Cognitive Training Shows Staying Power

 

According to an article published in the Journal of the American Geriatrics Society (2014; 62:6-24), training to improve cognitive abilities in older people lasted to some degree 10 years after the training program was completed. The report, from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, showed training gains for aspects of cognition involved in the ability to think and learn. However, the authors said that memory training did not have an effect after 10 years.

 

The original 2,832 volunteers for the ACTIVE study were divided into three training groups — memory, reasoning and speed-of-processing — and a control group. The training groups participated in 10, 60- to 70-minute sessions over five to six weeks, with some randomly selected for later booster sessions. The study measured effects for each specific cognitive ability trained immediately following the sessions and at one, two, three, five and 10 years after the training.

 

The investigators were also interested in whether the training had an effect on the participants’ abilities to undertake some everyday and complex tasks of daily living. They assessed these using standardized measures of time and efficiency in performing daily activities, as well as asking the participants to report on their ability to carry out everyday tasks ranging from preparing meals, housework, finances, health care, using the telephone, shopping, travel and needing assistance in dressing, personal hygiene and bathing.

 

At the end of the trial, all groups showed declines from their baseline tests in memory, reasoning and speed of processing. However, the participants who had training in reasoning and speed of processing experienced less decline than those in the memory and control groups. Results of the cognitive tests after 10 years show that 73.6% of reasoning-trained participants were still performing reasoning tasks above their pre-trial baseline level compared to 61.7% of control participants, who received no training and were only benefiting from practice on the test. This same pattern was seen in speed training: 70.7% of speed-trained participants were performing at or above their baseline level compared to 48.8% of controls. There was no difference in memory performance between the memory group and the control group after 10 years. Participants in all training groups said they had less difficulty performing the everyday tasks compared with those in the control group. However, standard tests of function conducted by the researchers showed no difference in functional abilities among the groups.

 

The ACTIVE study followed healthy, community-dwelling older adults from six cities-Baltimore; Birmingham, Ala.; Boston; Detroit; State College, Pa.; and Indianapolis. The participants averaged 74 years of age at the beginning of the study and 14 years of education, 76% were female, 74% were white and 26% were African-American. The 10-year follow-up was conducted with 44% of the original sample between April 1998 and October 2010.

Enzyme that Produces Melatonin Originated 500 Million Years Ago

 

Melatonin is a key hormone that regulates the body’s day and night cycle. it is manufactured in the brain’s pineal gland and is found in small amounts in the retina of the eye. Melatonin is produced from the hormone serotonin, the end result of a multistep sequence of chemical reactions. The next-to-last step in the assembly process consists of attaching a small molecule — the acetyl group — to the nearly finished melatonin molecule. This step is performed by an enzyme called arylalkylamine N-acetyltransferase, or AANAT. Because of its key role in producing the body clock-regulating melatonin, AANAT is often referred to as the timezyme.

 

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According to an article published online in PNAS (December 2013), an international team of scientists led by senior author David C. Klein, Ph.D., Chief of the Section on Neuroendocrinology in the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and at institutions in France, Norway, and Japan, has traced the likely origin of the enzyme needed to manufacture the hormone melatonin to roughly 500 million years ago. The work indicates that this crucial enzyme, which plays an essential role in regulating the body’s internal clock, likely began its role in timekeeping when vertebrates (animals with spinal columns) diverged from their nonvertebrate ancestors. According to the authors, an understanding of the enzyme’s function before and after the divergence may contribute to an understanding of such melatonin-related conditions as seasonal affective disorder, jet lag, and to the understanding of disorders involving vision. The findings also provide strong support for the theory that the time-keeping enzyme originated to remove toxic compounds from the eye and then gradually morphed into the master switch for controlling the body’s 24-hour cyclic changes in function. The authors also isolated a second, nonvertebrate form of the enzyme from sharks and other contemporary animals thought to resemble the prototypical early vertebrates that lived 500 million years ago.

 

According to the authors, the form of AANAT found in vertebrates occurs in the brain’s pineal gland and, in small amounts, in the retina. Another form of the enzyme, termed nonvertebrate AANAT, has been found only in other forms of life, such as bacteria, plants and insects. Interestingly, nonvertebrate AANAT appears to detoxify a broad range of potentially toxic chemicals,. In contrast, vertebrate AANAT is highly specialized for adding an acetyl group to melatonin. According to Dr. Klein, “the two are as different from each another as a Ferrari is from a Model-T Ford, considering the speed of the reaction and how fast it can be turned on and off.“

 

In 2004, Dr. Klein and his coworkers published a theory that melatonin was at first a kind of cellular waste, a by-product created in cells of the eye when normally toxic substances were rendered harmless. Because melatonin accumulated at night, the ancestors of today’s vertebrates became dependent on melatonin as a signal of darkness. As the need for greater quantities of melatonin grew, the pineal gland developed as a structure separate from the eyes, to keep serotonin and other toxic substances needed to make melatonin away from sensitive eye tissue.

