Happy Holidays and See You Next Year!
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website,
Joyce Hays, Founder and Chief Editor of On Target
Jules Mitchel, Editor
Vanessa Hays, Editorial Contributor
We Reached the Milestone of Over 5,000 Readers of On Target
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.
Festive Holiday Scene in the Reception Area (24th Floor) at Target Health – 2013 ©Target Health
ON TARGET has been published continuously since 1995. We started distribution via a manual fax and now, with just one click, ON TARGET goes worldwide. New features over the years have included the Quiz and History of Medicine and most recently, Target Healthy Eating, all brought to you by Target Health’s CEO, Joyce Hays.
Our readers come from all from over the world, and as a result, we communicate with colleagues and friends worldwide, whose common goals are to provide quality healthcare. Our mailing list includes all continents except for Antarctica, and most countries.
If you would like to say hello and let us know what you like about ON TARGET, just respond to this email.
Last Friday, THI Annual Holiday Party at the Columbia University Club of NY
12/14/13 (left to right) Dr. Jules Mitchel, President; Yong Joong Kim, Sr. Director Software andApplications Development; Mark Horn MD, MPH Chief Medical Officer
©Joyce Hays, CEO
Saturday 14 December 2013, Seagram’s Building, Park Avenue at E 52nd St, Blizzard Beginning
©Joyce Hays, Target Health Inc.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Chief Editor of On Target
Jules Mitchel, Editor
Vanessa Hays, Editorial Contributor
Make the Diagnosis
1. Sore Feet in Barbados
Case Findings: A 28-year-old man returned from a fun vacation in Barbados where he spent time surfing, walking on the beach, and eating a lot of local food. While he was happy with his tan, he was a bit concerned with a rash that he noticed on his foot the week after he returned. The cream for athlete’s foot he had at home was not helping.
Which disease do you diagnose this patient with?
2) Swimmer’s itch
3) Portuguese man of war sting
4) Cutaneous larva migrans
For the correct answer, go to the end of this Quiz section
2. Iraq War Vet’s Rash
Case Findings: A 28-year-old soldier just returned from active duty in Iraq. He said the rash started several weeks ago. It is somewhat pruritic, but otherwise he feels well. He was given doxycycline, but it did not resolve.
Which disease do you diagnose this patient with?
1) Lyme disease
3) erythema annulare centrifugum
4) granuloma annulare
For the correct answer, go to the end of this Quiz section
The correct diagnosis to quiz question one is number 4.
Cutaneous larva migrans is also known as creeping eruption, creeping verminous dermatitis, sandworm eruption, plumber’s itch, ground itch, and duck hunter’s itch. It is a parasitic infestation of a hookworm. It can be acquired from contact with soil or sand contaminated with dog or cat feces. It may not show up for weeks to months after exposure to sand or soil. The eruption is characterized by local itching. Four days after entry, the migration of the larvae begins and then progresses horizontally about 2 cm daily. Larvae may lie dormant in the skin in colder temperatures and become active again when the seasons change.
What To Look For:
1. pruritic, raised, red, serpiginous (snake-like), curvilinear trails with or without papules and/or vesicles
2. lesions most commonly found on ankles and feet
3. lesions occasionally found on buttocks, genitals, hands (or any area that had direct contact with sand or soil)
The correct diagnosis to quiz question two is number 3 .
Erythema annulare centrifugum (EAC) is a figurate erythema possibly related to hypersensitivity. The etiology of EAC has been postulated to be secondary to infection, inhalants, drugs, and malignancy, but in most cases, an etiologic agent is not identified. Most cases of EAC are idiopathic, but a number of agents have been reported to cause EAC-like lesions including piroxicam, penicillins, and others.
What To Look For:
1. single or multiple erythematous papules (may also appear urticarial) that advance peripherally by millimeters per day
2. erythematous papules eventually form large rings with central clearing and faint brownish pigmentation
3. the ring may have a trailing scale behind the advancing edge
4. lesions are slow moving and usually either arcuate or annular
Frederick Sanger (1918-2013) Genetics Pioneer, Two-Time Winner of Nobel Prize
Nobel prize-winning scientist Frederick Sanger pictured at home in 1993 at age 75.
Photograph: David Levenson/Getty Images
<<I heard a story that when Fred Sanger was working on dideoxy sequencing he didn’t publish a paper for 7 years. He got flak from his head of department for his lack of productivity only to respond by publishing his method, changing molecular biology forever and winning a second Nobel Prize.>> Comment from a Guardian reader, November 2013
Colin Blakemore, professor of neuroscience and philosophy at the School of Advanced Study in London and former chief executive of the Medical Research Council, said: The death of a great person usually provokes hyperbole, but it is impossible to exaggerate the impact of Fred Sanger’s work on modern biomedical science. His invention of the two critical technical advances – for sequencing proteins and nucleic acids – opened up the fields of molecular biology, genetics and genomics. He remains the only person to have won two Nobel prizes in chemistry – recognizing his unique contribution to the modern world.
