Direct Data Entry at the Time of the Office Visit is Realistic

 

Target Health is committed to the paperless clinical trial and to optimize clinical trial efficiency, with goals to:

 

1. maximize patient safety

2. eliminate errors that matter

3. assure that clinical trial data are fit for purpose

 

Based on a recent analysis of 4 out-patient studies, it is clear that the clinical sites are both able and willing to entry data in “real time.“ The value to all stakeholders, including study subjects, clinical sites and sponsoring pharmaceutical companies is “huge,“ because when data are available in real time, reactions and interaction can also occur in real time. Visit Publications on our website for peer-reviewed articles.

 

% of Forms Entered on the Day of the Office Visit

Study Phase Sites (n) Treated Subjects

(n)

Forms

(n)

Forms Entered on Day of Office Visit

(%)

1 1 12 885 97.4
2 3 38 1,308 90.6
2 6 124 6,424 90.4
3 18 180 13,311 90.9

 

 

View From the 24th Floor

20140721-20

Sunset from the 24th Floor at Target Health ©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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Free Radicals

20140721-17

20140721-18

The triphenylmethyl radical is a persistent radical and the first radical ever described in organic chemistry, by Dr. Moses Gomberg.

 

Free radical is a chemistry term that describes an atomic or molecular species with unpaired electrons on an otherwise open shell configuration. Dr. Moses Gomberg (1866-1947) was the founder of radical chemistry

 

When exposed to 1) ___ the triphenylmethyl radical rapidly oxidizes to the peroxide (above, Scheme 2) and the color of the solution changes from yellow to colorless. Likewise, the radical reacts with iodine to triphenylmethyl iodide.

 

 

20140721-19

The radical was discovered by Moses Gomberg in 1900, when he tried to prepare hexaphenylethane from triphenylmethyl chloride and zinc in benzene in a Wurtz reaction and found that the product, based on its behavior towards iodine and oxygen, was far more reactive than anticipated.

 

A radical (more precisely, a free radical) that has unpaired valence electrons or an open electron shell, may, therefore, be seen as having one or more “dangling“ covalent bonds. With some exceptions, these “dangling“ 2) ___ make free radicals highly chemically reactive towards other substances, or even towards themselves: their molecules will often spontaneously dimerize or polymerize if they come in contact with each other. Most radicals are reasonably stable only at very low concentrations in inert media or in a vacuum. A notable example of a free radical is the hydroxyl radical (HO?), a molecule that is one hydrogen atom short of a water molecule and thus has one bond “dangling“ from the oxygen. Two other examples are the carbene molecule (:CH2), which has two dangling bonds; and the superoxide anion (?O-2), the oxygen molecule O2 with one extra electron, which has one dangling bond.

 

Free radicals may be created in a number of ways, including synthesis with very dilute or rarefied reagents, reactions at very low temperatures, or breakup of larger 3) ___. The latter can be affected by any process that puts enough energy into the parent molecule, such as ionizing radiation, heat, electrical discharges, electrolysis, and chemical reactions. Indeed, radicals are intermediate stages in many chemical reactions. Free radicals play an important role in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes.

 

In living organisms, the free radicals superoxide and nitric oxide and their reaction products regulate many processes, such as control of vascular tone and thus blood 4) ___. They also play a key role in the intermediary metabolism of various biological compounds. Such radicals can even be messengers in a process dubbed redox signaling. A radical may be trapped within a solvent cage or be otherwise bound. Until late in the 20th century the word “radical“ was used in chemistry to indicate any connected group of atoms, such as a methyl group or a carboxyl, whether it was part of a larger molecule or a molecule on its own. The qualifier “free“ was then needed to specify the unbound case. Following recent nomenclature revisions, a part of a larger molecule is now called a functional group or substituent, and “radical“ now implies “free“. However, the old nomenclature may still occur in the literature.

 

Free radicals play an important role in a number of biological processes. Many of these are necessary for life, such as the intracellular killing of 5) ___ by phagocytic cells such as granulocytes and macrophages. Researchers have also implicated free radicals in certain cell signalling processes, known as redox signaling. The two most important oxygen-centered free radicals are superoxide and hydroxyl radical. They derive from molecular 6) ___ under reducing conditions. However, because of their reactivity, these same free radicals can participate in unwanted side reactions resulting in cell damage. Excessive amounts of these free radicals can lead to cell injury and death, which may contribute to many diseases such as cancer, stroke, 7) ___ infarction, diabetes and major disorders.

 

Many forms of cancer are thought to be the result of reactions between free 8) ___ and DNA, potentially resulting in mutations that can adversely affect the cell cycle and potentially lead to malignancy. Some of the symptoms of aging such as atherosclerosis are also attributed to free-radical induced oxidation of cholesterol to 7-ketocholesterol. In addition free radicals contribute to alcohol-induced liver damage, perhaps more than 9) ___ itself. Free radicals produced by cigarette smoke are implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema.