 

“The pineal glands of birds and reptiles can detect light,“ Dr. Klein said. “And the retinas of human beings and other species also make melatonin. So it would appear that both tissues evolved from a common, ancestral, light-detecting tissue.“ Before the current study, the researchers lacked proof of their theory, particularly in regard to the question of how the vertebrate form of the enzyme originated because it did not appear to exist in non-vertebrates and had been found only in bony fishes, reptiles, birds, and mammals – all of which lacked the non-vertebrate form. The first evidence of how the vertebrate form of the enzyme originated came when study co-author Steven L. Coon, also of NICHD, discovered genes for the nonvertebrate and vertebrate forms of AANAT in genomic sequences from the elephant shark, considered to be a living representative of early vertebrates. This finding indicated that the vertebrate form of AANAT may have resulted after a phenomenon known as gene duplication. Gene duplication typically results from any of a number of genetic mishaps during cell division. Instead of one copy of a gene resulting from the process, an additional copy results, so that there are two versions of a gene where only one existed previously. The phenomenon is thought to be a major factor influencing evolutionary change.

 

The authors theorized that following duplication, one form of AANAT remained unchanged and the other gradually evolved into the vertebrate form. The authors hypothesized that at some point after vertebrate AANAT developed, vertebrates appear to have stopped making the nonvertebrate form, perhaps because it was no longer needed or because its function was replaced by a similar enzyme.

 

Before the authors could continue, they needed to confirm their finding, to rule out that the nonvertebrate AANAT they found didn’t result from accidental contamination with bacteria or some other organism. As a result, DNA from Mediterranean sharks and sea lampreys was obtained via fishermen’s catches by Jack Falcon of the Arago Laboratory, a marine biology facility that is part of the CNRS and the Pierre and Marie Curie University in France. Samples from a close relative of the elephant shark — the ratfish — were provided by Even-Jorgensen at the Arctic University of Norway. Finally, Susumo Hyodo of the University of Tokyo contributed samples from elephant sharks he collected off the coast of Australia. Next, the Hyodo and Falcon groups isolated RNA from the retinas and pineal glands of the animals. RNA is used to direct the assembly of amino acids into proteins. From these RNA sequences, it was possible to assemble working versions of AANAT molecules — both the vertebrate and nonvertebrate forms.

 

The sequences of the proteins encoded by the AANAT genes were analyzed by Eugene Koonin and Yuri Wolf of the National Library of Medicine using computer techniques designed to study evolution. Peter Steinbach, of NIH’s Center for Information Technology, examined the three-dimensional structures of nonvertebrate and vertebrate AANAT in the study animals and determined that the two forms of the enzyme likely had a common ancestor.

 

Taken together, their results provide evidence for the hypothesis that nonvertebrate AANAT resulted from duplication of the non-vertebrate AANAT gene about 500 million years ago and that following this event one copy of the duplicated gene eventually changed into the gene for vertebrate AANAT. In addition to providing information on the origin of melatonin and the evolution of AANAT, the findings also have implications for research on disorders affecting vision. Vertebrate AANAT and melatonin are found in small amounts in the eyes of humans and other vertebrates. Although they may play a role in detoxifying compounds, it is also reasonable to consider that this detoxifying function is shared with other enzymes.

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

 

FDA Allows Marketing for First of-its-Kind Post-Natal Test to Help Diagnose Developmental Delays and Intellectual Disabilities in Children

 

According to the National Institutes of Health and the American Academy of Pediatrics, 2-3% of children in the US have some form of intellectual disability. Many intellectual and developmental disabilities, such as Down syndrome and DiGeorge syndrome, are associated with chromosomal variations.

 

The FDA has authorized for marketing the Affymetrix CytoScan Dx Assay, which can detect chromosomal variations that may be responsible for a child’s developmental delay or intellectual disability. Based on a blood sample, the test can analyze the entire genome at one time and detect large and small chromosomal changes.

 

The FDA reviewed the Affymetrix CytoScan Dx Assay through its de novo classification process, a regulatory pathway for some novel low-moderate-risk medical devices. For the de novo petition, the FDA’s review of the CytoScan Dx Assay included an analytical evaluation of the test’s ability to accurately detect numerous chromosomal variations of different types, sizes, and genome locations when compared to several analytically validated test methods. The FDA found that the CytoScan Dx Assay could analyze a patient’s entire genome and adequately detect chromosome variations in regions of the genome associated with intellectual and developmental disabilities.