Sanger was awarded a share of the Nobel prize for chemistry in 1980 for his work on sequencing DNA. It was his second Nobel prize, having also won the chemistry award in 1958 for his pioneering work on the structure of the protein insulin. He is one of only four people to have won two Nobel prizes – the highest honors in science – and the only person to have won two Nobel prizes in chemistry.
Compared with his contemporaries, the discoverers of the structure of DNA, James Watson and Francis Crick, Sanger was a relatively unknown figure outside science. He never courted fame (describing himself as a chap who messed about in his lab) and retired at the age of 65 to devote time to his garden. He even rejected a knighthood because, he told a journalist in 2000, he did not care to be called Sir. He was awarded the Order of Merit by the Queen in 1986.
Reading the DNA letters that make up genes of living organisms is done routinely in modern laboratories, and understanding how particular sequences influence a person’s susceptibility to diseases such as cancer and heart disease is a major focus of medical research. Though Watson and Crick had worked out the structure of DNA’s double helix in the early 1950s, and revealed that it held a linear code of base pairs (C, G, T and A), it took Sanger and his team at Cambridge to work out a way to read the DNA sequence. In the 1960s and 70s, Sanger developed techniques to clone the DNA of the genes under investigation and then add chemicals to break it into short pieces. Sanger’s group were the first to produce a whole genome sequence – 5,000 letters long of the virus phiX174 – and they also sequenced the first bit of human genetic material, the 16,000-letter sequence of DNA in a mitochondrion, the batteries inside biological cells.
In 1962, he moved to the new Medical Research Council Laboratory of Molecular Biology along with leading scientists including Nobel laureates Max Perutz and Francis Crick and began working on the problem of sequencing DNA. His technique – dideoxy or Sanger sequencing – is still in use today to read DNA code, including the 3bn base pairs of the first ever complete human genome sequence published in 2003.
Sanger was the fourth person to have been awarded two Nobel Prizes, either individually or in tandem with others.
When Sanger was around five years old the family moved to the small village of Tanworth-in-Arden in Warwickshire. The family were reasonably wealthy and employed a governess to teach the children. In 1927, at the age of nine, he was sent to the Downs School, a residential preparatory school run by Quakers near Malvern. His brother Theo was a year ahead of him at the same school. In 1932, at the age of 14, he was sent to the recently established Bryanston School in Dorset. This used the Dalton system and had a more liberal regime which Sanger much preferred. At the school he liked his teachers and particularly enjoyed scientific subjects.
He achieved good results in the School Certificate examinations and in 1936 moved as an undergraduate to St John’s College, Cambridge to study natural sciences. His father had attended the same college. For Part I of his Tripos (The University of Cambridge, divides the different kinds of honors bachelor’s degree by Tripos, plural Triposes) he took courses in physics, chemistry, biochemistry and mathematics but struggled with physics and mathematics. Many of the other students had studied more mathematics at school. In his second year he replaced physics with physiology. He took three years to obtain his Part I. For his Part II he studied biochemistry. It was a relatively new department founded by Gowland Hopkins with enthusiastic lecturers who included Malcolm Dixon, Joseph Needham and Ernest Baldwin.
Sanger began studying for a PhD in October 1940 under N.W. Bill Pirie. His project was to investigate whether edible protein could be obtained from grass. After little more than a month Pirie left the department and Albert Neuberger became his adviser. Sanger changed his research project to study the metabolism of lysine and a more practical problem concerning the nitrogen of potatoes. His thesis had the title, The metabolism of the amino acid lysine in the animal body. He was examined by Charles Harington and Albert Charles Chibnall and awarded his doctorate in 1943.
Neuberger moved to the National Institute for Medical Research in London, but Sanger stayed in Cambridge and in 1943 joined the group of Charles Chibnall, a protein chemist who had recently taken up the chair in the Department of Biochemistry. Chibnall had already done some work on the amino acid composition of bovine insulin and suggested that Sanger look at the amino groups in the protein. Insulin could be purchased from Boots (Boots UK Limited, formerly Boots the Chemist is a pharmacy chain in the United Kingdom) and was one of the very few proteins that were available in a pure form. Up to this time Sanger had been funding himself. In Chibnall’s group he was initially supported by the Medical Research Council and then from 1944 until 1951 by a Beit Memorial Fellowship for Medical Research.
