Mark Citron (1950-2011)


My very dear friend and colleague, Mark B. Citron, died peacefully last week after a courageous battle with brain cancer.  Mark was an unusual person and lives on in all he touched.


I met Mark many years ago through my good friends from Johnson & Johnson, Dr. Eli Pines and Dr. Tibor Sipos. It has been a wonderful journey. Mark was one of the best regulatory strategists in the industry, and we shared novel approaches to problems when demands of our clients or his company were making us a bit “crazy.“


Mark spent over 30 years working in the medical device industry at the FDA, Johnson & Johnson, Bristol Myers Squibb, Genzyme, Biomimetic Therapeutics, and most recently TYRX. Mark was immensely driven, goal-oriented, and devoted his life and career to advocating for the improved health of others.


When Mark’s wife Barbara called and told me that Mark was sick and what had happened, we all jumped into full gear to see what we could do. Unfortunately there were no appropriate clinical trials which Mark would have volunteered for in a second. After all, it is our business. In the hospital I had a chance to spend more time with Mark’s family who are very special and committed people. They made sure that he always got the best of care.


The first time I saw Mark in the hospital, he said to me “that if I ever needed a craniostomy, Memorial Sloan Kettering (MSK) was the place to have it.” This guy had some sense of humor. Even during his illness Mark was immensely curious, solved crossword puzzles and made sure all drugs and devices were not being used “off label.“ Mark was the consumate FDA regulatory expert who wanted everything done by the “book”, even his life-saving treatments.


When Mark got sick there was an outpouring of concern and deep affection from those he knew and worked with him. Here are 2 tributes from Mark’s friends and colleagues in the Industry. Their privacy is being respected:


“Thank you for keeping me informed on this sad turn of events. Mark was a very good person and losing him makes the world a lesser place.“


“Words are inadequate to express our sadness and our sense that somethone good has passed from us. Mark will forever be remembered as a dear friend and wonderful, incredibly dedicated colleague.“


Jules T. Mitchel


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


Living at High Altitude Reduces Risk of Dying from Heart Disease: Low Oxygen May Spur Genes to Create Blood Vessels





The Western Rocky Mountains provide an ideal setting for the Wasatch Front metropolitan area of Utah, but they also prevent the population from expanding eastward


In one of the most comprehensive studies of its kind, researchers at the University of Colorado School of Medicine in partnership with the Harvard School of Global Health have found that people living at higher altitudes have a lower chance of 1) ___ from ischemic heart disease and tend to live longer than others. “If living in a lower oxygen environment such as in our Colorado mountains helps reduce the risk of dying from heart disease it could help us develop new clinical treatments for those conditions,“ said Benjamin Honigman, MD, professor of Emergency Medicine at the CU School of Medicine and director of the Altitude Medicine Clinic. “Lower oxygen levels turn on certain genes and we think those genes may change the way heart 2) ___ function. They may also produce new blood vessels that create new highways for blood flow into the heart.“


Another explanation, he said, could be that increased solar radiation at higher altitude helps the body better synthesize vitamin 3) ___ which has also been shown to have beneficial effects on the heart and some kinds of cancer. The study was recently published in the Journal of Epidemiology and Community Health (DOI: 10.1136/jech.2010.112938).


At the same time, the research showed that altitudes above 4,900 feet were detrimental to those suffering from chronic obstructive 4) ___ disease. “Even modestly lower 5) ___ levels in people with already impaired breathing and gas exchange may exacerbate hypoxia and pulmonary hypertension [leading to death],“ the study said. Honigman, senior author of the study, along with researchers that included Robert Roach, PhD, director of the School of Medicine’s Altitude Research Center, Deborah Thomas, PhD, a geographer at the University of Colorado Denver and Majid Ezzati of the Harvard School of Global Health, spent four years analyzing death certificates from every county in the U.S. They examined cause-of-6) ___, socio-economic factors and other issues in their research.


They found that of the top 20 counties with the highest life expectancy, eleven for men and five for women were located in 7) ___ and Utah. And each county was at a mean elevation of 5,967 feet above sea level. The men lived between 75.8 and 78.2 years, while women ranged from 80.5 to 82.5 years. Compared to those living near sea-level, the men lived 1.2 to 3.6 years longer and women 0.5 to 2.5 years more. Despite these numbers, the study showed that when socio-economic factors, solar radiation, smoking and pulmonary disease were taken into account, the net effect of 8) ___ on overall life expectancy was negligible.