 

Additionally, the agency’s review included a study that compared the performance of the CytoScan Dx Assay to tests that are commonly used for detecting chromosomal variations associated with a developmental delay or intellectual disability. A comparison of test results from 960 blood specimens showed the CytoScan Dx had improved ability over commonly used tests, including karyotyping and FISH chromosomal tests, to detect certain chromosomal abnormalities.

 

This device should not be used for stand-alone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for acquired or genetic aberrations occurring after birth, such as cancer. The test results should only be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, evaluation of parental samples, clinical genetic evaluation, and counseling as appropriate. Interpretation of test results is intended to be performed only by health care professionals who are board certified in clinical cytogenetics or molecular genetics.

 

Affymetrix CytoScan Dx Assay is manufactured by Affymetrix, Inc., located in Santa Clara, Calif.

Thai Sweet Potatoes with Halibut and Ginger-Lime Peanut Sauce

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Sweet Potatoes & Halibut before adding the Peanut Sauce, Photo: ©Joyce Hays, Target Health Inc.

 

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Sweet Potato on left, Halibut on right, with Peanut sauce drizzled over both. Photo: ©Joyce Hays, Target Health Inc.

 

Halibut

Buy very fresh halibut. Figure 1 lb fillet (okay to buy in small pieces) for every two people. Prepare the halibut in your own way, just before serving. Place an individual portion of fish, centered on a plate, now put a filled half sweet potato, over part of the fish and spoon the sauce over fish and potato. Garnish with a small amount of shredded coconut & pinch of cilantro. We did the halibut in the photo, by dipping the cleaned halibut first, both sides of the fish, into a beaten egg mixture, then into Panko crumbs; then into 1 Tablespoon hot olive oil mixed with 1 Tablespoon chicken stock (or canola) in fry pan, getting the Panko a golden brown on each side, removing to serving dish, placed into a warming drawer.

 

Ingredients

 

Potatoes

  • 3 medium-sized sweet potatoes
  • 3 Tablespoons olive oil + extra to rub on potatoes
  • 1 heaping Tablespoon shredded coconut
  • 1 onion, chopped
  • 1 cup fresh sliced cremini mushrooms
  • 3 cloves garlic, minced
  • 1 teaspoon turmeric
  • 1 bunch kale, cleaned, stems removed, any hard veins cut out
  • 1/2 cup chicken stock or broth
  • 2/3 cup fresh cilantro, chopped
  • 1 cup salt-free peanuts, chopped

 

Sauce

  • 3/4 cup hot chicken broth
  • 1 garlic clove, juiced
  • 3/4 cup chunky Peanut Butter
  • 1 teaspoon turmeric
  • 2 Tablespoons tahini
  • 2 Tablespoons freshly squeezed lime juice (1 to 2 limes)
  • 1 Tablespoon fresh grated ginger

 

Garnish

1/2 cup shredded coconut; pinch chopped peanuts, pinch chopped cilantro

 

Directions

1. Preheat oven to 4000F.

2. Scrub potatoes well.

3. With a paper towel, rub each potato with olive oil.

 

Bake sweet potatoes 30 to 40 minutes, until a knife easily goes through the potatoes. Remove potatoes from oven and set aside. When potatoes are cooler, cut them in half and set aside. Leave the oven on.

 

Roll up the Kale leaves, then slice them thinly, to get thin julienned kale strips

 

To make the filling:

In a saute pan over medium heat, add the olive oil, onions and kale strips cook 3 to 4 minutes, until golden brown. Stir in mushrooms and garlic, cook 2 minutes longer. Now, stir in the cilantro, turmeric, coconut and chopped peanuts and cook another 2 minutes, while stirring constantly. Finally, scoop out the flesh of each potato, carefully, so you don’t break the skins and set the skins aside in an oiled baking dish. Stir all ingredients together.

 

Now, fill each skin half with the potato mixture and place back into the oiled baking dish.  Keep warm in a warming drawer or low-heat oven, until ready to serve.

 

To make the Peanut sauce:

Whisk together peanut butter, tahini, lime juice, garlic and ginger. Add the hot chicken broth last, very slowly as you whisk, to create a thick sauce and not a runny thin sauce. Set aside. If sauce needs to be thicker, add 1 teaspoon agar and mix well.

 

Serve sweet potato and fish drizzled with extra peanut sauce and topped with chopped peanuts pinch cilantro, pinch shredded coconut

 

 

We clinked glasses to our Anniversary this past Friday, and celebrated with these recipes, preceded by one of many kale salad recipes. We both agree that the addition of the peanut sauce, really makes the sweet potato and halibut sing out. It has taken about a year to perfect the Peanut sauce, because the peanut flavor is so overpowering. The final version, shared with you, retains a faint nutty flavor, that when combined with tahini, turmeric, ginger, lime and garlic, is totally different from a year ago, when I first started to experiment with a peanut sauce for fish, chicken, or veggies. (And you know who, was the amiable, but stern critic guinea pig for a year)

 

Cheers to staying married!

