Target Health Inc. in the Public Eye

 

At the recent Fall meeting of the eClinical Forum, hosted by Biogen-Idec in Cambridge, MA, Dean Gittleman, Sr. Director at Target Health, summarized the current status of the eClinical Forum task force, addressing the hosting of eSource data when using EDC systems. One of the issues is whether EDC systems can host eSource data in the context of GCP, EMA and FDA guidances. While there was a robust technical and regulatory discussion, in our opinion, the most important issue is to assess the perspective from the clinical research sites. That is, will the sites be “happy“ if EDC companies host their source data when data are entered directly into EDC systems with no independent backup records. At least, when using EMRs, the clinical sites have real-time access to their data and they have their own backup systems. It is also clear that EMA prefers that Sponsors themselves not host EDC systems and that even if there are paper records, there are source data collected by EDC systems such as who entered the data and when. These meta-data, in the opinion of some regulators, might be useful during an investigation or pre-approval inspection.

 

In spite of a lot of discussion, our eSource solution, Target e*CTR® (eClinical Trial Record), which is compatible with any EDC system, addresses all concerns and is currently operational and available.

 

The 2nd presentation by Target Health Inc. at eClinical Forum addressed “Challenges and Recommendations When Implementing New eSystems.“ The presentation was all about how to implement “disruptive innovative ideas“ within organizations. And yes, there are big pharma companies addressing these issues when it comes to the paperless clinical trial. The following are some highlights:

 

What Are Some of the Issues That Prevent Change?

  1. There are no incentives to risk-taking
  2. What is in it for me?
  3. FDA will beat us up and issue a 483

When FDA issues a 483

The hammer comes down, that’s the end of me.

We’re out of business, I lose my job

Get me outta this mess, I pray to God

  1. Risk avoidance
  2. Will I lose my job if I fail?
  3. I am retiring soon

 

How to Implement Change

  1. Have a Culture That Supports Risk-taking Within an Organization Separate From Current Operations
  2. Identify Needs
  3. Identify the Barriers
  4. Convince Management to Experiment
  5. Do Not Be Afraid to Fail

 

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.

 

QUIZ

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Viruses

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HIV Virus

 

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Influenza (Avian Flu) virus. A/H5N1 subtype

 

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Rota Virus

 

A virus is a small infectious agent that replicates only inside the living cells of other organisms. Viruses can infect all types of life forms, from animals and plants to bacteria and archaea. Viruses are found wherever there is life and have probably existed since living cells first evolved. The origin of viruses is unclear because they do not form fossils, so molecular techniques have been used to compare the DNA or 1) ___ of viruses and are a useful means of investigating how they arose.

 

The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids – pieces of DNA that can move between cells – while others may have evolved from bacteria. In evolution, viruses are an important means of horizontal gene transfer, which increases 2) ___ diversity. Viruses are considered by some to be a life form, because they carry genetic material, reproduce, and evolve through natural selection. However they lack key characteristics, such as cell structure, that are generally considered necessary to count as life. Because they possess some but not all such qualities, viruses have been described as “organisms at the edge of life“. Viruses are by far the most abundant biological entities on Earth and they outnumber all the others put together. They infect all types of cellular life including animals, plants, bacteria and fungi. However, different types of viruses can infect only a limited range of hosts and many are species-specific. Some, such as smallpox virus for example, can infect only one species – in this case 3) ___, and are said to have a narrow host range. Other viruses, such as rabies virus, can infect different species of mammals and are said to have a broad range. The viruses that infect plants are harmless to animals, and most viruses that infect other animals are harmless to humans.

 

Viruses are now recognized as ancient and as having origins that pre-date the divergence of life into the three domains: archaea, 4) ___, and eukaryote. This discovery has led modern virologists to reconsider and re-evaluate these three classical hypotheses. The evidence for an ancestral world of RNA cells and computer analysis of viral and host DNA sequences are giving a better understanding of the evolutionary relationships between different viruses and may help identify the ancestors of modern viruses. To date, such analyses have not proved which of these hypotheses is correct. However, it seems unlikely that all currently known viruses have a common ancestor, and viruses have probably arisen numerous times in the past by one or more mechanisms.

 

Since Dmitri Ivanovsky’s 1892 article describing a non-bacterial pathogen infecting tobacco plants, and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, about 5,000 viruses have been described in detail, although there are millions of different types. Viruses are found in almost every ecosystem on Earth and are the most abundant type of biological entity. The study of viruses is known as 5) ___, a sub-speciality of microbiology. Virus particles, known as virions, consist of two or three parts: i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; ii) a protein coat that protects these genes; and in some cases iii) an envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of viruses range from simple helical and icosahedral forms to more complex structures. The average virus is about one one-hundredth the size of the average bacterium. Most viruses are too small to be seen directly with an optical microscope. Viruses spread in many ways; viruses in plants are often transmitted from plant to plant by insects that feed on plant sap, such as aphids. Viruses in animals can be carried by blood-sucking insects. These disease-bearing organisms are known as vectors.