Sanger’s first triumph was to determine the complete amino acid sequence of the two polypeptide chains of bovine insulin, A and B, in 1952 and 1951, respectively. Prior to this it was widely assumed that proteins were somewhat amorphous. In determining these sequences, Sanger proved that proteins have a defined chemical composition. For this purpose he used the Sanger Reagent, fluorodinitrobenzene (FDNB), to react with the exposed amino groups in the protein and in particular with the N-terminal amino group at one end of the polypeptide chain. He then partially hydrolyzed the insulin into short peptides, either with hydrochloric acid or using an enzyme such as trypsin. The mixture of peptides was fractionated in two dimensions on a sheet of filter paper, first by electrophoresis in one dimension and then, perpendicular to that, by chromatography in the other. The different peptide fragments of insulin, detected with ninhydrin, moved to different positions on the paper, creating a distinct pattern that Sanger called fingerprints. The peptide from the N-terminus could be recognized by the yellow color imparted by the FDNB label and the identity of the labeled amino acid at the end of the peptide determined by complete acid hydrolysis and discovering which dinitrophenyl-amino acid was there. By repeating this type of procedure Sanger was able to determine the sequences of the many peptides generated using different methods for the initial partial hydrolysis. These could then be assembled into the longer sequences to deduce the complete structure of insulin. Finally, because the A and B chains are physiologically inactive without the three linking disulfide bonds (two interchain, one intrachain on A), Sanger and coworkers determined their assignments in 1955. Sanger’s principal conclusion was that the two polypeptide chains of the protein insulin had precise amino acid sequences and, by extension, that every protein had a unique sequence. It was this achievement that earned him his first Nobel prize in Chemistry in 1958. This discovery was crucial for the later sequence hypothesis of Crick for developing ideas of how DNA codes for proteins.
From 1951 Sanger was a member of the external staff of the Medical Research Council and when they opened the Laboratory of Molecular Biology in 1962, he moved from his laboratories in the Biochemistry Department of the university to the top floor of the new building. He became head of the Protein Chemistry division. Soon after his move he started looking at the possibility of sequencing RNA molecules and began developing methods for separating ribonucleotide fragments generated with specific nucleases. One of the problems was to obtain a pure piece of RNA to sequence. In the course of this he discovered in 1964, with Kjeld Marcker, the formylmethionine tRNA which initiates protein synthesis in bacteria. He was beaten in the race to be the first to sequence a tRNA molecule by a group led by Robert Holley from Cornell University, who published the sequence of the 77 ribonucleotides of alanine tRNA from Saccharomyces cerevisiae in 1965. By 1967 Sanger’s group had determined the nucleotide sequence of the 5S ribosomal RNA from Escherichia coli, a small RNA of 120 nucleotides.
He then turned to sequencing DNA, which would require an entirely different approach. He looked at different ways of using DNA polymerase I from E. coli to copy single stranded DNA. In 1975 together with Alan Coulson he published a sequencing procedure using DNA polymerase with radio labeled nucleotides that he called the Plus and Minus technique. This involved two closely related methods that generated short oligonucleotides with defined 3′ termini. These could be fractionated by electrophoresis on a polyacrylamide gel and visualized using autoradiography. The procedure could sequence up to 80 nucleotides in one go and was a big improvement on what had gone before, but was still very laborious. Nevertheless, his group were able to sequence most of the 5,386 nucleotides of the single-stranded bacteriophage phagX174. This was the first fully sequenced DNA-based genome. To their surprise they discovered that the coding regions of some of the genes overlapped with one another.
In 1977 Sanger and colleagues introduced the dideoxy chain-termination method for sequencing DNA molecules, also known as the Sanger method. This was a major breakthrough and allowed long stretches of DNA to be rapidly and accurately sequenced. It earned him his second Nobel prize in Chemistry in 1980, which he shared with Walter Gilbert and Paul Berg. The new method was used by Sanger and colleagues to sequence human mitochondrial DNA (16,569 base pairs) and bacteriophage ? (48,502 base pairs). The dideoxy method was eventually used to sequence the entire human genome.
As of 2013, he is the only person to have been awarded the Nobel Prize in Chemistry twice, and one of only four two-time Nobel laureates: The other three were Marie Curie (Physics, 1903 and Chemistry, 1911), Linus Pauling (Chemistry, 1954 and Peace, 1962) and John Bardeen (twice Physics, 1956 and 1972).
Sanger married Margaret Joan Howe in 1940. They had three children ? Robin, born in 1943, Peter born in 1946 and Sally Joan born in 1960. He said that his wife had contributed more to his work than anyone else by providing a peaceful and happy home.