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To Health, Love, Friendship, and Successful Achievement in 2014! Photo: ©Joyce Hays, Target Health Inc. 

Target e*CTR® – eClinical Trial Record and Direct Data Entry

 

Target Health is pleased to announce that it will be initiating at least 3 direct data entry (DDE) clinical trials this quarter. This comes on top 12 studies initiated over the past 3 years under 7 INDs and 1 IDE. We expect 2 regulatory submissions in 2014 where DDE was used exclusively.

 

Together with risk-based monitoring, we are reducing on-site monitoring by at least 50% with an estimated savings of at least $10,000/site/year. Other savings include virtual elimination of protocol violations, increased capacity for the study sites to see more subjects since there is virtually no additional work once the subject leaves the clinic, fewer queries and the ability to implement changes early in the trial before there is too much “damage.” Let us know if you want to see a demo.

 

A paper will be published online in Applied Clinical Trials, within a few weeks, which summarizes our experience from an 18 center study. It is a very convincing story.

 

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

 

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

Joyce Hays, Founder and Chief Editor of On Target

Jules Mitchel, Editor

Vanessa Hays, Editorial Contributor

Bacteriophages

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Since ancient times, reports of river waters having the ability to cure infectious diseases have been documented, such as leprosy. In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Yamuna rivers in India had marked antibacterial action against cholera and could pass through a very fine porcelain filter. In 1915, British bacteriologist Frederick Twort, superintendent of the Brown Institution of London, discovered a small agent that infected and killed 1) ___. He believed the agent must be one of the following:

 

1. a stage in the life cycle of the bacteria;

2. an enzyme produced by the bacteria themselves; or

3. a virus that grew on and destroyed the bacteria.

 

Twort’s work was interrupted by the onset of World War I and shortage of funding. Independently, French-Canadian microbiologist Felix d’Herelle, working at the Pasteur Institute in Paris, announced on 3 September 1917, that he had discovered “an invisible, antagonistic microbe of the dysentery bacillus”. For d’Herelle, there was no question as to the nature of his discovery: “In a flash I had understood: what caused my clear spots was in fact an invisible microbe – a virus parasitic on bacteria.”  D’Herelle called the virus a bacteriophage or bacteria-eater (from the Greek phagein meaning to eat). He also recorded a dramatic account of a man suffering from dysentery who was restored to good health by the 2) ___.

 

In 1923, the Eliava Institute was opened to research this new science and put it into practice and in 1969, Max Delbrück, Alfred Hershey and Salvador Luria were awarded the Nobel Prize in Physiology and Medicine for their discoveries of the replication of viruses and their genetic structure.

 

Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses are capable of carrying out both. With lytic phages such as the T4 phage, bacterial 3) ___ are broken open (lysed) and destroyed after immediate replication of the virion. As soon as the cell is destroyed, the phage progeny can find new hosts to infect. Lytic phages are more suitable for phage therapy. Some lytic phages undergo a phenomenon known as lysis inhibition, where completed phage progeny will not immediately lyse out of the cell if extracellular phage concentrations are high. This mechanism is not identical to that of temperate phage going dormant and is usually temporary. In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA and replicate along with it fairly harmlessly, or may even become established as a plasmid. The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients; then, the endogenous phages (known as prophages) become active. At this point they initiate the reproductive cycle, resulting in lysis of the 4) ___ cell. As the lysogenic cycle allows the host cell to continue to survive and reproduce, the virus is reproduced in all of the cell’s offspring. An example of a bacteriophage known to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli. Sometimes prophages may provide benefits to the host bacterium while they are dormant by adding new functions to the bacterial genome in a phenomenon called lysogenic conversion. An eminent example is the conversion of a harmless strain of Vibrio cholerae by a phage into a highly virulent one, which causes cholera.

 

Attachment and Penetration

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In this electron micrograph of bacteriophages attached to a bacterial cell, the viruses are the size and shape of coliphage T1. To enter a host cell, bacteriophages attach to specific 5) ___ on the surface of bacteria, including lipopolysaccharides, teichoic acids, proteins, or even flagella. This specificity means a bacteriophage can infect only certain bacteria bearing receptors to which they can bind, which in turn determines the phage’s host range. Host growth conditions also influence the ability of the phage to attach and invade them. As phage virions do not move independently, they must rely on random encounters with the right receptors when in solution (blood, lymphatic circulation, irrigation, soil water, etc.).