 

Influenza viruses are spread by coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, are transmitted by the fecal-oral route and are passed from person to person by contact, entering the body in food or water. HIV is one of several viruses transmitted through intimate contacts and by exposure to infected blood. The range of host cells that a virus can infect is called its “host range“. This can be narrow or, as when a virus is capable of infecting many species, broad.

 

Viral epidemiology is the branch of medical science that deals with the transmission and control of virus infections in humans. Transmission of viruses can be vertical, which means from mother to child, or 6) ___, which means from person to person. Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. However, some viruses including those that cause AIDS and viral hepatitis evade these immune responses and result in chronic infections. Antibiotics have no effect on viruses, but several antiviral drugs have been developed.

 

 

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Structure of icosahedral cowpea mosaic virus

 

Viruses display a wide diversity of shapes and sizes, called morphologies. In general, viruses are much smaller than bacteria. Most viruses that have been studied have a diameter between 20 and 300 nanometres. Some filoviruses have a total length of up to 1400 nm; their diameters are only about 80 nm. Most viruses cannot be seen with an optical microscope so scanning and transmission electron microscopes are used to visualize virions. To increase the contrast between viruses and the background, electron-dense “stains“ are used. These are solutions of salts of heavy metals, such as tungsten, that scatter the electrons from regions covered with the stain. When virions are coated with stain (positive staining), fine detail is obscured. Negative 7) ___ overcomes this problem by staining the background only. A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein called a capsid. These are formed from identical protein subunits called capsomeres. Viruses can have a lipid “envelope“ derived from the host cell 8) ___. The capsid is made from proteins encoded by the viral genome and its shape serves as the basis for morphological distinction. Virally coded protein subunits will self-assemble to form a capsid, in general requiring the presence of the virus genome.

 

Viral populations do not grow through cell division, because they are acellular. Instead, they use the machinery and metabolism of a host cell to produce multiple copies of themselves, and they assemble in the9) ___.

 

 

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A typical virus replication cycle

 

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Some bacteriophages inject their genomes into bacterial cells (not to scale)

 

The life cycle of viruses differs greatly between species but there are six basic stages in the life cycle of viruses. Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface. This specificity determines the host range of a virus. For example, HIV infects a limited range of human leucocytes. This is because its surface protein,gp120, specifically interacts with the CD4 molecule – achemokine receptor – which is most commonly found on the surface of CD4+ T-Cells. This mechanism has evolved to favor those viruses that infect only cells in which they are capable of replication. Attachment to the receptor can induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or changes of non-enveloped virus surface proteins that allow the 10) ___ to enter. Penetration follows attachment: Virions enter the host cell through receptor-mediated m11 endocytosis or membrane fusion. This is often called viral entry.

 

ANSWERS: 1) RNA; 2) genetic; 3) humans; 4) bacteria; 5) virology; 6) horizontal; 7) staining; 8) membrane; 9) cell; 10) virus

 

Jonas Edward Salk MD (1914-1995) – A MUST READ

 

Editor’s note: In 1934, America was still in the grip of the worst depression in its history, and yet, free education was available to qualifying students not able to afford it. Why has this intelligent pathway to an equal playing field regarding the attainment of careers, not been continued today?

 

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This year, 2014 is the 100th birthday of a true medical hero, Jonas Edward Salk MD, discoverer of the Salk vaccine, to eradicate polio. Dr. Salk was an American medical researcher and virologist who discovered and developed the first successful inactivated polio vaccine. Born in New York City to Russian Jewish parents, he attended New York University School of Medicine, later choosing to do medical research instead of becoming a practicing physician.

 

Until 1957, when the Salk vaccine was introduced, polio was considered one of the most frightening public health problems in the world. The 1952 U.S. epidemic was the worst outbreak in the nation’s history. Of nearly 58,000 cases reported that year, 3,145 people died and 21,269 were left with mild to disabling paralysis, with most of its victims being children. The “public reaction was to a plague“, said historian Bill O’Neal. Citizens of urban areas were terrified every summer when this frightful visitor returned.“ As a result, scientists were in a frantic race to find a way to prevent or cure the disease. President, Franklin D. Roosevelt was the world’s most recognized victim of polio and founded the organization, the March of Dimes Foundation, that would fund the development of a vaccine.