Still, Honigman said, altitude seems to offer protection against 9) ___ disease deaths and may also play a role in cancer development. Colorado, the highest state in the nation, is also the leanest state, the fittest state, has the fewest deaths from heart disease and a lower incidence of colon and lung 10) ___ compared to others. “We want to now look at these diseases in a more focused way so we can see the mechanisms behind hypoxia and why they affect the body the way they do,“ Honigman said. “This is a public health issue in Colorado and the mountain West. We have more than 700,000 people living at over 7,000 feet above sea level. Does living at altitude change the way a disease progresses? Does it have health effects that we should be investigating? Ultimately, we hope this research will help people lead healthier lives.“


ANSWERS: 1) dying; 2) muscles; 3) D; 4) pulmonary; 5) oxygen; 6) death; 7) Colorado; 8) altitude; 9) heart; 10) cancer
Discovery of the Neuron – Part 3


Another significant development, apart from the evolution of the microscope, was the use of new methods to stain nervous tissue for examination. Gerlach, the main proponent of reticular theory, had introduced the use of carmine and gelatin, and then gold chloride, to stain tissues for microscopic examination. Although satisfactory, these methods left much to be desired.


Camillo Golgi (1843-1926)




A far more useful staining method was discovered by Camillo Golgi. Golgi was born in Corteno, a small mountain village in the Italian province of Brescia. He studied medicine at Pavia University, graduating in 1865 aged just 22. In 1872, Golgi took a post as resident physician at a hospital for the chronically ill, in a small town called Abbiategrasso, near Milan. Golgi discovered his method while working by candlelight in one of the hospital’s kitchens, which he had transformed into a laboratory. The method, now known as Golgi staining or Golgi impregnation, involves hardening of tissue in potassium bichromate and ammonia, followed by immersion in a silver nitrate solution. The Golgi stain visualizes a small number of cells in a tissue sample; the cells are stained at random and in their entirety, so that silhouettes of the cell body, axon and dendrites are clearly visible.


In a letter to a friend, he describes the discovery of la reazione nevo (the black reaction):


“I spend long hours at the microscope. I am delighted that I have found a new reaction to demonstrate…the structure of the interstitial stroma of the cerebral cortex. I let the silver nitrate react with pieces of brain hardened in potassium dichromate. I have obtained magnificent results and hope to do even better in the future.“


Despite discovering a technique which stained neurons in their entirety, Golgi thought that his observations confirmed the hypothesis that the nervous system consisted of a continuous network.


“If a method of preparation capable of demonstrating the anastamoses of different cells exists, it must be that of black staining…Thanks to this reagent one notes not only the cell body with its primary extension [the axon] clearly revealed, but, in addition, the most delicate ramifications. The use of the black dye can be limited to a small number of cells or to more extensive groups; occasionally one may even obtain a comprehensive view of an entire area of the central nervous system.“


In 1873, Golgi published a paper containing descriptions of hippocampal and cerebellar tissue that he had stained using his new technique. In that paper, Golgi reasserts his belief that the nervous system consists of a reticulum: “I was confronted by the concrete fact; this was the existence of the formation which I have called the diffuse nerve network.“ Golgi argued that, because there were so many connections between the nerve cells he had seen in his samples, a law for transmission between nerve cells could not be formulated. Nervous tissue must, then, be composed of a continuous network rather that discrete units. He also believed that only axons fused by anastomosis, and that delivered nutrients from the blood vessels to neurons. Because of his adherence to reticular theory, Golgi took a holistic approach to brain function. His belief that the nervous system consisted of a reticulum went against the theory of localization of cerebral function, which by then was gaining ground, due largely to the work of early neurologists such as Paul Broca.


Although it turned out that Golgi was mistaken about reticular theory, he was nevertheless a great scientist who made a number of important discoveries, including the identification of projection neurons, interneurons and tendon organs. He also elucidated the part of the Plasmodium life cycle that took place in red blood cells, and correlated the fever and chills, which are symptoms of the disease, with release of the microbe into the blood. In 1898 he identified what he termed the “internal reticular apparatus”; the identification of this structure, which would later be named the Golgi complex, was a major breakthrough in cytology. The staining method Golgi discovered was of vital significance; using that method, he laid the foundations of the discipline we now call histology.


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The Cancer Genome Atlas Completes Detailed Ovarian Cancer Analysis


Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85% of all ovarian cancer deaths.


According to a report published in Nature (2011;474:609-615), an analysis of genomic changes in ovarian serous adenocarcinoma tumors from 500 patients, has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. The Cancer Genome Atlas (TCGA) Research Network completed whole-exome sequencing, which examines the protein-coding regions of the genome, on an unprecedented 316 tumors. They also completed other genomic characterizations on these tumors and another 173 specimens.


TCGA is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health.


Among the specific findings is the confirmation that mutations in a single gene, TP53, are present in more than 96% of all such cancers. TP53 encodes a tumor suppressor protein that normally prevents cancer formation. Mutations in the gene disrupt this protein’s function, which contributes to uncontrolled growth of ovarian cells. In addition, TCGA identified a multitude of less-frequent mutations in other genes.