 

Free radicals may also be involved in Parkinson’s disease, senile and drug-induced deafness, schizophrenia, and Alzheimer’s. The classic free-radical syndrome, the iron-storage disease hemochromatosis, is typically associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentary melanin abnormalities, deafness, arthritis, and diabetes mellitus. The free-radical theory of aging proposes that free radicals underlie the aging process itself. Similarly, the process of mitohormesis suggests that repeated exposure to free radicals may extend life span.

 

Because free radicals are necessary for life, the body has a number of mechanisms to minimize free-radical-induced damage and to repair damage that occurs, such as the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. In addition, antioxidants play a key role in these defense mechanisms. These are often the three vitamins, vitamin A, vitamin C and vitamin E and polyphenol antioxidants. Furthermore, there is good evidence indicating that bilirubin and uric acid can act as antioxidants to help neutralize certain free radicals. Bilirubin comes from the breakdown of red blood cells’ contents, while uric acid is a breakdown product of purines. Too much bilirubin, though, can lead to jaundice, which could eventually damage the central nervous system, while too much uric acid causes 10) ___.

 

ANSWERS: 1) air; 2) bonds; 3) molecules; 4) pressure; 5) bacteria; 6) oxygen; 7) myocardial; 8) radicals; 9) alcohol; 10) gout

 

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Moses Gomberg, Father of Radical Chemistry (1866- 1947)

20140721-8

Dr. Moses Gomberg

 

Moses Gomberg, one of the greatest chemists of the 20th Century, and a chemistry professor at the University ofMichigan, discovered an organic free radical in 1900 and affirmed what had been thought impossible. A century later, free radical organic chemistry researchers look back to Gomberg as the founder of their field. His work led to modern theories of the structure and reactivity of organic molecule – theories whose application has had tremendous impact on modern life.

 

Nineteenth century scientists speculated that there could be a free radical containing carbon – an organic free radical. But after many attempts to isolate it failed, they concluded they were wrong and that carbon must always be tetravalent (form four bonds). Moses Gomberg was trying to synthesize a carbon compound called hexaphenylethane when he inadvertently synthesized triphenylmethyl (trityl for short), a mysterious, highly reactive, unstable substance. He recognized that he had found the long-elusive free radical and showed that carbon is not always tetravalent – the then prevailing view. Gomberg published his findings in 1900, but the existence of triphenylmethyl and other organic free radicals remained in dispute for nearly a decade. They were viewed as a curiosity even after the scientific community recognized their existence. Not until the 1930s did free radicals enter the mainstream of organic chemistry.

 

We now know that organic free radicals are essential to the way in which some enzymes function in the human body. We know that organic free radicals are involved in the body’s aging process, in its healthy functioning, and in the development of cancer and other serious diseases. Understanding organic free radicals has helped us explain DNA synthesis in the body and many other natural phenomena, from food spoilage to the effects of sunburn. Organic free radicals also play a major role in the production of plastics, synthetic rubber and other widely used synthetic materials.

 

Gomberg’s life is of a genius striving toward goals, unobtainable for most because of seeming insurmountable odds. Undaunted, he overcame obstacles placed in his way, with intelligence and grace, a timeless story. Moses Gomberg, one of the world’s great organic chemists, chemistry professor and research scientist at the University of Michigan, was born in Elizabetgrad, Russian Empire, an area now in the Ukraine. Russia, at this time, was extremely unstable, by the previous period of Crimean Wars (Russia was the loser), constant battles to break away from the Ottoman Empire, freeing of the serfs by Czar Alexander II (adding greatly to competition for work). Napoleon had emancipated the Jews of Europe. By 1871, every European country, except Russia, had emancipated its Jewish population.

 

Czar Alexander II became the first Russian leader attempting to rid persecution of the Jews. During his reign, some Jews became well educated and successful in all businesses and talked about becoming integrated into Russian society. There was also talk among Jews (Zionism) about the possibility of a real homeland, back in the lands of Israel and Judea, to escape persecution forever. Pamphlets were distributed. Jews began buying land there, that Arab owners deemed unusable. Although the Russian pograms began in 1821, they reached a mass movement status in March 1881, the date Czar Alexander II was assassinated. Jews lost a protected status, and serious plans for a home without persecution became more real. In Russia, the backlash also became more real. Vicious anti-Semitic propaganda began, culminating in an atrocious book, put out by the Russian oligarchs, The Protocols of the Elders of Zion, supposedly the record of secret meetings of Jewish leaders, describing an alleged conspiracy to dominate the world. The conspiracy and its leaders, the so-called Elders of Zion, never existed. The book was proven to be a fraud on many occasions.