 

In 1947, Salk accepted an appointment to the University of Pittsburgh School of Medicine. In 1948, he undertook a project funded by the National Foundation for Infantile Paralysis to determine the number of different types of polio virus. Salk saw an opportunity to extend this project towards developing a vaccine against polio, and, together with the skilled research team he assembled, devoted himself to this work for the next seven years.

 

The field trial set up to test the Salk vaccine involved 20,000 physicians and public health officers, 64,000 school personnel, and 220,000 volunteers. Over 1,800,000 school children took part in the trial.

 

When news of the vaccine’s success was made public on April 12, 1955, Salk was hailed as a “miracle worker“ and the day almost became a national holiday. Around the world, an immediate rush to vaccinate began, with countries including Canada, Sweden, Denmark, Norway, West Germany, the Netherlands, Switzerland, and Belgium planning to begin polio immunization campaigns using Salk’s vaccine.

 

Salk’s sole focus had been to develop a safe and effective vaccine as rapidly as possible, with no interest in personal profit. When asked who owned the patent to it, Salk said, “There is no patent. Could you patent the sun?“ In 1960, Salk founded the Salk Institute for Biological Studies in La Jolla, California, which is today a center for medical and scientific research, where he continued to conduct research and publish books, including Man Unfolding (1972), The Survival of the Wisest (1973), World Population and Human Values: A New Reality (1981), and Anatomy of Reality: Merging of Intuition and Reason (1983). Salk’s last years were spent searching for a vaccine against HIV. His personal papers are stored at the University of California, San Diego Library.

 

Jonas Salk was born in New York City on October 28, 1914. His parents, Daniel and Dora  Salk, were Ashkenazi Jewish immigrants who had not received extensive formal education. According to historian David Oshinsky, Salk grew up in the “Jewish immigrant culture“ of New York. He had two younger brothers, Herman and Lee, a child psychologist. The family moved from East Harlem to the Bronx, with some time spent in Queens. When he was 13, Salk entered Townsend Harris High School, a public school for intellectually gifted students. Named after the founder of City College of New York (CCNY), it was, said Oshinsky, “a launching pad for the talented sons of immigrant parents who lacked the money – and pedigree – to attend a top private school.“ In high school Salk was known as a perfectionist who read everything he could lay his hands on,“ according to one of his fellow students. Students had to cram a four-year curriculum into just three years. As a result, most dropped out or flunked out, despite the school’s motto “study, study, study.“ Of the students who graduated, however, most would have the grades to enroll in CCNY, noted for being a highly competitive college. Salk then enrolled in CCNY from which he earned a BS degree in chemistry in 1934. At that time for working-class immigrant families, City College represented the apex of public higher education. Getting in was tough, tuition was free and competition was intense. But the rules were fairly applied. No one got an advantage based on an accident of birth.

 

At his mother’s urging, Salk put aside aspirations of becoming a lawyer, and instead concentrated on classes necessary for admission to medical school. However, the facilities at City College were barely second rate and there were no research laboratories; the library was also inadequate. The faculty contained few noted scholars. “What made the place special,“ Oshinsky wrote, “was the student body that had fought so hard to get there – driven by their parents. From these ranks, of the 1930s and 1940s, emerged a wealth of intellectual talent, including more Nobel Prizewinners – eight – and PhD recipients than any other public college.“ Salk entered CCNY at the age of 15, a common age for a freshman who had skipped multiple grades along the way.

 

As a child, Salk did not show any interest in medicine or science in general. He said in an interview with the Academy of Achievement, “As a child I was not interested in science. I was merely interested in things human, the human side of nature, if you like, and I continue to be interested in that.“ After City College, Salk enrolled in New York University to study medicine. At that time, NYU based its modest reputation on famous alumni, such as Walter Reed, who helped conquer yellow fever. Tuition was also comparatively low, and it did not discriminate against Jews, while most of the surrounding medical schools had rigid quotas in place. For example, one school accepted 76 applicants in 1935, out of a pool of 501. Although 200 of the applicants were Jewish, only five got in.