The Sanger Institute
Sanger retired in 1983 to his home, Far Leys, in Swaffham Bulbeck outside Cambridge and next to Sanger Wood. In 1992, the Wellcome Trust and the Medical Research Council founded the Sanger Centre (now the Sanger Institute), named after him. The Institute is located on the Wellcome Trust Genome Campus near Hinxton, only a few miles from Sanger’s home. He agreed to having the Centre named after him when asked by John Sulston, the founding director, but warned, It had better be good. It was opened by Sanger in person on 4 October 1993, with a staff of fewer than 50 people, and went on to take a leading role in the sequencing of the human genome. The Institute now has over 900 people and is one of the world’s largest genomic research centers.
He declined the offer of a knighthood, as he did not wish to be addressed as Sir. He is quoted as saying, A knighthood makes you different, doesn’t it, and I don’t want to be different. In 1986, he accepted the award of an Order of Merit, which can have only 24 living members.
In 2007 the British Biochemical Society was given a grant by the Wellcome Trust to catalogue and preserve the 35 laboratory notebooks in which Sanger recorded his remarkable research from 1944 to 1983. In reporting this matter, Science noted that Sanger, the most self-effacing person you could hope to meet, was now spending his time gardening at his Cambridgeshire home.
In 2008, and with his express consent, NHS Gloucestershire Primary Care Trust named their newly built HQ building Sanger House in recognition of his pre-eminent work and as a citizen of the county.
Sanger died on 19 November 2013. As The Times noted in his obituary, he had described himself as just a chap who messed about in a lab.
Keystone/Hulton Archive, via Getty Images. Dr. Sanger in 1958 at his home in Cambridge, England.
Sources: The New York Times, by Denise Gellene; Daniel E. Slotnik contributed reporting, Wikipedia, The Guardian, The Sanger Institute
Exercise as Potent Medicine
Johner Images/Getty Images
According to an article which was published in October in the British Medical Journal, exercise can be as effective as many frequently prescribed drugs in treating some of the leading causes of death. The study raises important questions about whether our health care system focuses too much on medications and too little on activity and preventative medicine to combat physical ailments.
Comparative effectiveness studies are a staple of science, of course, especially in pharmaceutical research. Scientists often track how well one drug treats a condition compared with the outcome if they use a different drug. But few studies have directly compared drugs with exercise, and even fewer have compared outcomes in terms of mortality or whether the intervention significantly lessens the chance that someone with a disease will die from it, despite treatment.
So Huseyin Naci, a graduate student at the London School of Economics and Political Science, and Dr. John Ioannidis, the director of the Stanford Prevention Research Center at the Stanford University School of Medicine, decided to create a comprehensive comparison of the effectiveness of drugs and exercise in lessening mortality among people who had been diagnosed with one of four diseases: heart disease, chronic heart failure, stroke or diabetes. They chose these particular conditions because those were the only ones for which they could find studies that had examined whether exercise lessened the risk of death among patients with that disease.
For the study, the authors compared how well various drugs and exercise succeed in reducing deaths among people who had been diagnosed with several common and serious conditions, including heart disease and diabetes. The authors gathered all of the recent randomized controlled trials, as well as previous reviews and meta-analyses of older experiments relating to mortality among patients with those diseases, whether they had been treated with drugs or exercise. They ended up with data covering 305 past experiments that, collectively, involved almost 340,000 participants, which is an impressive total. But most of the volunteers had received drugs. Only 57 of the experiments, involving 14,716 volunteers, had examined the impact of exercise as a treatment.
Still, the numbers were large enough that Mr. Naci and Dr. Ioannidis could create an elaborate network of cross-references, comparing the outcomes when people received certain drugs, followed exercise regimens or, occasionally, both. The exercise routines, typically part of rehabilitation programs, usually involved walking or other aerobic routines but sometimes consisted of weight training or other exercises.
The researchers compared mortality risks for people following any of the treatment options.
The results consistently showed that drugs and exercise produced almost exactly the same results. People with heart disease, for instance, who exercised but did not use commonly prescribed medications, including statins, angiotensin-converting-enzyme inhibitors or antiplatelet drugs, had the same risk of dying from – or surviving – heart disease as patients taking those drugs. Similarly, people with diabetes who exercised had the same relative risk of dying from the condition as those taking the most commonly prescribed drugs.
On the other hand, people who once had suffered a stroke had significantly less risk of dying from that condition if they exercised than if they used medications – although the authors noted that stroke patients who can exercise may have been unusually healthy to start with. Only in chronic heart failure were drugs noticeably more effective than exercise. Diuretics staved off mortality better than did exercise.
Over all, Dr. Ioannidis said, our results suggest that exercise can be quite potent in treating heart disease and the other conditions, equaling the lifesaving benefits available from most of the commonly prescribed drugs, including statins. Statins are at the center of a debate about new treatment guidelines that could vastly expand the number of people taking the drugs.