 

A bacteriophage is a virus that infects bacteria. Bacteriophages, first discovered around 1915, have played a unique role in viral biology. They are perhaps the best understood 6) ___, yet at the same time, their structure can be extraordinarily complex. The use of bacteriophages played a prominent role in elucidating that DNA in viruses can reproduce through two mechanisms: the lytic cycle and the lysogenic cycle.

 

Viruses that kill their infected host cell are called 7) ___. The DNA in these types of viruses reproduce through the lytic cycle. When these viruses reproduce, they break open, or lyse, their host cells, resulting in the destruction of the host. The whole cycle can be complete in 20 – 30 minutes depending on a variety of factors such as temperature. Phage reproduction is much faster than typical bacterial reproduction, so entire colonies can be destroyed very quickly.

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Temperate Viruses and the Lysogenic Cycle

 

Temperate viruses are those that reproduce without killing their host cell. Typically they reproduce in two ways: through the lytic cycle and the lysogenic cycle. In the lysogenic 8) ___, the phage’s DNA recombines with the bacterial chromosome. Once it has inserted itself, it is known as a prophage. A host cell that carries a prophage has the potential to lyse, thus it is called a lysogenic cell. The image above illustrates both the lytic and lysogenic cycles of a bacteriophage.

 

ANSWERS: 1) bacteria; 2) bacteriophages; 3) cells; 4) host; 5) receptors; 6) viruses; 7) virulent; 8) cycle

Felix d’Herelle (April 25, 1873 – February 22, 1949)

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Felix d’Herelle

 

Editor’s note: The short bio information, compiled below, reads like a movie promo about a scientific genius (nominated many times for a Nobel Prize) jumping from one biological adventure to another, across many continents. One extraordinary aspect of all this, is that Felix d’Herelle, who finished high school but never attended college, was completely self-taught. His brilliance was acknowledged with an honorary doctorate, plus other awards for outstanding discoveries in areas of microbiology. He became a professor at Yale University. We’re giving this week’s History of Medicine biography more space than usual because the story is so colorful and unusual and because Felix d’Herelle has caught our attention and respect.

 

Felix d’Herelle (April 25, 1873 – February 22, 1949) was a French-Canadian microbiologist, the co-discoverer of bacteriophages (viruses that infect bacteria) and experimented with the possibility of phage therapy. D’Herelle has also been credited for his contributions to the larger concept of applied microbiology.

 

D’Herelle was born in Montreal, Quebec, the son of French emigrants. His father died when Felix was 6 years old. Following his father’s death, Felix, his mother and his younger brother Daniel, moved back to Paris. From 7 to 17 years of age, d’Herelle attended school in Paris, including the Lycee Condorcet and Lycee Louis-le-Grand high schools. In the fall of 1891, d’Herelle traveled to Bonn where he attended lectures at the University of Bonn for several months. Thus, d’Herelle only obtained a high school education and was self-taught in the sciences.

 

At age 24, now father of a daughter, d’Herelle and his family moved back to Canada. He built a home laboratory and studied microbiology from books and his own experiments. Through the influence of a friend of his late father, he earned a commission from the Canadian government to study the fermentation and distillation of maple syrup to schnapps. His father’s friend shrewdly pointed out that Pasteur “made a good beginning by studying fermentations, so it might be interesting to you, too.”  He also worked as a medic for a geological expedition, even though he had no medical degree or real experience. Together with his brother, he invested almost all his money in a chocolate factory, which soon went bankrupt. During this period, d’Herelle published his first scientific paper, “De la formation du carbone par les vegetaux”in the May 1901 issue of Le Naturaliste Canadien. The paper is noteworthy for two reasons: it shows an exceptional level of scientific development for a self-taught scientist and reveals a broad level of interest, namely the global balance of carbon in nature. However, the claims of the paper were in error, as d’Herelle contended that the results of his experiments indicated that carbon was a compound, not an element. With his money almost gone and his second daughter born, he took a contract with the government of Guatemala as a bacteriologist at the General Hospital in Guatemala City. Some of his work included organizing defenses against the dread diseases of the time: malaria and yellow fever. He also studied a local fungal infection of coffee plants, and discovered that acidifying the soil could serve as an effective treatment As a side job, he was asked to find a way to make whiskey from bananas. Life in the rough and dangerous environment of the country was hard on his family, but d’Herelle, always adventurer at heart, rather enjoyed working close to “real life”, compared to the sterile environments of a “civilized” clinic. He later stated that his scientific path began on this occasion.