 

During Salk’s medical studies, he stood out from his peers, not just because of his continued academic prowess (he was Alpha Omega Alpha, the Phi Beta Kappa Society of medical education) but because he had decided he did not want to practice medicine. Instead, he became absorbed in research, even taking a year off to study biochemistry. He later focused more of his studies on bacteriology which had replaced medicine as his primary interest. He said his desire was to help humankind in general rather than single patients. It was the laboratory work, in particular, that gave new direction to his life. According to Salk: “My intention was to go to medical school, and then become a medical scientist. I did not intend to practice medicine, although in medical school, and in my internship, I did all the things that were necessary to qualify me in that regard. I had opportunities along the way to drop the idea of medicine and go into science. At one point at the end of my first year of medical school, I received an opportunity to spend a year in research and teaching in biochemistry, which I did. And at the end of that year, I was told that I could, if I wished, switch and get a Ph.D. in biochemistry, but my preference was to stay with medicine. And, I believe that this is all linked to my original ambition, or desire, which was to be of some help to humankind, so to speak, in a larger sense than just on a one-to-one basis.“

 

After graduating from NYU medical school in 1939, Salk began his residency at New York’s Mount Sinai Hospital, where he again worked in Dr. Thomas Francis’ laboratory. Few hospitals in Manhattan had the status of Mount Sinai, particularly among the city’s Jews. Out of 250 who sought the opportunity, only a dozen were chosen. In 1941, during his postgraduate work in virology, Salk chose a two-month elective to work in the laboratory of Dr. Thomas Francis, then at the University of Michigan. Francis had recently joined the faculty of the medical school after working for the Rockefeller Foundation, where he had discovered the type B influenza virus. The two-month stint in Francis’s lab was Salk’s first introduction to the world of virology, and he was hooked.

 

Salk quickly made his mark. Although focused mainly on research, he showed tremendous skills as a clinician and a surgeon. But it was his leadership as president of the house staff of interns and residents at Mount Sinai that best defined him to his peers. The key issue for many of them in 1939, for example, was not the fate of the hospital, but rather the future of Europe after Nazi Germany’s invasion of Poland. In one instance, several interns responded by wearing badges to signify support for the Allies, but the hospital’s director told them to remove them “lest they upset some of the patients.“ The interns then took the matter to Salk. Salk replied that everyone should wear the badge as an act of solidarity. One intern recalled, “Jonas was a very staunch guy. He never took a backward step on that issue or any other issue of principle between us and the hospital.“ The hospital administrators backed off and there was no further interference from the director. At the end of his residency, Salk began applying for permanent research positions, but he discovered that many of the jobs he desired were closed to him due to Jewish quotas, which, according to historian, Bookchin, “prevailed in so much of the medical research establishment.“ Nor could he apply at Mount Sinai, as its policy prevented it from hiring its own interns. As a last resort, he contacted Dr. Francis for help, but Francis had left New York University a year earlier after accepting an offer to direct the University of Michigan’s School of Public Health. However, Dr. Thomas Francis did not let him down and he secured extra grant money and offered Salk a job working on an army-commissioned project in Michigan to develop an influenza vaccine. Salk and Francis eventually perfected a vaccine that was soon widely used at army bases, where Salk had been responsible for discovering and isolating one of the flu strains that was included in the final vaccine.

 

It was in Pittsburgh that Salk began to put together the techniques that would lead to his polio vaccine. He was already struck by the principle of vaccination: that if the body is artificially exposed to a harmless form of a disease virus, the body will produce antibodies that resist or kill the dangerous form of the virus if later exposed. In contrast to the Pasteurian dogma of the times, Salk believed that protective immunity could be induced without infection by a living virus such as those used in the vaccines against smallpox and rabies. In developing the influenza vaccine, he had observed that protection could be established using noninfectious, inactivated (killed) viruses. Salk’s research caught the attention of Basil O’Connor, president of the National Foundation for Infantile Paralysis (now known as the March of Dimes Birth Defects Foundation). The organization decided to fund Salk’s efforts to develop a killed virus vaccine against the most frightening scourge of the time: paralytic poliomyelitis. Using formaldehyde, Salk killed the poliovirus, but kept it intact enough to trigger the necessary immune response. His work was enabled by a key achievement made by Harvard researcher John Enders. Enders and his team had figured out how to grow poliovirus in test tubes. This step was necessary to obtain the quantities of pure virus needed to develop and manufacture a vaccine. The resulting injectable vaccine was tested first in monkeys and then in patients at the D.T. Watson Home for Crippled Children (now The Watson Institute), who already had polio. Next, vaccine was given to volunteers who had not had polio, including Salk, his laboratory staff, his wife and their children. The volunteers developed anti-polio antibodies and none had bad reactions to the vaccine. Finally, in 1954, national testing began on one million children, ages six to nine, who became known as the Polio Pioneers: half received the vaccine, and half received a placebo. One-third of the children, who lived in areas where vaccine was not available, were observed to evaluate the background level of polio in this age group. On April 12, 1955, the results were announced: the vaccine was safe and effective. In the two years before vaccine was widely available, the average number of polio cases in the U.S. was more than 45,000. By 1962, that number had dropped to 910. Salk never patented the vaccine, nor did he earn any money from his discovery, preferring to see it distributed as widely as possible.