The study also established how sets of genes are expressed in a fashion that can predict patient survival – identifying patterns for 108 genes associated with poor survival and 85 genes associated with better survival. Patients whose tumors had a gene-expression signature associated with poor survival, lived for a period that was 23% shorter than patients whose tumors did not have such a signature. The overall five-year survival rate for ovarian cancer is 31%, which means that 69% of patients diagnosed this year will not be alive in 2016, highlighting the urgent need for a better understanding of the disease.


To identify opportunities for targeted treatment, the investigators searched for existing drugs that might inhibit amplified or over-expressed genes that were suggested to play a role in ovarian cancer. The search identified 68 genes that could be targeted by existing FDA-approved or experimental therapeutic compounds. The investigators noted that one type of drug, a PARP (Poly ADP ribose polymerase) inhibitor, might be able to counteract the DNA repair gene observed in half of the ovarian tumors studied. While researchers have known that these drugs could be effective against the disease, this study revealed that 50% of tumors might be responsive to drugs that exploit the genetic instability of the tumors and induce the cancer cells to die.


The results of this study support the existence of four distinct subtypes of the disease, based on the patterns seen in the transcription of RNA from DNA. They also support the existence of four related subtypes based on the patterns of DNA methylation – a chemical reaction in which a small molecule called a methyl group is added to DNA, changing the activity of individual genes. These patterns likely reflect the functional changes associated with ovarian serous adenocarcinoma, but are not strongly associated with survival duration.


Mutations in BRCA1 and BRCA2 genes, which are associated with some forms of breast cancer, also confer increased risk for ovarian cancer. In this study, approximately 21% of the tumors showed mutations in these genes. Analysis of these tumors confirmed observations that patients with mutated BRCA1 and BRCA2 genes have better survival odds than patients without mutations in these genes. Importantly, investigators identified that the mechanism by which the BRCA1 and BRCA2 genes become defective also relates to survival. If either of the BRCA1 and BRCA2 genes is mutated, there is improved survival duration. However, if BRCA1 activity is instead reduced by methylation, there is no improved survival duration.


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20% Reduction in Lung Cancer Mortality with Low-Dose CT Compared to Chest X-Ray


According to an article published online in the New England Journal of Medicine (4 August 2011), a 20% reduction in deaths from lung cancer was observed among current or former heavy smokers who were screened with low-dose helical computed tomography (CT) versus those screened by chest X-ray. The article provides a more extensive analysis of the original data reported in November 2010 while providing additional data to the public and research community without barriers to access. Sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, the National Lung Screening Trial (NLST) is a nearly decade-long study that establishes low-dose helical CT as the first validated screening test which can reduce mortality due to lung cancer.


The NLST was a randomized national trial involving 53,454 current and former heavy smokers ages 55 to 74. Participants were required to have a smoking history of at least 30 pack-years and were either current or former smokers without signs, symptoms, or history of lung cancer. Pack-years are calculated by multiplying the average number of packs of cigarettes smoked per day by the number of years a person has smoked. Participants in the NLST were randomly assigned to receive three annual screens with either low-dose helical CT (often referred to as spiral CT) or standard chest X-ray. Helical CT uses X-rays to obtain a multiple-image scan of the entire chest, while a standard chest X-ray produces a single image of the whole chest in which anatomic structures overlie one another.


The report provides important details about the number of screens that identified abnormalities potentially related to lung cancer (positive screens) and how many of those positive screens turned out to be false positives, meaning that the positive finding did not prove to be lung cancer upon follow-up. Over the three rounds of screening exams, 39.1% of the low-dose helical CT screens were positive and 16.0% of the chest X-rays were positive. In both arms of the trial, the majority of positive screens led to additional tests.


Across all three rounds, when a positive screening result was found, 96.4% of the low-dose helical CT tests and 94.5% of the chest X-ray exams were false positive. The vast majority of false positive results was probably due to the detection of normal lymph nodes or inflamed tissues. False positive results not due to lung cancer were typically confirmed by follow-up CT scans that showed no change in the finding over time.


The results also provide insight into the type of lung cancers found by screening and the stages at which they were diagnosed. Adenocarcinomas, which begin in cells that line the lungs, and squamous cell carcinomas, which arise from the thin, flat fish-scale-like cells that line passages of the respiratory tract, were detected in the early stages of disease in both arms of the trial. Both types of carcinomas were detected more frequently at their earliest stage by low-dose helical CT compared to chest X-ray. Small-cell lung cancers, which are very aggressive tumors and grow in the tissues of the lung, were infrequently detected at early stages by low-dose helical CT or chest X-ray. Additional studies based on the complete NLST data set are ongoing and will include reports on cost-effectiveness of low-dose helical CT as well as the ability to use the data to develop models that may help indicate whether other groups of smokers, such as light smokers or younger smokers, would benefit from screening with low-dose helical CT. Other modeling studies are expected to examine the optimal frequency and duration of screening.