 

One month after the assassination of Czar Alexander II, on April 27, 1881, there was a violent pogrom against the Jewish citizens of Elisavetgrad, the town where the Gomberg family lived. A religious dispute at an inn sparked off the riot. The attack focused at first on the systematic destruction of Jewish shops and warehouses. The Jewish citizens tried to protect their businesses, but this only led to more outrage. The soldiers joined in the rioting rather than trying to stop it. After two days of attacks, many were killed, 500 houses and 100 shops were demolished and approximately 2,000,000 rubles’ worth of property were stolen or destroyed. The assassins encouraged mass rebellions and the situation in Russia became anarchic and chaotic for everyone. The Jews were blamed. This was the beginning of mass pogroms which broke out primarily in southern Russia in what is now Ukraine.

 

Moses Gomberg and his father, were accused of participating in an anti-government political group. Their property was confiscated. Somehow, the four Gombergs were able to flee to America, which was one of the alternatives to purchasing land from Arab sellers, in Palestine, through the Zionist movement. It is not known which of their relatives, remained behind. They settled in Chicago, without knowing a word of English. Moses Gomberg was 18 years old. His sister, Sonia was two years younger. Speaking no English, he worked at odd jobs, most involving menial labor. He toiled in the Chicago stockyards under the brutal conditions described in Upton Sinclair’s novel, The Jungle.

 

Through sheer force of will and brainpower, Gomberg learned English, completed his secondary education, and in 1886 entered the University of Michigan. He tried to enroll in a beginning course in physics, but the department head turned him down because he had no formal training in trigonometry. Three days later, he tried again. When the department again rejected him for the same reason, Gomberg insisted he knew the subject. The department head quizzed him, and was stunned to find that what he claimed was true. He had learned trigonometry in three days. He chose University of Michigan over Chicago, because he had to work his way through, and the jobs available in Michigan paid better than in Chicago. Moses entered the University of Michigan, where he obtained his B.Sc in 1890 and his doctorate, four years later, in 1894 under the supervision of A. B. Prescott. His thesis, titled “Trimethylxanthine and Some of its Derivatives“, dealt with the derivatization of caffeine. Appointed an instructor in 1893, Gomberg worked at the University of Michigan for the duration of his professional academic career, becoming chair of the Department of Chemistry from 1927 until his retirement in 1936. Dr. Gomberg served as President of the American Chemical Society in 1931.

 

 

20140721-9

Dr. Moses Gomberg

 

Moses Gomberg, one of the greatest chemists of the 20th Century, and a chemistry professor at the University ofMichigan, discovered an organic free radical in 1900 and affirmed what had been thought impossible. A century later, free radical organic chemistry researchers look back to Gomberg as the founder of their field. His work led to modern theories of the structure and reactivity of organic molecule – theories whose application has had tremendous impact on modern life.

 

Nineteenth century scientists speculated that there could be a free radical containing carbon – an organic free radical. But after many attempts to isolate it failed, they concluded they were wrong and that carbon must always be tetravalent (form four bonds). Moses Gomberg was trying to synthesize a carbon compound called hexaphenylethane when he inadvertently synthesized triphenylmethyl (trityl for short), a mysterious, highly reactive, unstable substance. He recognized that he had found the long-elusive free radical and showed that carbon is not always tetravalent – the then prevailing view. Gomberg published his findings in 1900, but the existence of triphenylmethyl and other organic free radicals remained in dispute for nearly a decade. They were viewed as a curiosity even after the scientific community recognized their existence. Not until the 1930s did free radicals enter the mainstream of organic chemistry.

 

We now know that organic free radicals are essential to the way in which some enzymes function in the human body. We know that organic free radicals are involved in the body’s aging process, in its healthy functioning, and in the development of cancer and other serious diseases. Understanding organic free radicals has helped us explain DNA synthesis in the body and many other natural phenomena, from food spoilage to the effects of sunburn. Organic free radicals also play a major role in the production of plastics, synthetic rubber and other widely used synthetic materials.

 

Gomberg’s life is of a genius striving toward goals, unobtainable for most because of seeming insurmountable odds. Undaunted, he overcame obstacles placed in his way, with intelligence and grace, a timeless story. Moses Gomberg, one of the world’s great organic chemists, chemistry professor and research scientist at the University of Michigan, was born in Elizabetgrad, Russian Empire, an area now in the Ukraine. Russia, at this time, was extremely unstable, by the previous period of Crimean Wars (Russia was the loser), constant battles to break away from the Ottoman Empire, freeing of the serfs by Czar Alexander II (adding greatly to competition for work). Napoleon had emancipated the Jews of Europe. By 1871, every European country, except Russia, had emancipated its Jewish population.