 

Given the fear and anxiety that polio caused during the first half of the century, the vaccine’s success in 1955 made Salk an international hero, and he spent the late 1950s refining the vaccine and establishing the scientific principles behind it. By 1960, however, Salk was ready to move on. Salk’s dream was to create an independent research center where a community of scholars interested in different aspects of biology – the study of life – could come together to follow their curiosity. For more than a year, Salk toured the country in search of the right location for his research center. For San Diego mayor Charles Dail, a polio survivor, bringing the Salk Institute to San Diego was a personal quest. Dail showed Salk 27 acres on a mesa in La Jolla, just west of the proposed site for the new University of California campus then planned for San Diego. In June 1960, in a special referendum, the citizens of San Diego voted overwhelmingly to give the land for Salk’s dream. With initial financial support from the National Foundation/March of Dimes, Salk and Kahn were able to proceed. To bring his concept of free-flowing labs and quiet studies to life, Salk recruited architect Louis Kahn. The resulting collaboration is a series of elegant concrete structures that overlook the Pacific Ocean. Under Salk’s direction, the Institute began research activities in 1963 and gradually expanded its faculty and the areas of their research interests. Salk’s personal research activities included multiple sclerosis and autoimmune diseases, cancer immunology, improved manufacture and standardization of killed poliovirus vaccine, and the development of an AIDS vaccine. He published several philosophical books and advocated cooperative rather than confrontational approaches to addressing human needs.

 

Completed in 1967, the original Institute buildings were declared an historic landmark in 1991. During Salk’s tenure as Founding Director, a major building addition consistent with his and Louis Kahn’s original architectural vision was designed and constructed. The Institute now has 61 faculty members and a scientific of staff of more than 850, with labs that house research on everything from cancer, diabetes and birth defects to Alzheimer’s disease, Parkinson’s disease, AIDS and plant biology. The campus was designed by Louis Kahn. Salk had sought to make a beautiful campus in order to draw the best researchers in the world. Salk and Kahn having both descended from Russian Jewish parents that had immigrated to the United States, had a deeper connection than just mere partners on an architectural project. Their connection is seen in the design that resulted from their collaboration. The original buildings of the Salk Institute were designated as a historical landmark in 1991. The entire 27-acre site was deemed eligible by the California Historical Resources Commission in 2006 for listing on the National Register of Historic Places. The Salk Institute truly reflects the broad, humanistic interests of its namesake.

 

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The design of the Basilica of San Francesco d’Assisi, in Italy, helped prompt the polio vaccine. (Photo: GETTY IMAGES)

 

In science and art, one thing always leads to another and another and another. Early in his career, when he was still struggling to find a cure for polio, Jonas Salk retreated to Umbria, Italy, to the monastery at the Basilica of Assisi. The 13th-century Franciscan monastery rises out of the hillside in geometric white stone, with Romanesque arches framing its quiet courtyards. Salk would insist, for the rest of his life, that something about this place – the design and the environment in which he found himself – helped to clear his obstructed mind, inspiring the solution that led to his famous polio vaccine. “He really thought there was something to this,“ says the architect Alison Whitelaw, “that the quality of the built environment could affect the performance of the brain.“ Today, at the Academy of Neuroscience for Architecture, Whitelaw believes that enriched environments might enhance the performance of the human brain, and the growth of new brain cells. Whitelaw is cautious about this profound idea. “I’m not saying that we’re going to be able to evolve the human brain further,“ she says. Using color, lighting, and layout, though, architects may be able to design places to provide the sensory experiences that produces the best brain response, the most creativity. This past September, the academy held its first national conference at, fittingly, the Salk Institute, in La Jolla, California.

 

 

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One view of The Salk Institute in La Jolla, California

 

When Dr. Jonas Salk envisioned the idea of the Salk Institute for Biological Studies, it was with the idea of creating a vibrant, intellectual community, dedicated to pursuing the kinds of scientific achievements that had made him an international figure only five years before. Salk came to La Jolla following a brilliant career in clinical medicine and virology research. Jonas Salk’s Assisi experience makes you think: architects could even design environments expressly to foster research breakthroughs. Salk actually tried to achieve this in working with architect Louis Kahn to design the Salk Institute in La Jolla. The campus, with its ample natural light, views of the Pacific Ocean, and vast central plaza, echoes the monastic tranquility of Assisi. The architecture is inspiring; Salk’s successors must now translate that advantage into science. Salk died at age 80 on June 23, 1995. A memorial at the Institute with a statement from Salk captures his vision: “Hope lies in dreams, in imagination and in the courage of those who dare to make dreams into reality.