The results also underscore how infrequently exercise is considered or studied as a medical intervention, Dr. Ioannidis said. Only 5% of the available and relevant experiments in his new analysis involved exercise. We need far more information about how exercise compares, head to head, with drugs in the treatment of many conditions, he said, as well as what types and amounts of exercise confer the most benefit and whether there are side effects, such as injuries. Ideally, he said, pharmaceutical companies would set aside a tiny fraction of their profits for such studies.
For now, Mr. Naci said, he hopes that this new study will prompt smaller-scale negotiations. We are not suggesting that anyone stop taking their medications, he said. But maybe people could think long and hard about their lifestyles and talk to their doctors about whether exercise could and should be incorporated into their care. Source: The New York Times, by Gretchen Reynolds, December 11, 2013
Fertility Treatments and Multiple Births in the United States
The advent of fertility treatments has led to an increase in the rate of multiple births in the United States. However, the trends in and magnitude of the contribution of fertility treatments to the increase are uncertain. As a result, a study published in the New England Journal of Medicine (2013;369:2218-2225), and funded by the CDC, derived the rates of multiple births after natural conception from data on distributions of all births from 1962 through 1966 (before fertility treatments were available). Publicly available data on births from 1971 through 2011 were used to determine national multiple birth rates, and data on in vitro fertilization (IVF) from 1997 through 2011 were used to estimate the annual proportion of multiple births that were attributable to IVF and to non-IVF fertility treatments, after adjustment for maternal age. Trends in multiple births were examined starting from 1998, the year when clinical practice guidelines for IVF were developed with an aim toward reducing the incidence of multiple births.
Results showed that by 2011, a total of 36% of twin births and 77% of triplet and higher-order births resulted from conception assisted by fertility treatments. The observed incidence of twin births increased by a factor of 1.9 from 1971 to 2009. The incidence of triplet and higher-order births increased by a factor of 6.7 from 1971 to 1998 and decreased by 29% from 1998 to 2011. This decrease coincided with a 70% reduction in the transfer of three or more embryos during IVF (P<0.001) and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF (P<0.001).
According to the authors, over the past four decades, the increased use of fertility treatments in the United States has been associated with a substantial rise in the rate of multiple births, but that the rate of triplet and higher-order births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
FDA Takes Significant Steps to Address Antimicrobial Resistance
Certain antimicrobials have historically been used in the feed or drinking water of cattle, poultry, hogs, and other food animals for production purposes such as using less food to gain weight. Some of these antimicrobials are important drugs used to treat human infection, prompting concerns about the contribution of this practice to increasing the ability of bacteria and other microbes to resist the effects of a drug. Once antimicrobial resistance occurs, a drug may no longer be as effective in treating various illnesses or infections.
The FDA is implementing a plan to help phase out the use of medically important antimicrobials in food animals for food production purposes, such as to enhance growth or improve feed efficiency. The plan would also phase in veterinary oversight of the remaining appropriate therapeutic uses of such drugs.
Because antimicrobial drug use in both humans and animals can contribute to the development of antimicrobial resistance, it is important to use these drugs only when medically necessary. The plan announced today focuses on those antimicrobial drugs that are considered medically important (i.e., are important for treating human infection) and which are approved for use in feed and water of food animals.
In a final guidance issued last week, the FDA lays out a road map for animal pharmaceutical companies to voluntarily revise the FDA-approved use conditions on the labels of these products to remove production indications. The plan also calls for changing the current over-the-counter (OTC) status to bring the remaining appropriate therapeutic uses under veterinary oversight. Once a manufacturer voluntarily makes these changes, its medically important antimicrobial drugs can no longer be used for production purposes, and their use to treat, control, or prevent disease in animals will require veterinary oversight.
The FDA is asking animal pharmaceutical companies to notify the agency of their intent to sign on to the strategy within the next three months. These companies would then have a three-year transition process.
In order to help phase in veterinary oversight of those drugs covered by the guidance that are intended for medically appropriate uses in feed, the FDA also has issued a proposed rule to update the existing regulations relating to Veterinary Feed Directive (VFD) drugs. The use of VFD drugs requires specific authorization by a licensed veterinarian using a process outlined in the agency’s VFD regulations. The VFD proposed rule is intended to update the existing VFD process and facilitate expanded veterinary oversight by clarifying and increasing the flexibility of the administrative requirements for the distribution and use of VFD drugs. Such updates to the VFD process will assist in the transition of OTC products to their new VFD status.
The guidance for animal pharmaceutical companies is now in final form, and the proposed VFD rule is open for public comment for 90 days starting on Dec. 12, 2013. To electronically submit comments on the proposed VFD rule, go towww.regulations.gov and insert docket FDA-2010-N-0155. Send written comments to the Division of Dockets Management, Food and Drug Administration, Room 1061, 5630 Fishers Lane, Rockville, MD 20852.