 

Czar Alexander II became the first Russian leader attempting to rid persecution of the Jews. During his reign, some Jews became well educated and successful in all businesses and talked about becoming integrated into Russian society. There was also talk among Jews (Zionism) about the possibility of a real homeland, back in the lands of Israel and Judea, to escape persecution forever. Pamphlets were distributed. Jews began buying land there, that Arab owners deemed unusable. Although the Russian pograms began in 1821, they reached a mass movement status in March 1881, the date Czar Alexander II was assassinated. Jews lost a protected status, and serious plans for a home without persecution became more real. In Russia, the backlash also became more real. Vicious anti-Semitic propaganda began, culminating in an atrocious book, put out by the Russian oligarchs, The Protocols of the Elders of Zion, supposedly the record of secret meetings of Jewish leaders, describing an alleged conspiracy to dominate the world. The conspiracy and its leaders, the so-called Elders of Zion, never existed. The book was proven to be a fraud on many occasions.

 

One month after the assassination of Czar Alexander II, on April 27, 1881, there was a violent pogrom against the Jewish citizens of Elisavetgrad, the town where the Gomberg family lived. A religious dispute at an inn sparked off the riot. The attack focused at first on the systematic destruction of Jewish shops and warehouses. The Jewish citizens tried to protect their businesses, but this only led to more outrage. The soldiers joined in the rioting rather than trying to stop it. After two days of attacks, many were killed, 500 houses and 100 shops were demolished and approximately 2,000,000 rubles’ worth of property were stolen or destroyed. The assassins encouraged mass rebellions and the situation in Russia became anarchic and chaotic for everyone. The Jews were blamed. This was the beginning of mass pogroms which broke out primarily in southern Russia in what is now Ukraine.

 

Moses Gomberg and his father, were accused of participating in an anti-government political group. Their property was confiscated. Somehow, the four Gombergs were able to flee to America, which was one of the alternatives to purchasing land from Arab sellers, in Palestine, through the Zionist movement. It is not known which of their relatives, remained behind. They settled in Chicago, without knowing a word of English. Moses Gomberg was 18 years old. His sister, Sonia was two years younger. Speaking no English, he worked at odd jobs, most involving menial labor. He toiled in the Chicago stockyards under the brutal conditions described in Upton Sinclair’s novel, The Jungle.

 

Through sheer force of will and brainpower, Gomberg learned English, completed his secondary education, and in 1886 entered the University of Michigan. He tried to enroll in a beginning course in physics, but the department head turned him down because he had no formal training in trigonometry. Three days later, he tried again. When the department again rejected him for the same reason, Gomberg insisted he knew the subject. The department head quizzed him, and was stunned to find that what he claimed was true. He had learned trigonometry in three days. He chose University of Michigan over Chicago, because he had to work his way through, and the jobs available in Michigan paid better than in Chicago. Moses entered the University of Michigan, where he obtained his B.Sc in 1890 and his doctorate, four years later, in 1894 under the supervision of A. B. Prescott. His thesis, titled “Trimethylxanthine and Some of its Derivatives“, dealt with the derivatization of caffeine. Appointed an instructor in 1893, Gomberg worked at the University of Michigan for the duration of his professional academic career, becoming chair of the Department of Chemistry from 1927 until his retirement in 1936. Dr. Gomberg served as President of the American Chemical Society in 1931.

 

 

20140721-9

Graduate student, Moses Gomberg, in 1890

 

In 1896-1897, he took a year’s leave to work as a postdoctoral researcher with Baeyer and Thiele in Munich and with Victor Meyer in Heidelberg, where he successfully prepared the long-elusive tetraphenylmethane. During attempts to prepare the even more sterically congested hydrocarbon hexaphenylethane, he correctly identified the triphenylmethyl radical, the first persistent radical to be discovered, and is thus known as the founder of radical chemistry. The work was later followed up by Wilhelm Schlenk. Gomberg was a mentor to Werner Emmanuel Bachmann who also carried on his work and together they discovered the Gomberg-Bachmann reaction. In 1923, he claimed to have synthesized chlorine tetroxide via the reaction of silver perchlorate with iodine, but was later shown to have been mistaken.

 

 

20140721-10

Gomberg’s chemical lab at the University of Michigan, in 1877

 

Gomberg was the first to successfully synthesize tetraphenylmethane. This was accomplished by the thermal decomposition of 1-phenyl-2-trityldiazene to the desired product in 2-5% yield.