 

In 1907, he took an offer from the Mexican government to continue his studies on fermentation. He and his family moved to a sisal plantation near Merida, Yucatan. Disease struck at him and his family, but in 1909, he had successfully established a method to produce sisal schnapps. Machines for mass production of sisal schnapps were ordered in Paris, where he oversaw the machines’ construction. Meanwhile, in his spare time, he worked for free in a laboratory at the Pasteur Institute. He was soon offered the job of running the new Mexican plant, but declined, considering it “too boring”. He did, however, take the time to attempt stopping a locust plague at the plantation using their own diseases. He extracted bacteria pathogenic to locusts from their guts. This innovative approach to locust plagues anticipated modern biological pest control using Bacillus thuringiensis also known as Bt. D’Herelle and his family finally moved to Paris in early 1911, where he worked again as an unpaid assistant in a lab at the Pasteur Institute. He got attention in the scientific community the same year, when the results of his successful attempt to counter the Mexican locust plague with Coccobacillus were published. At the end of the year, restless d’Herelle was again on the road, this time in Argentina, where he was offered a chance to test these results on a much larger scale. Thus, in 1912 and 1913, he fought the Argentinian locust plagues with coccobacillus experiments. Even though Argentina claimed his success was inconsistent, he himself declared it a full success, and was subsequently invited to other countries to demonstrate the method.

 

During World War I, d’Herelle and assistants (his wife and daughters among them) produced over 12 million doses of medication for the allied military. At this point in history, medical treatments were primitive, compared to today’s standards. The smallpox vaccine, developed by Edward Jenner, was one of the few vaccines available. The primary antibiotic was the arsenic-based salvarsan against syphilis, with severe side effects. Common treatments were based mercury, strychnine, and cocaine. As a result, in 1900, the average life span was 45 years, and WWI did not change that to the better. In 1915, British bacteriologist Frederick W. Twort discovered a small agent that infects and kills bacteria, but did not pursue the issue further. Independently, the discovery of “an invisible, antagonistic microbe of the dysentery bacillus” by d’Herelle was announced on September 3, 1917. The isolation of phages by d’Herelle works like this:

 

1. Nutritional medium is infected with bacteria; the medium turns opaque.

2. The bacteria are infected with phages and die, producing new phages; the medium clears up.

3. The medium is filtered through porcelain filter, holding back bacteria and larger objects; only the smaller phages pass through.

 

In early 1919, d’Herelle isolated phages from chicken feces, successfully treating a plague of chicken typhus with them. After this successful experiment on chicken, he felt ready for the first trial on humans. The first patient was healed of dysentery using phage therapy in August 1919. Many more followed. At the time, none, not even d’Herelle, knew exactly what a phage was. D’Herelle claimed that it was a biological organism that reproduces, somehow feeding off bacteria. Others, the Nobelist Jules Bordet chief among them, theorized that phages were inanimate chemicals, enzymes specifically, that were already present in bacteria, and only trigger the release of similar proteins, killing the bacteria in the process. Due to this uncertainty, and d’Herelle using phages without much hesitation on humans, his work was under constant attack from many other scientists. It was not until the first phage was observed under an electron microscope by Helmut Ruska in 1939 that its true nature was established.

 

In 1920, d’Herelle travelled to Indochina, pursuing studies of cholera and the plague, from where he returned at the end of the year. D’Herelle, officially still an unpaid assistant, found himself without a lab; d’Herelle later claimed this was a result of a quarrel with the assistant director of the Pasteur Institute, Albert Calmette. The biologist Edouard Pozerski had mercy on d’Herelle and lent him a stool (literally) in his laboratory. In 1921, he managed to publish a monograph, The Bacteriophage: Its Role in Immunity about his works as an official Institute publication, by tricking Calmette. During the following year, doctors and scientists across western Europe took a heightened interest in phage therapy, successfully testing it against a variety of diseases. Since bacteria become resistant against a single phage, d’Herelle suggested using “phage cocktails” containing different phage strains. Phage therapy soon became a boom, and a great hope in medicine. In 1924, January 25, d’Herelle received the honorary doctorate of the University of Leiden, as well as the Leeuwenhoek medal, which is only awarded once every ten years. The latter was especially important to him, as his idol Louis Pasteur received the same medal in 1895). The next year, he was nominated eight times for the Nobel prize, though he was never awarded one.

 