The Best Green Bean Salad You’ve Ever Tasted
Green Bean Salad, Photo ©Joyce Hays, Target Health Inc.
1.5 pounds green beans
5 Tablespoons extra virgin olive oil (use your best), + 1 teaspoon
2 teaspoons chicken stock
4 Tablespoons balsamic vinegar (use your best)
1/2 cup capers
1 cup fresh basil, chopped
1 cup pine nuts, toasted
1 cup red seedless grapes, cut in half
1 garlic clove, juiced (use 2 if you like garlic)
Toast the pine nuts in a fry pan, with 1 teaspoon olive oil, and 1-2 teaspoons chicken stock, stirring constantly for about 3 minutes. Then set aside on paper towel to drain any excess liquid from the nuts.
Steam the green beans, until slightly cooked, al dente, you do not want mushy. Rinse under cold water to stop them from cooking (and enhance the beautiful green color) and dry with paper towel. Depending on the length of the beans, cut them in half or in thirds.
In a small bowl, mix the Olive oil with the balsamic vinegar, garlic juice, pinch salt, pinch black pepper.
Into your salad bowl, add the green beans, basil and capers. Toss gently. Then, add the grapes. Slowly pour the dressing over the salad. Use a spatula to get every drop of the dressing poured over the salad. Toss. Finally, add the pine nuts, toss gently once more and serve.
You are in for a treat with this delicious salad.
Something wonderful happens when sweet grapes and sour capers combine, along with crunchy green beans, and toasted pine nuts. Basil adds a mysterious depth. Of course, gourmet olive oil and balsamic vinegar add their magic too. It’s rare to get such a delicious result from so few ingredients, and so little work. It’s taken me a long time, of trial and error, to get the exact delicious flavor mix, of this particular green bean salad.
Although, this salad would go with poultry, the best entre to serve would be fish or seafood. This salad could be served as a first course, then the fish with rice or polenta, and a cauliflower casserole or ratatouille or whatever veggie casserole you like. We had a selection of warm breads, chilled Sauvignon Blanc and a fruit and cheese platter.
Life is good!
Charles Perry, MBA, MD Joins Target Health as Medical Director
Target Health Inc. is pleased to announce that Charles Perry, MD, MBA, has joined the company as Medical Director. Dr. Perry holds an MD degree from Columbia University School of Medicine and is board certified in internal medicine. He also received an MBA at Columbia and a BS from Duke. Prior to joining Target Health, Dr. Perry spent 2 years at Pfizer where he led cross-functional teams of clinical, regulatory, and commercial experts in analysis and financial modeling of business development efforts, and supported licensing and acquisition due diligence.
Dr. Perry will work closely with Glen Park, PharmD in Clinical Research, Dean Gittleman in Operations, Yong Jong Kim in IT, and with Jules Mitchel, MBA, PhD as part of the Executive Management Team.
Over 15% of our employees are now from Pfizer/Wyeth:
1. Dean Gittleman, MS
2. Ron Harris, RN
3. Mark Horn, MD
4. Judith Schloss Markowitz, MS
5. Jules Mitchel, MBA, PhD
6. Warren Pearlson, RPh
7. Charles Perry, MD
8. Louella White, MS
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
Marfan Syndrome – Learning to Defuse the Aorta
Dr. Hal Dietz, who found that the blood-pressure drug losartan eased Marfan symptoms
When Dr. Hal Dietz arrived at Johns Hopkins University in the 1980s, he became obsessed with helping children with Marfan syndrome, a rare and often 1) ___ disorder that can cause the aorta, the large blood vessel that carries blood from the heart, to grow and grow until it bursts. These doomed children had a distinctive look that clearly had a genetic basis. They were typically very tall and thin, with long arms, legs and fingers. They often had unusually flexible joints, flat feet and teeth that were crowded in their 2) ___. I decided to study genetics with the sole incentive to identify the 3) ___ for Marfan syndrome and ultimately to understand the mechanism, said Dr. Dietz, now director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins. That journey has led to surprising discoveries about Marfan’s causes and a soon-to-be published clinical trial of a drug that may help its sufferers.
Dr. Dietz’s work also inspired research that may lead to a blood test that detects enlarged aortas, potentially saving thousands of lives, even among those who do not have 4) ___ syndrome. Every year about 10,000 Americans die from ruptured aortas; two victims were the actor John Ritter and the diplomat Richard C. Holbrooke. The hope is that such a test will allow doctors to operate before the aorta bursts, or to quickly identify aortas that have ruptured so 5) ___ can be performed without delay.
Patients whose aortas are breaking apart all need immediate treatment, said Dr. Scott A. LeMaire, a professor of surgery and of molecular physiology and biophysics at the Baylor College of Medicine. The longer you delay the diagnosis, the greater the chance their aorta will 6) ___ while you are trying to figure out what is going on.