 

 

20140721-11

Discovery of persistent radicals

 

20140721-12

Seeking to prepare hexaphenylethane (5), Gomberg attempted a Wurtz coupling of triphenylmethyl chloride (1). Elemental analysis of the resultant white crystalline solid, however, uncovered discrepancies with the predicted molecular formula:

 

  Calculated Observed
 % Carbon 93.83 87.93
 % Hydrogen 6.17 6.04

 

Hypothesizing that had combined with molecular oxygen to form the peroxide, Gomberg found that treatment of (1; see above) with sodium peroxide was another means of synthesizing (4; see above). By performing the reaction of triphenylchloromethane with zinc under an atmosphere of carbon dioxide Gomberg obtained the free radical (2; see above). This compound reacted readily with air, chlorine, bromine and iodine. On the basis of his experimental evidence Gomberg concluded that he had discovered the first instance of a persistent radical and trivalent carbon. This was a controversial conclusion for many years as molecular weight determinations of (2; see above) found a value that was double that of the free radical. Gomberg postulated that some non-tetravalent carbon structure existed in solution because of the observed activity towards oxygen and the halogens. Gomberg and Bachmann later found that treatment of “hexaphenylethane“ with magnesium resulted in a Grignard reagent, the first instance of the formation of such a compound from a hydrocarbon. Studies of other triarylmethyl compounds gave results similar to Gomberg’s, and it was hypothesized that (2; see above) existed in equilibrium with its dimer hexaphenylethane (5; see above). However this structure was later disproven in favor of the quinoid dimer (3; see above).

 

Upon his death in 1947 Moses Gomberg bequeathed his estate to the Chemistry Department of the University of Michigan for the creation of student fellowships. In 2000, the centennial of his paper “Triphenylmethyl, a Case of Trivalent Carbon“, a symposium was held in his memory and a plaque was installed in the Chemistry Building at the University of Michigan designating a National Historic Chemical Landmark. In 1993, the Chemistry Department of the University of Michigan instituted the Moses Gomberg Lecture series to provide assistant professors an opportunity to invite distinguished scientists to the Chemistry department.

 

 

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Gomberg never married, living quietly, sharing a house in Ann Arbor with his sister Sonia, for his adult life. Her health began to fail around the time of his retirement, and he spent most of the rest of his life caring for her. She died when Gomberg was 71. Gomberg died on February 12, 1947, four days after his 81st birthday. Those who knew Gomberg remembered him as kind, generous and modest, as well as a man with strong convictions. He was unfailingly courteous.

 

In medicine, understanding free radicals, particularly those formed by oxygen, has illuminated the nature of oxidative stress – damage that results when free radicals form faster than the body removes them. This, in turn, has revealed ways human health can be improved – for example, by using antioxidants. We now recognize that many free radicals are essential components of enzymes in the body, while others can damage DNA, leading to cancer or other diseases. We know, for example, that free radicals formed by excessive exposure to the sun’s ultraviolet light can lead to cataracts.

 

Many free radical processes involve chain reactions that begin when an unpaired electron fails to find another unpaired electron with which it can easily bond. The free radical removes an atom (usually hydrogen) from another molecule, turning itself into a stable molecule; the molecule it attacked becomes a free radical. Such chain reactions are used to make environmentally friendly products such as recyclable automobile tires and soaps free of salts.

 

Gomberg’s free radicals leave a wide-reaching legacy.

 

Conventional polymerization continued to be used to produce nylon and other products. But free radical polymerization had advantages such as high tolerance of chemical impurities and extreme temperatures, and the ability to be used with a wide range of monomers (organic molecules). Today, free radicals are used to produce nearly half the polymers we use – materials used in everything from food wrapping to paint, adhesives, film, carpeting, piping, and more. Although Gomberg is best known for his discovery of organic free radicals, he made many other contributions to organic and applied chemistry. He developed new solvents for automobile lacquers, the first antifreeze compound used in cars, and a procedure for producing mustard gas during World War I. He received honorary degrees from the University of Chicago, Brooklyn Polytechnic Institute, and the University of Michigan, as well as three medals from the American Chemical Society: the Nichols Medal in 1914, the Willard Gibbs Medal in 1925, and the Chandler Medal in 1927. He was elected to the National Academy of Sciences in 1914, and served as president of the American Chemical Society in 1931.Click here to read more about the life of this genius.

 

 

20140721-14

The Discovery of Organic Free Radicals by Moses Gomberg“ commemorative booklet produced by the National Historic Chemical Landmarks program of the American Chemical Society in 2000.

 

A Landmark Designation: The American Chemical Society designated the discovery of organic free radicals by Moses Gomberg as a National Historic Chemical Landmark in a ceremony at the University of Michigan in Ann Arbor, Michigan, on June 25, 2000, during the 100thanniversary of the discovery. The plaque commemorating the event reads:

 

In 1900, Moses Gomberg, Professor of Chemistry at the University of Michigan, confirmed the existence of a stable, trivalent organic free radical: triphenylmethyl. In so doing, he challenged the then prevailing belief that carbon could have only four chemical bonds. Gomberg’s discovery made a major contribution to theoretical organic chemistry and fostered a field of research that continues to grow and expand. Today, organic free radicals are widely used in plastics and rubber manufacture, as well as medicine, agriculture and biochemistry.

