. They tested for diabetes which they called “sweet urine disease“ by determining if ants were attracted to a person’s urine. In Greek, “diabetes“ means “to pass through.“ Greek physicians named the disorder for its top symptom: the excessive passing of urine through the body’s system. Historical documents show that Greek, Indian, Persian, Chinese, Japanese, and Korean doctors were aware of the condition, but none could determine its cause. In earlier times, a diagnosis of diabetes was likely a death sentence.

 

Born Schafer, Edward was the third son of city merchant James William Henry Schafer who had been born in Hamburg but came to Britain as a young man, became a naturalized citizen and settled in Highgate, North London. Edward attended Clewer House School and then University College London in 1868 where he was taught by the physiologist William Sharpey and became the first Sharpey Scholar in 1873. He was appointed Assistant Professor of Practical Physiology in 1874 and was elected to the Royal Society in 1878 when he was only 28 years old. He was Fullerian Professor at the Royal Institution and became Jodrell Professor at UCL in 1883, a position he held until 1899 when he was appointed to the chair of physiology at the University of Edinburgh where he remained until his retirement in 1933 and becoming Emeritus Professor thereafter. His chair was filled by Prof Ivan De Burgh Daly.

 

Schafer was a founding member of the Physiological Society and from 1908 until 1933 edited the Quarterly Journal of Experimental Physiology. He was the recipient of many honorary degrees and prestigious medals both at home and abroad and his book on the Essentials of Histology ran to sixteen editions between 1885 and 1954. He introduced suprarenal extract (containing adrenaline as well as other active substances) into medicine. Schafer became a Fellow of the Royal Society in 1878, was president of the British Science Association in 1911-1912, was president of the British Medical Association in 1912. He was knighted in 1913.

 

Schafer was married twice, first to Maud Dixey and after her death in 1896, to Ethel Maud Roberts. There were four children by his first marriage, however, he outlived three of them: his eldest daughter died in 1905 and both his sons died in action in World War I. Following the death of his eldest son, John Sharpey Schafer, the name of ?Sharpey’, which had been given as a middle name, was prefixed by Schafer to his own surname in 1918, both in memory of his son and to perpetuate the name of his teacher, William Sharpey. His grandson, Edward Peter Sharpey-Schafer, was Professor of Medicine at St Thomas’ Hospital, London from 1948 until his death in 1963.

 

The American Diabetes Association (ADA) reported that in 1910, medical professionals took the first steps toward discovering a cause and treatment mode for diabetes. Edward Albert Sharpey-Shafer announced that the pancreas of a diabetes patient was unable to produce what he termed “insulin,“ a chemical the body uses to break down sugar. Thus, excess sugar ended up in the urine. Physicians promoted a fasting diet combined with regular exercise to combat the disorder. Despite attempts to manage the disorder through diet and exercise, people with diabetes inevitably died prematurely. In 1921, scientists experimenting with dogs had a breakthrough in reversing the effects of diabetes. Two Canadian researchers Frederick Grant Banting and Charles Herbert Best successfully extracted insulin from healthy dogs. They then injected it into diabetic dogs to improve their condition.

 

 

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Frederick Grant Banting and Charles Herbert Best

 

Although insulin injection began to successfully combat diabetes, some cases were unresponsive to this form of treatment. Harold Himsworth finally distinguished between the two types of diabetes in 1936, according to writings published by his son Richard in Diabetic Medicine. He defined them as “insulin-sensitive“ and “insulin-insensitive.“ Today, these classifications are commonly referred to as “type 1“ and “type 2“ diabetes. Type 2 diabetes was not treated successfully for many years. According to the ADA, oral medications were finally developed in the 1950s. These drugs helped sufferers of type 2 diabetes control their blood sugar levels by stimulating the pancreas to develop more insulin.