For families who have recently learned that a child has Marfan syndrome, Dr. Dietz’s discoveries and the clinical trial he designed have divided their world into before and after, dread and hope. Daniel Speck of Knoxville, Md., was given a diagnosis of Marfan six years ago, when he was 8, after his pediatrician noticed his 7) ___ was curved and suggested a test for scoliosis. It turned out that the curvature was caused by Marfan syndrome. By then, Dr. Dietz and his colleagues had finally found the gene mutation that causes Marfan. It had been a slow and frustrating process: The sequencing machines now used to quickly map DNA had not been invented. Researchers had to sort through every gene in large regions of 8) ___ shared by members of families in which someone had the syndrome. Yet when the researchers first found the mutation, in 1990, it seemed to lead to a dead end. The mutation was in fibrillin-1, a protein in connective tissue, suggesting that the tissue was falling apart because its molecular rivets did not work. And if that was true, Dr. Dietz said, there was nothing you could do to alter the course of the disease. Or as Dr. David Altshuler of the Broad Institute of Harvard and M.I.T., who was not part of the research team, put it, How can we fix the rivets when every rivet in the 9) ___ is broken? Those were the dark days of Marfan research, Dr. Dietz said. But then he began to question the rivet hypothesis. It did not explain some of Marfan’s most notable features: the strikingly long bones of the children’s arms, legs and fingers, their deeply set eyes that slanted downward, their flat cheekbones, small chins, extremely low muscle mass and small amount of body10) ___.
About 10 years ago, he and his colleagues discovered the answer in another protein, T.G.F.-beta, short for transforming growth factor beta, which tells cells how to behave during development and is used in repairing wounds. The protein’s function depends on fibrillin-1, the very protein that is altered in Marfan syndrome. Normally, fibrillin-1 hooks T.G.F.-beta to connective tissue. But in someone with Marfan, the researchers discovered, the fibrillin-1 is defective, and the process goes awry. Instead of attaching to the connective tissue, T.G.F.-beta drifts away from it. Floating free in the bloodstream, it makes cells behave abnormally, leading to many of the problems caused by Marfan, including excessive growth of the aorta. In short, the rivet model was entirely wrong. That, Dr. Dietz said, was one of the few ?aha’ moments in my life. He tested his theory in mice, giving them the mutated fibrillin-1 gene. Sure enough, levels of the T.G.F. 11) ___ were very high. The mice showed Marfan symptoms, including emphysema, weak skeletal muscles and a thickening of the mitral valve in the heart. He then sought a way to block the function of T.G.F.-beta and found a widely used blood pressure drug, losartan, that did just that. In the mice, the drug prevented features of the syndrome, including ballooning of the aorta. Instead of dying of aortic aneurysms by three months of age, the mice lived a normal life span of two years.
In 2006, the National Heart, Lung, and Blood Institute started a randomized trial based on Dr. Dietz’s work in which some children with Marfan got the drug and others got the standard treatment, with a beta blocker that slows the 12) ___ rate. But Dr. Dietz worried about the children who were most severely affected. Most died in the first few years of life. By the time he finished the clinical trial, they would be dead. They had an unrelenting growth of the aorta, he said. If the drug worked, it could save their lives immediately. I felt compelled to treat them. One morning in 2006, Kari Dostalik of Urbandale, Iowa, whose daughter, Haley, has the disorder, went to a lecture by Dr. Dietz at the annual Marfan syndrome conference. He showed a slide of a boy who had a severe form of Marfan and had been given losartan outside the clinical trial. Ms. Dostalik had met the child and his family at a previous conference. Before treatment, the boy looked weak and tired. But after having taken the drug, she said, he was grinning ear to ear. Even better, Dr. Dietz told the group, as soon as the boy and other children took the drug, their aortas stopped growing. And losartan appeared to reverse some of the disease’s effects. When we heard the word ?reversed,’ Ms. Dostalik said, our first gut reaction was, ?How soon can we get Haley enrolled?’ The study was just beginning, and children would be in it for three years. Neither the families nor the doctors would know which drug they were taking, losartan or the beta blocker. As tempting as it was to just give Haley losartan, Ms. Dostalik said, she and her husband worried about possible side effects, and they wanted to help science find an answer. This was our chance to help the Marfan community, she said. Two years later, Dr. Dietz and his colleagues published data in The New England Journal of Medicine on 17 severely affected children who were given the drug outside the clinical trial. Before they took it, their 13) ___ were growing about three and a half millimeters a year; afterward, the rate slowed to half a millimeter a year.