 

National Historic Chemical Landmark Honoring Professor Moses Gomberg Dedicated June 25, 2000, at the University of Michigan in Ann Arbor, Michigan. Commemorative Booklet)

 

 

20140721-15

Portrait of Moses Gomberg (undated)

 

Sources: Moses Gomberg (University of Michigan Faculty History Project); Moses Gomberg, 1866-1947 (National Academy of Sciences); Wikipedia

 

 

20140721-16

Portrait of Moses Gomberg. Courtesy Bentley Historical Library, University of Michigan. 

 

Landmark Designation and Acknowledgments

 

Landmark Designation

The American Chemical Society designated the discovery of organic free radicals by Moses Gomberg as a National Historic Chemical Landmark in a ceremony at the University of Michigan in Ann Arbor, Michigan, on June 25, 2000, during the 100thanniversary of the discovery. The plaque commemorating the event reads:

 

In 1900, Moses Gomberg, Professor of Chemistry at the University of Michigan, confirmed the existence of a stable, trivalent organic free radical: triphenylmethyl. In so doing, he challenged the then prevailing belief that carbon could have only four chemical bonds. Gomberg’s discovery made a major contribution to theoretical organic chemistry and fostered a field of research that continues to grow and expand. Today, organic free radicals are widely used in plastics and rubber manufacture, as well as medicine, agriculture and biochemistry.

 

Filed Under History of Medicine, News | Leave a Comment 

Gene Linked to Fatal Inflammatory Disease in Children

 

Autoinflammatory diseases are a class of conditions in which the immune system, seemingly unprovoked, becomes activated and triggers inflammation. Normally, the inflammatory response helps quell infections, but the prolonged inflammation that occurs in these diseases can damage the body.

 

According to an article published online in the New England Journal of Medicine (16 July 2014), investigators at the NIH have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Fortunately, several existing drugs have shown therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which is named STING-associated vasculopathy with onset in infancy (SAVI). The senior author of the study, Raphaela Goldbach-Mansky, M.D., and the co-lead authors, Yin Liu, M.D., Ph.D., Adriana A. Jesus, M.D., Ph.D., and Bernadette Marrero, Ph.D., are in the NIAMS Translational Autoinflammatory Disease Section.

 

In 2004, a 10-year-old girl with signs of systemic inflammation, especially in the blood vessels, who had not responded to any medications, presented at NIH. She had blistering rashes on her fingers, toes, ears, nose and cheeks, and had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. Tragically, she died a few years later.

 

By 2010, two other patients were seen with the same symptoms. The research team suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. As a result, DNA comparison revealed a novel mutation in a gene that encodes a protein called STING, a known signaling molecule whose activation leads to production of interferon, a key immune regulator. When overproduced, however, interferon can trigger inflammation. Blood tests on the affected children had shown high levels of interferon-induced proteins, so it was not surprising when the mutated gene turned out to be related to interferon signaling. Then, when the DNA of five other patients with similar symptoms was tested, mutations in the same gene were found, confirming STING’s role in the disease.

 

It was, therefore, concluded that the mutations in STING boosted the protein’s activity resulting in excessive inflammation along with other evidence of interferon pathway activation. Interferon normally works to restrict an invading pathogen’s ability to replicate by triggering a function that stimulates immune cells. But prolonged activation of the pathway leads to chronic inflammation and damage to tissues and organs. The researchers also found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by the disease.

 

The research team next looked for ways to mitigate the inflammatory response in patients with SAVI. Several drugs in the janus kinase (JAK) inhibitor class: tofacitinib (Pfizer), ruxolitinib (Incyte and Novartis) and baricitinib (Incyte and Lilly), are known to work by blocking the interferon pathway. As a result, when the effect of the drugs were tested on SAVI patients’ blood cells in the lab, a marked reduction in interferon-pathway activation was observed.

 

SAVI patients are now being enrolled in an expanded access program, also known as a compassionate use protocol. Compassionate use protocols allow doctors to give investigational medicines to patients with serious diseases or conditions for which there is no comparable or satisfactory alternative therapy to treat the patient’s disease or condition.

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New Treatment Increases Pregnancy Rate in Women With PCOS

 

Polycystic ovary syndrome (PCOS) affects from 5 to 10% of reproductive age women and may be the most common cause of female infertility. With PCOS, the ovaries are enlarged and contain multiple small cyst-like structures (immature ovarian follicles). Women with PCOS may produce an excess of male hormones, which interferes with ovulation. In addition to infertility, PCOS symptoms include irregular menstrual periods, excessive body and facial hair, acne, and obesity. Women with PCOS also may experience insulin resistance, a prediabetic condition in which higher-than-normal amounts of insulin are produced to maintain normal blood glucose levels.