 

 

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A closer view of the water running through the campus of the Salk Institute

Do the Mitochondria in Our Cells “Shake“?

 

According to the NIH, “Elvis did it, Michael Jackson did it, and so do the mitochondria in our cells. They shake. While Elvis and Michael shook for decades before loud and appreciative audiences, mitochondrial oscillations have quietly bewildered scientists for more than 40 years.“

 

The mitochondrion (the singular of mitochondria) is of one of several distinct compartments, or organelles, in the cell cytoplasm. Although mitochondria are jacks of many biochemical trades, they are best known as the power plants of the cell. They generate a continuous supply of the molecule ATP that, like bits of coal, serve as the cell’s main source of energy to power the heart to beat, muscles to stretch, and virtually every movement that the body makes.

 

Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. Mitochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body except red blood cells. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is becoming more and more common. Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems. Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection

 

A team of scientists at National Institutes of Health’s National Institute of Dental and Craniofacial Research (NIDCR) has now imaged mitochondria for the first time oscillating in a live animal, in this case, the salivary glands of laboratory rats. The report, published online in the journal Cell Reports (20 October 2014), shows the oscillations occur spontaneously and often in the rodent cells, which has led the authors to believe the oscillations almost surely also occur in human cells. According to the authors, the movements could last from tens of seconds to minutes, which was far longer and frequently at a faster tempo than observed previously in cell culture. The mitochondria also appear to synchronize their movements not only in an individual cell but, quite unexpectedly, into a linked network of oscillators vibrating throughout the tissue.

 

To keep cells fully charged, mitochondria operate four biochemical production lines that coalesce with oxygen molecules from normal respiration to produce ATP. One of these production lines starts with processing the molecule nicotinamide adenine dinucleotide, or NADH. The authors recognized that they could use their high-magnification microscope to visualize NADH as it naturally emits electrons as part of the ATP production process. The key was their choice of microscopy. Known as intravital microscopy, an extremely high-resolution technique that dates back to the 19th century. However, until recently, it had been too powerful to use in live animals.

 

According to the authors, animals breathe, their hearts beat, and their appendages twitch and this combined effect under very high magnification is like watching a 6.0 earthquake. Everything shakes and blurs out of focus. To address this, the authors developed new approaches to better stabilize the organ being studied and to minimize the motion artifacts. The powerful optics used allowed the authors to visualize the oscillations in their native milieu and to puzzle over their cause. Based on a series of subsequent experiments and observations, it was discovered that the oscillations are linked to the production of reactive oxygen species, a chemically interactive byproduct of making ATP. This finding suggests that the oscillations likely are not inherent to mitochondria but a response to conditions in their environment.

 

These findings emphasize how important it is scientifically to study biology on its own terms, not under artificial laboratory conditions. As a result, the authors were able to see things in live animals that one does not see in cell culture. The reasons, in this case, very well may be that the mitochondria continue to receive an influx of natural signals from the blood vessels, the nervous system, and their surrounding environment which are not available in cell cultures.

 

The authors noted that these findings should be of broad interest scientifically in framing studies of mitochondria, and may have future clinical implications. An estimated 2 million Americans have mitochondrial disease, an energy-depleting failure of mitochondria to function properly, which can have disabling effects on the brain, heart, kidneys, and other body systems. Many scientists also suspect that as mitochondria become better understood, they likely will be understood to play a more prominent role in human health and disease.

 

Candidate H7N9 Avian Flu Vaccine Works Better With Adjuvant

 

The first recognized human H7N9 avian influenza (Bird Flu) cases occurred in China in early 2013. Most people who have become infected with the virus had contact with infected poultry. The virus does not sicken birds, but can cause people to become seriously ill, with approximately 67% of reported cases requiring hospitalization. As of September 4, 2014, a total of 452 laboratory confirmed cases, including 166 deaths, had been reported to the World Health Organization.

 

According to an article published in the Journal of the American Medical Association (8 October 2014), an experimental vaccine to protect people against H7N9 avian influenza has resulted in immune responses in 59% of volunteers who received two injections at the lowest dosage tested, but only if the vaccine was mixed with adjuvant, a substance that boosts the body’s response to vaccination. Without adjuvant, immune responses produced by the investigational vaccine were minimal regardless of vaccine dosage. The Phase 2 trial enrolled 700 healthy adults aged 19 to 64 years old at four NIAID-sponsored Vaccine and Treatment Evaluation Units (VTEU) in the United States.