 

Large portable glucose meters were created in 1969, and have since been reduced to the size of a hand-held calculator. Portable glucose meters are a key tool in managing diabetes today. They allow you to monitor your blood sugar levels at home, at work, and anywhere else. Fairly simple to use, they produce accurate results. To learn more about glucose meters, click on this hot link. In 1970, insulin pumps were developed to mimic the body’s normal release of insulin. Today, these pumps are light and portable, allowing for comfortable wearing on a daily basis.

 

As recently as 20 years ago, type 2 diabetes was not observed to occur in children. In fact, it was once referred to as “adult-onset diabetes“ and type 1 diabetes was called “juvenile diabetes.“ However, more cases began appearing in children and teenagers in the past two decades due to poor eating habits, lack of exercise, and excess weight. As such, adult-onset diabetes was renamed “type 2 diabetes.“ In the 1960’s, diabetes management improved significantly. The development of urine strips made detecting sugar easier and simplified the process of managing blood sugar levels, the Mayo Clinic reports. Introduction of the single-use syringe allowed for faster and easier insulin therapy options. Sugary drinks put anyone at risk. According to an international review of existing research, drinking too many sugary drinks – including soda and fruit juice – is positively associated with type 2 diabetes, regardless of weight. Researchers found that these drinks contribute to between 4-13% of type 2 diabetes cases in the United States.

 

Despite the medical strides made since diabetes was first described in ancient times, it still remains a major cause of death and health complications throughout the world. As of 2011, diabetes was the seventh-leading cause of death in the United States, according to the National Diabetes Information Clearinghouse. Now that blood sugar can be tested at home, diabetes is more manageable than ever. Insulin remains the primary treatment for type 1 diabetes. Those with type 2 diabetes can reduce their risk of health complications through regular exercise, healthy diets, and other medications. As we continue to increase our understanding of type 2 diabetes, new and more effective treatments and prevention methods will emerge. DNP, or 2,4-Dinitrophenol, is a controversial chemical with potentially toxic side effects. While it’s been labeled “not fit for human consumption“ by regulatory boards in both the United States and the U.K., it remains widely available in supplement form. While dangerous in large quantities, a recent study considered the possibility that a controlled-release version of DNP could reverse diabetes in rats. This was because it has been successful in previous laboratory treatment of nonalcoholic fatty liver disease and insulin resistance, which is a precursor to diabetes. The controlled-release version, called CRMP, was found to not be toxic to rats, and the researchers posited that it could be safe and effective in controlling diabetes in humans.

 

Pink1 Protein Crucial For Removing Broken-Down Energy Reactors

 

Cells are powered by tiny energy reactors called mitochondria. When damaged, they leak destructive molecules that can cause substantial harm and eventually kill brain cells. Mutations in PINK1 and its partner molecule Parkin cause hereditary forms of Parkinson’s disease. Moreover, the inability to remove defective mitochondria from nerve cells has been linked to numerous neurodegenerative diseases, including the more common forms of Parkinson’s disease and amyotrophic lateral sclerosis (ALS). According to an article published online in the journal Nature (12 August 2015), PINK1 does this by triggering an intricate process called mitophagy that breaks down and removes damaged mitochondria from the cell.

 

The authors discovered that PINK1 recruits two proteins called Optineurin and NDP52 to the surface of mitochondria. These proteins, in turn, recruit a variety of other protein molecules that mark the mitochondria for degradation. Optineurin and NDP52 are members of a group of proteins called autophagy receptors. When the authors created cells that contained no autophagy receptors, they found that the cells could not dispose of malfunctioning mitochondria. However, when the the function of either Optineurin or NDP52 was restored, the cells regained this ability. Reinstating other autophagy receptors had little or no effect.

 

According to the authors, knowing that Optineurin and NDP52 are the primary autophagy receptors involved in this process can inform us about the cause of different human diseases. For example, Optineurin is mutated in ALS and also in certain forms of glaucoma, whereas NDP52 is known to be mutated in Crohn’s disease. This suggests that problems with mitophagy may be involved in those diseases.