 

Letrozole, currently used as a treatment for breast cancer in women who have gone through menopause, inhibits the production of estrogen, which influences the action of the brain’s hypothalamus and pituitary on the functioning of the ovaries. Clomiphene prevents estrogen from binding to its target on the cell and so acts on the pituitary to cause the ovary to release the egg cell.

 

According to an article published in the new England Jornal of Medicine (2014;371:119-129), letrozole appears to be more effective than the standard drug clomiphene for helping women with PCOS to achieve pregnancy. The study found that that women treated with letrozole not only were more likely to ovulate than were women treated with the standard drug, clomiphene, but were also more likely to have a live birth.

 

The study enrolled 750 infertile women with PCOS who were between 18 and 40 years of age, from February 2009 through January 2012. The women were assigned at random to receive either clomiphene or letrozole for 5 days, beginning on the third day of their menstrual cycle, for up to 5 monthly cycles. If a woman failed to ovulate or if their test results indicated that they produced insufficient progesterone following ovulation, the dose of the drug was increased during the next monthly cycle. Women with test results indicating conception had occurred were followed until an ultrasound exam could confirm that a pregnancy had been established and throughout pregnancy until delivery.

 

Results showed that of the 374 women who received letrozole, 103 (27.5%) eventually had a live birth, and of the 376 women who received clomiphene, 72 (19.1%) experienced a live birth. The cumulative ovulation rate was also higher for the letrozole group, with ovulation occurring 834 times in 1352 cycles, or 61.7% of the time. The women in the clomiphene group ovulated 688 times out of a total of 1425 cycles, or 48.3% of the time.

 

There were no statistically significant differences between the groups for:

 

1. Multiple pregnancy, with twin pregnancies occurring in 3.4% among the letrozole group and 7.4% of the clomiphene group

2. Pregnancy loss (31.8% of the letrozole group and 29.1% of the clomiphene group

3. Infants born with birth defects (3.9% with letrozole and 1.4% with clomiphene)

 

In terms of adverse events, women treated with letrozole had significantly fewer hot flashes than those treated with clomiphene, but more dizziness and fatigue.

 

The study authors noted that one prior study suggested that letrozole might increase the risk of birth defects, but added that their study results do not support the earlier study’s findings. Although the study did not uncover an increased risk of birth defects, the authors concluded that additional studies are needed to rule out whether letrozole could pose a similar or greater risk of birth defects than do other infertility treatments.

 

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TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

FDA Approves Drug to Treat Acute Hereditary Angioedema (HAE)

 

Target Health began working in 2003 with Dr. Bernd Rosenkranz and Jerini AG (acquired by Shire, now Abbvie) for the first product approved by FDA for Hereditary angioedema (HAE). We worked with Bernd on obtaining orphan drug designation and the original IND, and Target e*CRF was used for the first clinical trial. FDA Approved FIRAZYR® (icatibant injection) for acute attacks of HAE in 2011.

 

HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6,000 to 10,000 people in the United States. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection. Swelling of the airway is potentially fatal without immediate treatment.

 

The FDA has approved Ruconest, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with HAE. Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits. Ruconest is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.

 

The safety and efficacy of Ruconest was evaluated in a multicenter controlled clinical trial. Forty-four adult and adolescent patients with acute attacks were treated with Ruconest. The most common adverse reactions reported in patients treated with Ruconest were headache, nausea and diarrhea.

 

Ruconest received orphan-drug designation for acute attacks by the FDA because it is intended for treatment of a rare disease or condition.

 

Ruconest is manufactured by Pharming Group NV, Leiden, the Netherlands, and will be distributed in the United States by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., Raleigh, North Carolina.

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Almond Pear Cake

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For the pears

 

1 pound pears, rinsed and dried

1 lemon

3/4 cup granulated Splenda

 

For the almond cake

 

Canola spray for 9 inch spring-form pan

7 ounces almond paste

1/4 cup granulated Splenda

4 ounces unsalted butter, cut into small pieces and chilled

2 Tablespoons honey

3 large eggs

4 Tablespoons Amaretto, plus a lot extra to pour over cake

1/3 cup almond flour, sifted

Kosher salt

1/2 cup additional Amaretto, to go with the fruit

1 cup sliced almonds, toasted at home (garnish)

Confectioners’ Splenda

Cool whip (garnish), Creme fraiche, whipped to soft peaks

 

 

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Make the pears

 

1. Select about 3 slices of the pears, after cut in half. Then cut the half in lengthwise slices, and set aside.

2. Cut the remaining pears in halves or quarters so that the pieces are about the same size. (You should have about 1 1/2 cups.) Place them in a medium saucepan.