 

The experimental vaccine, made from inactivated H7N9 virus grown in chicken eggs, was manufactured by Sanofi Pasteur (Swiftwater, PA). The adjuvant, MF59, used widely in Europe but not licensed in the United States, was manufactured by Novartis Vaccines (Marburg, Germany) and was mixed with the vaccine just prior to use. Both products were supplied by the Biomedical Advanced Research and Development Authority (BARDA, a part of the Department of Health and Human Services) from the National Pre-Pandemic Influenza Vaccine Stockpile. The 700 study volunteers were divided into groups of approximately 100 each. All received two injections, spaced 21 days apart, and had blood drawn on both inoculation days as well as on three additional time points. Two groups received vaccine at either 15 micrograms (mcg) or 45 mcg without adjuvant. Without adjuvant, even those participants who received the higher dosage vaccine had minimal immune responses. This was not unexpected, as an earlier clinical trial of an experimental unadjuvanted vaccine based on H7 avian influenza virus elicited little or no detectable antibody responses. The remaining five groups of participants received two injections of vaccine at one of three different dosages (3.75 mcg, 7.5 mcg or 15 mcg). Three of the groups received MF59 adjuvant with both inoculations, while the final two groups received only one dose of adjuvant with their first or second injection of vaccine. No serious vaccine-related adverse events were reported in any of the groups. Participants who received adjuvant reported more mild pain and tenderness at the inoculation site than those who received only vaccine. In general, the inoculations were well-tolerated and side effects were mild.

 

The authors used a standard test called the hemagglutination inhibition (HAI) antibody assay to assess the likelihood that the experimental vaccine would provide protection against influenza disease. HAI levels of 40 or more signal that an influenza vaccine induced an immune reaction that is likely to prevent influenza disease. In this trial, the key HAI assays were performed on blood samples taken at 42 days after the first inoculation. Among the volunteers who received two injections of the lowest dose of vaccine along with two doses of adjuvant, 59% had HAI levels of 40 or more. The most surprising finding came from the volunteer group that received 15 mcg dose vaccines and just one dose of MF59 at the time of the first vaccine. Among that group, the antibody responses were not significantly lower than those who received two doses of adjuvant, suggesting that a single dose of adjuvant given with the first dose of vaccine may be sufficient to prompt a significant immune response. If true, this would be of particular importance in the event of a pandemic, when adjuvant-sparing and vaccine antigen-sparing vaccine regimens could be used to stretch available supplies of vaccine and adjuvant as far as possible.

 

Orphan Diseases

 

The following was excerpted from FDA Voice.

 

There are about 7,000 rare diseases and when added together, there are about 30 million – or almost one in ten – people in the U.S. with some form of rare disease. Sadly, although great progress has been made in some areas, many of these people have no FDA approved drug to cure their condition, help them feel better, or even slow the disease’s progress. This is why FDA is supporting an exciting new tool researchers are using to study rare diseases. It’s a new database with information about the diseases’ “natural history.“

 

“Natural history“ is the scientific term to describe how a disease would progress with no treatment. Since a disease can affect different people differently, many cases of a disease must be studied to acquire a thorough understanding of its natural history. Well-conducted studies of natural history can yield vital information about:

 

  1. Biomarkers, demographic, genetic, and environmental variables that correlate with the course and stages of the disease;
  2. Identification of patient subpopulations with different characteristics and effects of the disease;
  3. Patient perspectives on what aspects of disease are most important to treat; and,

How to quantify those aspects so that they can serve as useful outcome measures for clinical trials.

 

But when it comes to rare diseases, their natural histories frequently are not fully understood because there are simply not enough cases that have been observed and studied. This lack of knowledge limits researchers’ ability to study rare diseases and develop new treatments. Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.

 

Recently The National Organization for Rare Diseases (NORD), has teamed up with the patient advocacy group that represents people with the rare disease known as Von Hippel Lindau disease. This is a condition with many debilitating symptoms that also predisposes individuals to benign and malignant tumors. The Von Hippel Lindau Alliance and NORD have created an online tool that enables people with this rare disease to enter information about their experiences with the disease, such as the progression of symptoms, and to add to this information at intervals throughout their lives. This tool is now helping researchers compile valuable data about the natural history of Von Hippel Lindau disease. The even better news is that this tool is universal. If it can be used effectively to help researchers better understand Von Hippel Lindau disease, it can do the same for other rare diseases as well! Importantly, this online tool was developed with direct input from patients, as well as patient organizations, researchers, FDA, and other international drug regulatory agencies.