After holding a temporary position at the University of Leiden, d’Herelle got a position with the Conseil Sanitaire, Maritime et Quarantenaire d’Egypte in Alexandria. The Conseil was put in place to prevent plague and cholera spreading to Europe, with special emphasis on the sanitary concerns about Muslim pilgrim groups returning from Mecca and Medina. D’Herelle used phages he collected from plague-infected rats during his 1920 visit to Indochina on human plague patients, with claimed success. The British Empire initiated a vast campaign against plague based on his results. 1927, d’Herelle himself changed his focus to new targets: India and cholera. D’Herelle isolated phages from cholera victims in India. As usual, he did not choose a hospital run by European standards, but rather sought out a medical tent in a slum. According to his theory, one had to leave the sterile hospitals and study and defeat illness in its “natural” environment. His team then dropped phage solution in the wells of villages with cholera patients; the death toll went down from 60% to 8%. The whole India enterprise took less than seven months. D’Herelle refused a request the following year by the British government to work in India, as he had been offered a professorship at Yale University, which he accepted. Meanwhile, European and US pharmaceutical companies had taken up the production of their own phage medicine, and were promising impossible effects. To counteract this, d’Herelle agreed to co-found a French phage-producing company, piping the money back into phage research. All of the companies suffered from production problems, as results from commercial phage medicine were erratic. This was most likely due to the attempt to mass-produce something that was barely understood, leading to damaged phages in the product, or to insufficient amounts thereof. Another possibility is that wrong diagnoses lead to the use of the wrong type of phages, which are specific in the choice of their hosts. Furthermore, many studies on the healing effects of phages were badly conducted. All this led to important parts of the scientific community turning against d’Herelle, who, known for his temper, had made not a few enemies.

 

In or around 1934, d’Herelle went to Tbilisi. D’Herelle was welcomed to the Soviet Union as a hero, bringing the knowledge of salvation from diseases ravaging the eastern states all the way to Russia. He accepted Stalin’s invitation for two reasons: it was said he was enamored of communism, and he was happy to be working with his friend, Prof. George Eliava, founder of the Tbilisi Institute, in 1923. Eliava had become friendly with d’Herelle during a visit to the Pasteur Institute in Paris, where he had learned about phages in 1926. D’Herelle worked at the Tbilisi Institute off and on for about a year – and even dedicated one of his books, “The Bacteriophage and the Phenomenon of Recovery,” written and published in Tbilisi in 1935, to Comrade Stalin. He had planned to take up permanent residence in Tbililsi and had already started to build a cottage on the grounds of the Institute (it would later house KGB headquarters). But just then, his friend Eliava fell in love with the woman with whom the head of the secret police, Lavrenty Beria also happened to be in love, and Eliava’s fate was sealed. He was executed and denounced as an enemy of the people during one of Stalin’s purges. D’Herelle ran for his life and never returned to Tbilisi. His book was banned from distribution. Then, World War II began.

 

Phage therapy boomed, despite all problems, driven by the military on both sides in an effort to keep the troops safe, at least from infections. D’Herelle could not really enjoy this development; he was kept under house arrest by the German “Wehrmacht” in Vichy, France. He used the time to write his book “The Value of Experiment”, as well as his memoirs, the latter being 800 pages in length. After D-Day, the new antibiotic drug penicillin became public knowledge and found its way into the hospitals in the west. As it was more reliable and easier to use than phage therapy, it soon became the method of choice, despite side effects and problems with resistant bacteria. Phage therapy remained a common treatment in the states of the USSR, though, until its deconstruction.

 

Felix d’Herelle was stricken with pancreatic cancer and died a forgotten man in Paris in 1949. He was buried in Saint-Mards-en-Othe in the department of the Aube in France. In the 1960s Felix d’Hérelle’s name appeared on a list published by the Nobel Foundation of scientists who had been worthy of receiving the Nobel Prize but did not, for one reason or another. It is believed that d’Herelle was nominated for the prize eight times. However, France has not completely forgotten Felix d’Herelle. There is an avenue that bears his name in the 16th arrondissement in Paris. D’Herelle became widely known for his imaginative approaches to important problems in theoretical, as well as applied, microbiology. At the same time, he was widely reviled for his self-advertisement, his exaggerated claims of success and his sharp financial practices. He also had a talent for making enemies among powerful senior scientists. D’Herelle’s main legacy lies in the use of phage in the molecular revolution in biology. Max Delbruck and the “phage group” used bacteriophages to make the discoveries that led to the origins of molecular biology. Much of the initial work on the nature of genetic expression and its regulation was performed with bacteriophages by Francois Jacob, Andre Lwoff and Jacques Monod. In fact, immediately before his studies of the structure of DNA, James Watson had earned his Ph.D. by working on a bacteriophage-related project in Salvador Luria‘s laboratory. As one of the earliest applied microbiologists, d’Herelle’s microbe-centered worldview has been noted for its prescience, since microbes are playing increasingly important roles in bioremediation, microbial fuel cells, gene therapy, and other areas with relevance to human well-being.

 

The novel Arrowsmith written by Sinclair Lewis with scientific help from Paul de Kruif was based to a certain extent on the life of d’Herelle. The novel The French Cottage (Russ. Frantsuzskii kottedzh) by David Shrayer-Petrov deals at length with d’Herelle’s experiences in the Soviet Union.