3. Use a fine grater to zest the lemon. Add 1 teaspoon of the zest to the pan. Squeeze 1 Tablespoon of juice and add it to the pan. Add the Splenda and stir to coat the fruit.

4. Add Amaretto to the pears and stir.

5. Place the pan over medium-high heat and cook, stirring often to dissolve the sugar. By the time the sugar has dissolved, the fruit will have released a lot of juice. Boil for about 4 minutes to reduce the liquid somewhat, then reduce the heat and simmer for another 2 minutes. Don’t worry if some of the pear is soft and falls apart.

6. Take pan off the stove and stir in reserved pears. Cool to room temperature. Serve either on top of the cake, or next to each individual serving of cake. Garnish top of cake with the first 3 slices (see photo)

Refrigerate left-over fruit in a covered container.

 

 

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Bottom of cake after baking. Now, turn it over. But if you don’t want to, it doesn’t matter. ©Joyce Hays, Target Health Inc.

 

Make the cake

 

1. Spray sides of an 8 or 9-inch spring-form cake pan. Line bottom of pan with a circle of parchment paper.

2. Place the almond paste and Splenda in the bowl of a heavy-duty mixer fitted with the paddle attachment, or in another large bowl if using a handheld mixer. Begin to cream the mixture on low speed to break up the almond paste, then increase the speed to medium for about 2 minutes, or until the paste is broken into fine particles.

3. Add the butter and mix for 4 to 5 minutes, or until the mixture is light in color and airy; stop the machine and scrape down the sides as necessary. It is important to mix long enough or the cake will have a dense texture.

4. Mix in the honey, then add the eggs one at a time, beating until each one is fully incorporated before adding the next. Add the amaretto, flour, and a pinch of salt and mix just to combine.

5. Scrape the batter into the prepared pan and smooth the top. Bake for about 25 minutes, or until the cake is golden and springs back when pressed. Watch the cake constantly so it doesn’t burn. Transfer to a rack to cool.

6. Invert the large cake onto the rack, remove the parchment paper, and invert the cake again so that the top is once again facing upward. Brush the top of the cake(s) with Amaretto, or pour Amaretto into a measuring cup for easy pouring and slowly add 1/2 cup or more, to top of cake. It will sit on top for a while so let it get absorbed. Don’t be shy adding the Amaretto. Next, add the three sliced pears to top of cake. Now, sprinkle the toasted almonds, all over top of cake. Dust with Splenda confectioners’ sugar (optional). Serve with a dollop of cool whip or whipped creme fraiche and the cooked/cooled pears (optional).

 

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Going                                                                                                Going

 

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Nearly gone (one sitting, two people) ©Joyce Hays, Target Health Inc.

 

Pictures are worth many words – can you tell how delicious this cake is/was?

 

We ate light, a vegetarian dinner, of veggie burgers topped with chopped tomatoes, avocados and cooked shallots, some farfalle and the New Zealand sauvignon blanc we discovered in a previous newsletter. Our attention then turned to the new recipe – dessert. Out the window went our health concerns. Although, we don’t read Time Magazine for serious news, we did notice one of their recent cover photos, a close-up of butter, and, announcing that doctors were now giving their “okay“ to eat it again.  We don’t agree with these doctors or with Time Magazine, which is why we mention it here. But for a brief dessert time, usually allotted for fresh fruit, we sampled the new cake.  It was unbelievably delicious! Jules simply devoured it!

 

Let me come to the rescue. Let’s say you liked the photos of this Almond Pear Cake, but have the will power to, just say no. I’ve already thought about that. Take a look below, for the alternative:

 

 

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No butter alternative, pear almond cake with hundreds of fewer calories ©Joyce Hays, Target Health Inc.

 

This is 99.9% the same recipe. The only change is that I substituted the butter for 1/2 of a container of tofutti (soy cream cheese). I tried a slightly different garnish. After slowly pouring a great deal of Amaretto on top, waiting patiently for it to soak (by poking a fork all across the top, the soaking process was speeded up), I used some of the cooked pear mixture to cover the top (instead of sliced pears), then sprinkled the toasted almonds all over everything.

 

Here’s the thing. If you never tasted the cake with butter, you will love this version of the recipe. It’s delicious but dryer (so needs more Amaretto). It’s less rich, but you won’t know that if you didn’t make the butter version.

 

Which ever version you decide to make, this is the perfect anytime cake. Wonderful with coffee so serve for brunch, lunch dessert and of course an evening dessert. You will find your family members snacking on it, as well.

 

 

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From Our Table to Yours!

 

Bon Appetit !

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NOAA’s global update is out today.

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Friends really are the family you choose

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You’ll never guess what lab this research came from.

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