 

The natural history tool has important features such as these:

 

  1. It protects the security and privacy of personal information, while making valuable information available to a researcher or drug developer interested in creating a new therapy for a rare disease;
  2. It can be used by patients or health care professionals;
  3. It helps make sure that text and online tools data are accurate.

 

FDA is committed to working with patient advocates and other organizations to support natural history studies for rare diseases and is encouraging the use of natural history data collection tools to describe natural history for many rare diseases.

 

Cauliflower-Feta Fritters with Cumin/Yogurt & Pomegranate

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This delicious dish is versatile enough for dinner, lunch, and would be a welcome surprise served for brunch ©Joyce Hays, Target Health Inc.

 

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Topped with the Cumin/Yogurt and Arils – ©Joyce Hays, Target Health Inc.

 

Ingredients

1 or 2 heads cauliflower (stems, leaves removed), cut into chunks

2 or 3 eggs

2 garlic clove, minced

Few gratings of fresh lemon zest

8 ounces crumbled feta

1/2 cup almond flour

2/3 cup cilantro, chopped

1 teaspoon turmeric

3/4 teaspoon Kosher salt (optional) or to your taste

1/2 teaspoon baking powder

Olive oil for frying

 

Ingredients For Topping

1 cup Fage yogurt

1 teaspoon ground cumin

Pinch Salt and pepper to taste

Pomegranate arils for garnish

 

 

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Such a beautiful vegetable! ©Joyce Hays, Target Health Inc.

 

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Clean it, core it, steam it! – ©Joyce Hays, Target Health Inc.

 

Directions

Steam the cauliflower until firm but tender. Use a slotted spoon, and transfer to a bowl of ice water to stop cooking. Drain well. Spread on towels to dry as much as possible.

 

 

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If you can, use fresh healthy locally grown ingredients – ©Joyce Hays, Target Health Inc.

 

In the bottom of a large bowl, whisk together egg, garlic and lemon zest. Add the cauliflower and mash with a potato masher until crushed into pea-sized pieces. Add the feta and stir to combine with the egg mixture, cauliflower and feta. In a small dish, whisk flour, salt, pepper and baking powder until evenly combined. Sprinkle over cauliflower batter and stir just until combined.

 

 

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Heat oven to 200 degrees and place a tray inside (or use a warming drawer). On the stove, heat a large, heavy skillet over moderate heat. Once hot, add a good slick of oil, about 2 to 3 Tablespoons. Once the oil is hot and a drop of water sputters, scoop a two Tablespoon-size mound of the batter and drop it into the pan, then flatten it slightly with your spoon or spatula. Repeat with additional batter, leaving a couple inches between each. Once brown underneath, about 2 to 3 minutes, flip each fritter and cook on the other side until equally golden, about another 1 to 2 minutes.

 

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Two pans full. Second pan: flipped over, browning the other side ©Joyce Hays, Target Health Inc.

 

Transfer briefly to paper towels to drain, then to the tray in the oven to keep them warm until needed. Once all fritters are cooked, mix yogurt with cumin, salt and pepper. Spread fritters on serving platter. Dollop each with the cumin yogurt and sprinkle with pomegranate arils.

 

If you want to make these cauliflower fritters ahead of time, not only do they freeze but they also reheat well. When you want to warm them, lay them on a cookie sheet and bake them at 400 degrees in the oven until toasted and crispy.

 

 

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Unlike some people, I am really not a witch; however, I am married to a spook. Yup, born on October 31st, otherwise known as Halloween.

 

It’s always fun to celebrate his birthday, and this past Friday, was no exception. The amazing cauliflower fritters were for him, with creamed spinach and the tiniest oiled and baked red skinned potatoes I have ever seen (the size of a robin’s egg) – literally a one-bite potato and delicious. Among many other birthday gifts, I gave him a case of a new “Cab” discovery from Australia. In a wine email (Wine Spectator, I think) giving this bold red 93 points, it was the name that first caught my eye. The Australian vineyard isTwo Hands; the name of this wine is just /below. I wasn’t going to buy it for the name, cute as it was, but read up and found it rated highly for much more and bought a case. The first toast was this past Friday at Jules’ birthday party. As you can see from the photo, the wine is a deep purple. The first deep inhale is auspicious, but doesn’t quite prepare you for a sock to the palate, which you recover from to enjoy a flavor which lingers, tasting robust right to the end. It has earned its name; it doesn’t disappoint. We recommend it if you like strong robust “Cabs“. If you have a significant other, try making the delicious cauliflower fritters with topping and serve this Australian Cab, as well. You won’t be disappointed. This was a weekend filled with fun and laughs and gifts galore. We hope yours was also.

 

 

 

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From Our Table to Yours!

 

Bon Appetit!