 

When PINK1 accumulates on the surface of defective mitochondria, it alters a molecule called ubiquitin. The modified ubiquitin then recruits autophagy receptors as well as Parkin. Parkin promotes mitophagy by bringing more ubiquitin to the mitochondria to form long chains that flag damaged mitochondria for removal. Since PINK1 is needed to start building these ubiquitin chains, results from the present study suggests a new avenue for creating drugs that treat disease by boosting the disposal of damaged mitochondria. The authors added that a while a number of drug companies are trying to develop drugs to activate this pathway, by trying to find drugs that activate Parkin, this new model might suggest a different strategy. It may not be so important to activate Parkin; it may be more important to activate PINK1.”

 

Gene Therapy Staves Off Blindness From Retinitis Pigmentosa in Canine Model

 

Retinitis pigmentosa is the most common inherited disease that causes degeneration of the retina, the light-sensitive tissue lining the back of the eye. Roughly 1 in 4,000 people are affected and about 10-20% have a particularly severe form called X-linked retinitis pigmentosa, which predominately affects males. This X-linked form causes night blindness by age 10 and progressive loss of the visual field by age 45. About 70% of people with the X-linked form carry mutations that cause loss of function of the retinitis pigmentosa GTPase Regulator (RPGR) gene, which encodes a protein important for maintaining the health of photoreceptors. These are photoreceptors in the retina absorb and convert light into electrical signals, which are then sent to the brain. The disease damages both types of photoreceptors: rods (which allow us to see in dim and dark light) and cones (which allow for seeing fine detail and color).

 

According to an article published in the Proceedings of the National Academy of Sciences (2015:43: E5844-E5853), gene therapy has preserved vision in a study involving dogs with naturally occurring, late-stage retinitis pigmentosa. The findings should now contribute to the groundwork needed to move gene therapy forward into clinical trials for people with the blinding eye disorder, for which there is currently no cure. The study also determined for the first time that gene therapy may be of potential benefit even after there has been significant loss of cells in the eye. Up to this point, animal studies had shown benefits from gene therapy only when it was used in the earliest stages of the disease.

 

For the study, to overcome the effects of RPGR mutations, the authors packaged healthy RPGR genes into an adeno-associated virus that is not known to cause any human diseases. The aim was for the virus to deliver the genes into retinal cells and for the genes to produce the RPGR protein. The authors then tested the gene therapy in a naturally occurring canine form of RPGR X-linked retinitis pigmentosa that appears among some mixed breeds. Dogs with early to late stages of the disease were treated with the therapy in one eye; the untreated eye was evaluated as the control. Serial imaging suggested that the therapy halted the thinning of the retinal layer where photoreceptors are located and that commonly degenerates from the disease. Using immunolabeling, a technique that helps tag features inside cells, the authors showed that the structure of rod and cone photoreceptors was improved in the treated eye and better preserved when compared to the untreated eye. Electrical recordings from the retina also suggested that the therapy preserved cell function. Overall, the findings suggest that gene therapy halted disease-associated cell death for at least the length of the 2.5-year study. Even in dogs with later-stage disease, gene therapy halted the loss of retinal thickness and preserved the structure of surviving photoreceptors. By contrast, untreated eyes continued to lose retinal thickness and photoreceptor function. Visual performance under dim light in an obstacle course, and in a maze that required detecting a dim light, were also significantly better in dogs using their treated eye compared with the untreated eye.

 

FDA Outlines Cybersecurity Recommendations for Medical Device Manufacturers

 

Cybersecurity threats to medical devices are a growing concern. The exploitation of cybersecurity vulnerabilities presents a potential risk to the safety and effectiveness of medical devices. While manufacturers can incorporate controls in the design of a product to help prevent these risks, it is essential that manufacturers also consider improvements during maintenance of devices, as the evolving nature of cyber threats means risks may arise throughout a device’s entire lifecycle.