Some researchers worried that publishing the data might doom efforts to persuade parents to enroll children in the trial when they could get a drug like losartan on their own. But over the next three years, 604 families joined the study, with results expected in the coming months. The Specks enrolled Daniel, and suspect he got 14) ___. His mother said the family saw wonderful changes – everything started to stabilize. Daniel’s aorta had been growing astronomically, she said, and that growth slowed so much that he would not qualify if he tried to enter the trial today. He also developed better muscle tone and more body fat.
When his time in the trial ended, the Specks were told Daniel could take losartan or the older drug, whichever they preferred. Ms. Speck did not want to take any chances. They chose both. Daniel, now 15, continues to do well.
The Marfan discoveries are starting to affect a bigger group – those without Marfan but whose aortas have bulged and torn, a life-threatening emergency. Symptoms of a torn aorta can vary enormously, depending on which of the arteries branching from it are disrupted. The aorta begins at the heart and runs all the way down to the abdomen, feeding blood to more than a dozen major arteries. If a tear interferes with branches that deliver blood to the heart, it can look like a heart attack. If it interferes with branches that deliver blood to the brain, it can look like a 15) ___. People come in with this life-threatening condition and are either misdiagnosed or there is a long delay in diagnosis, Dr. LeMaire said. Once the vessel ruptures, the operation to fix it is risky. Patients have to be put on a heart-lung machine, and their torn aortas repaired with a piece of synthetic fabric. The stretched and torn aorta has become something akin to tissue paper. Even the most experienced surgical teams lose as many as a quarter of their patients. But it appears that these patients may have the same telltale molecular signals as Marfan patients. When an aorta ruptures, it releases high levels of the Marfan protein, fibrillin-1, into the blood. That led Lynn Sakai, a biochemist at the Shriners Research Centerin Portland, Ore., to suggest using fibrillin-1 levels as a blood test for aortic ruptures. She, Dr. LeMaire and their colleagues studied blood and tissue samples, stored at the Baylor College of Medicine, that belonged to patients with ballooning or ruptured aortas. In a recent paper, they reported that fibrillin-1 levels in the blood of patients with bulging aortas were two and a half times higher than in those who did not have enlarged aortas. And high fibrillin-1 levels were three times as common in those with tears in their aortas as in those whose aortas were bulging but not torn. Dr. LeMaire and his colleagues say they need to validate their results with blood tests from many more emergency room patients. They hope that such tests can be used to predict who is at risk for an aortic aneurysm or needs emergency surgery. We’d like to round up all the people who come to an emergency room with some symptom of chest pain, Dr. Sakai said, people like John Ritter, who died because the emergency room guy did not recognize that he was having an aortic dissection. Steve Marpman, of Queens, 42, director of social work for a managed care company, could have used a blood test when he went to an emergency room and almost died of an aortic aneurysm. He was training to be a policeman and passed several physical exams without trouble. Then one day he was dizzy and had a hollow feeling in his chest. His vision blurred. His speech became incoherent. By the time he got to an emergency room, he was near death – vomiting blood, going in and out of consciousness, with a weak pulse and rapid heartbeat. A cardiology intern came in, looked at Mr. Marpman’s long legs and fingers, and said, Marfan. Mr. Marpman had never heard of the syndrome.
An adult aorta is normally three to four centimeters, or 1.2 to 1.6 inches, in diameter. When it reaches five centimeters, doctors often suggest elective surgery. Mr. Marpman’s aorta was 10 centimeters wide, and had split open. His heart was spilling 16) ___ into his abdominal cavity and lungs. He had emergency surgery and awoke from the 12-hour operation intubated and strapped to a bed.
Losartan, the blood pressure drug, has not been tested on adults with Marfan, but Mr. Marpman has begun taking it. His baby boy inherited the Marfan gene. And if the clinical trial turns out to prevent excessive growth of the aorta, son will join father in taking the drug. Sources: The New York Times (By Gina Kolate, Published: December 2, 2013), Johns Hopkins Medical School, Wikipedia
Click on this link, to hear a presentation by Dr. Hal Dietz
Dr. Hal Dietz, Victor A. McKusick Professor of Institute of Genetic Medicine and Professor of Pediatrics and Investigator of Howard Hughes Medical Institute at The Johns Hopkins Hospital and Chair of the Loeys-Dietz Syndrome Foundation Medical Advisory Council (MAC), presents Research Update on Loeys-Dietz Syndrome at the 2012 LDSF Conference in Baltimore, Maryland, USA. Dr. Dietz discusses the latest on LDS mice model research findings.
ANSWERS: 1) fatal; 2) mouth; 3) gene; 4) Marfan; 5) surgery; 6) rupture; 7) spine; 8) DNA; 9) body; 10) fat;; 11) protein; 12) heart; 13) aortas; 14) losartan; 15) stroke; 16) blood