Stem Cells as a Treatment for TB

20140113-3

 

Mesenchymal stromal cells (MSCs) are immunomodulatory, and it has been hypothesized that adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Therefore, novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. As a result, a study published online in The Lancet Respiratory Medicine (9 January 2014), was performed to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis.

 

For the study, 30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×106 cells/kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. To be included in the study, patients had to present with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; or had to present with MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood hematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol.

 

The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory – i.e., increased plasma potassium ion concentrations in one patient and a transitory grade 3 gamma-glutamyltransferase elevation in another patient.

 

According to the authors, MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. The authors added that adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.

Family Structure and High Blood Pressure in African-American Men

 

Hypertension underlies an array of life-threatening conditions, including heart disease, stroke, heart attack and kidney disease. Diet, sedentary lifestyle and obesity all contribute to risk of hypertension, but researchers also think genetics plays an important role. About one-third of U.S. adults suffer from hypertension. The burden is considerably greater in the African-American community, in which the condition affects 39% of men and 43% of women.

 

According to a study published in the journal Hypertension (12 December 2013), African-American men who grew up in two-parent homes were less likely to have high blood pressure as adults compared to those raised by a single parent. This is the first study of an African-American population to document an association between childhood family living arrangements and blood pressure.

 

The authors analyzed blood pressure rates and the incidence of hypertension, a persistent state of high blood pressure, in a group of 515 African-American men enrolled in the Howard University Family Study (HUFS). The NIH-funded study conducted in the 2000s produced a repository of health history information about a group of African-American families from the Washington, D.C., metropolitan area.

 

According to the study, African-American men who grew up in a household with both parents, had a significantly lower blood pressure as adults compared with African- American men who grew up in a household with a single parent, regardless of whether the parent was a mother or father. The authors saw the most positive health effects in men who lived with both parents for one to 12 years. This group of adults had a 46% lower chance of being diagnosed with hypertension compared to adults who for those years were raised by a single parent.

 

Among several possible explanations for their findings, the authors suggested that compared with children who reside with two parents, those who live with their mothers alone are about three times more likely to live in poverty. Other studies have linked blood pressure rates with socioeconomic aspects of childhood, including household income and parents’ education and occupation. The findings reported in the current study held up, however, when these factors were statistically accounted for.

 

The authors suggest that living with both parents early in life may represent a critical opportunity when children develop biologically protective mechanisms that last throughout life. In an attempt to shed light on the potential molecular mechanisms, the authors are conducting research to understand the role that incremental DNA fine tuning, or epigenetics, impacts the way various cells behave or are transformed throughout the lifespan of an individual. Clearly, more research is needed in different settings to confirm that family living arrangements negatively affect children’s health outcomes later in life. The authors hope their study will be replicated on a larger scale in populations of ethnically diverse men and women.

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

 

FDA Approves Farxiga to Treat Type 2 Diabetes

 

Congratulations to our friends at BMS and AZ.

 

Type 2 diabetes affects about 24 million people and accounts for more than 90% of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness, and nerve and kidney damage.

 

The FDA has approved Farxiga (dapaglifozin) tablets to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes. Farxiga is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels. The drug’s safety and effectiveness were evaluated in 16 clinical trials involving more than 9,400 patients with type 2 diabetes. The trials showed improvement in HbA1c (hemoglogin A1c or glycosylated hemoglobin, a measure of blood sugar control).

 

Farxiga has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. Farxiga should not be used to treat people with type 1 diabetes; those who have increased ketones in their blood or urine (diabetic ketoacidosis); or those with moderate or severe renal impairment, end stage renal disease, or patients on dialysis.

 

An increased number of bladder cancers were diagnosed among Farxiga users in clinical trials so Farxiga is not recommended for patients with active bladder cancer. Patients with a history of bladder cancer should talk to their physician before using Farxiga. Farxiga can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk.

 

The FDA is requiring six post-marketing studies for Farxiga:

 

1. cardiovascular outcomes trial (CVOT) to evaluate the cardiovascular risk of Farxiga in patients with high baseline risk of cardiovascular disease;

2. double-blind, randomized, controlled assessment of bladder cancer risk in patients enrolled in the CVOT;

3. animal study evaluating the role of Farxiga-induced urinary flow/rate and composition changes on bladder tumor promotion in rodents;

4. two clinical trials to assess the pharmacokinetics, efficacy, and safety in pediatric patients; and

5. enhanced pharmacovigilance program to monitor reports of liver abnormalities and pregnancy outcomes.

 

In clinical trials the most common side effects observed in patients treated with Farxiga were genital mycotic (fungal) infections and urinary tract infections.

 

Farxiga is marketed by Bristol-Meyers Squibb Company, Princeton, N.J. and AstraZeneca Pharmaceuticals L.P., Wilmington, Del.

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