 

The FDA has been actively working to improve cybersecurity information sharing and to collaboratively develop and implement risk-based standards since 2013, when the White House issued Executive Order 13636 and Presidential Policy Directive 21 to mobilize the public and private sectors to collectively strengthen critical cybersecurity infrastructure. In October 2014, the FDA finalized its guidance containing recommendations for incorporating premarket management of cybersecurity during the design stage of device development. Other activities have included establishing formal partnerships with the Department of Homeland Security’s Industrial Control Systems Cyber Emergency Response Team and the National Health Information Sharing and Analysis Center; providing input on the NIST voluntary cybersecurity framework; holding in-person meetings with stakeholders, including a 2014 FDA public workshop; and issuing product-specific safety communications on medical device cybersecurity vulnerabilities.

 

Last week, the FDA issued a draft guidance outlining important steps medical device manufacturers should take to continually address cybersecurity risks to keep patients safe and better protect the public health. The draft guidance details the agency’s recommendations for monitoring, identifying and addressing cybersecurity vulnerabilities in medical devices once they have entered the market. The draft guidance is part of the FDA’s ongoing efforts to ensure the safety and effectiveness of medical devices, at all stages in their lifecycle, in the face of potential cyber threats.

 

The draft guidance outlines postmarket recommendations for medical device manufacturers, including the need to proactively plan for and to assess cybersecurity vulnerabilities, consistent with the FDA’s Quality System Regulation. It also addresses the importance of information sharing via participation in an Information Sharing Analysis Organization (ISAO), a collaborative group in which public and private-sector members share cybersecurity information. The draft guidance recommends that manufacturers should implement a structured and systematic comprehensive cybersecurity risk management program and respond in a timely fashion to identified vulnerabilities. Critical components of such a program should include:

 

Applying the 2014 NIST voluntary Framework for Improving Critical Infrastructure Cybersecurity, which includes the core principles of “Identify, Protect, Detect, Respond and Recover;“

Monitoring cybersecurity information sources for identification and detection of cybersecurity vulnerabilities and risk;

Understanding, assessing and detecting presence and impact of a vulnerability;

Establishing and communicating processes for vulnerability intake and handling;

Clearly defining essential clinical performance to develop mitigations that protect, respond and recover from the cybersecurity risk;

Adopting a coordinated vulnerability disclosure policy and practice; and

Deploying mitigations that address cybersecurity risk early and prior to exploitation.

 

For the majority of cases, actions taken by manufacturers to address cybersecurity vulnerabilities and exploits are considered “cybersecurity routine updates or patches,“ for which the FDA does not require advance notification, additional premarket review or reporting under its regulations.  For a small subset of cybersecurity vulnerabilities and exploits that may compromise the essential clinical performance of a device and present a reasonable probability of serious adverse health consequences or death, the FDA would require medical device manufacturers to notify the agency. The draft guidance indicates that in cases where the vulnerability is quickly addressed in a way that sufficiently reduces the risk of harm to patients, the FDA does not intend to enforce urgent reporting of the vulnerability to the agency if certain conditions are met. These conditions include: there are no serious adverse events or deaths associated with the vulnerability; within 30 days of learning of the vulnerability, the manufacturer notifies users and implements changes that reduce the risk to an acceptable level; and the manufacturer is a participating member of an ISAO and reports the vulnerability, its assessment and remediation to the ISAO.

 

The FDA encourages public comments on the draft guidance, which will be open for 90 days. The FDA will also discuss the guidance at its upcoming public workshop, “Moving Forward: Collaborative Approaches to Medical Device Cybersecurity,“ January 20-21 at the FDA’s headquarters in Silver Spring, Maryland. The workshop will engage the multi-stakeholder community in focused discussions on unresolved gaps and challenges that have hampered progress in advancing medical device cybersecurity and identify specific solutions to addressing these issues moving forward.

 

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