Adverse events from the actual screening examinations were few and relatively minor in the NLST. The rate of complications among people who underwent a diagnostic evaluation prompted by a positive screen was under 2% for either type of screening. Among those who did have complications, 16 people screened with low-dose helical CT (10 of whom had lung cancer) and 10 chest X-ray participants (all with lung cancer) died within 60 days of a follow-up invasive diagnostic procedure.


Invasive diagnostic procedures include bronchoscopy, where an instrument is inserted through the nose or mouth into the airways, and percutaneous lung needle biopsy, where a needle is inserted into the lung through the chest to remove a small piece of tissue for examination. While it is not known whether the diagnostic procedures caused these deaths, the low frequency of death within 60 days of an invasive procedure in the NLST suggests that death from evaluation of positive screens occurs rarely.


Radiation exposure associated with low-dose helical CT in the NLST is much lower than that associated with a regular diagnostic CT. The authors note any harm from exposure to radiation during the screenings could not be measured directly. Because the effect of such exposure is a long-term outcome, potential harms will need to be modeled in future studies.


It should also be noted that the population enrolled in this study, while ethnically representative of the U.S. population of smokers at high risk for lung cancer, was a highly motivated and primarily urban group that was screened at major medical centers. Thus, these results alone may not accurately predict the effects of recommending low-dose helical CT scanning for other populations.

Dr. William P. Taylor, in 1987 in Sudan, examined a cow for rinderpest. The United Nations has just announcedthat the disease has been wiped off the face of the earth (photo F. Paladini)




The following is based on an article from the NY Times.
Rinderpest is an epizootic or animal disease. The name means “cattle plague“ in German, and it is a relative of the measles virus that infects cloven-hoofed beasts, including cattle, buffaloes, large antelopes and deer, pigs and warthogs, even giraffes and wildebeests. The most virulent strains killed 95% of the herds they attacked. Death from rinderpest is rapid and nasty. Animals get feverish; their eyes and noses run. Their digestive tracts are inflamed from mouth to anus, and they die of diarrhea and protein loss.


Rinderpest is not irrelevant to humans as it has been blamed for speeding the fall of the Roman Empire, aiding the conquests of Genghis Khan and hindering those of Charlemagne, opening the way for the French and Russian Revolutions, and subjugating East Africa to colonization.


Any society dependent on cattle – or relatives like African zebu, Asian water buffaloes or Himalayan yaks – was vulnerable.


The long but little-known campaign to conquer rinderpest, begun in 1945, is a tribute to the skill and bravery of “big animal“ veterinarians, who fought the disease in remote and sometimes war-torn areas – across arid stretches of Africa bigger than Europe, in the Arabian desert and on the Mongolian steppes. “The role of veterinarians in protecting society is underappreciated,“ said Dr. Juan Lubroth, chief veterinary officer of the Food and Agriculture Organization of the United Nations, at whose headquarters Tuesday’s ceremony is being held. “We do more than just take care of fleas, bathe mascots and vaccinate Pooch.“


The victory is also proof that the conquest of smallpox was not just an unrepeatable fluke, a golden medical moment that will never be seen again. Since it was declared eradicated in 1980, several other diseases – like polio, Guinea worm, river blindness, elephantiasis, measles and iodine deficiency – have frustrated intensive, costly efforts to do the same to them. The eradication of rinderpest shows what can be done when field commanders combine scientific advances and new tactics.


In 1998, a longtime leader of the effort, Sir Gordon R. Scott of the Center for Tropical Veterinary Medicine at the University of Edinburgh, wrote an article saying he had reluctantly concluded that it would fail. “The major obstacle,“ he wrote, “is man’s inhumanity to man. Rinderpest thrives in a milieu of armed conflict and fleeing refugee masses. Until world peace is secured, the nays win the argument.“ He cited Somalia, Sudan, Sri Lanka, Yemen and Kurdish parts of Iraq and Turkey as areas where war drove animals and their owners over borders and life was risky for vaccinators.


Dr. Scott will not be in Rome for the ceremony; he died in 2004. Yet perhaps without realizing it, he did outlive rinderpest. The last known case was in a wild buffalo tested in Mount Meru National Park in Kenya in 2001.


The modern eradication campaign began in 1945, when the Food and Agriculture Organization was founded. But it became feasible only as vaccines improved. An 1893 version made from the bile of convalescent animals was replaced by vaccines grown in goats and rabbits and finally in laboratory cell lines; a heat-stable version was developed in the 1980s. Another breakthrough occurred in the 1990s when a rapid diagnostic test was developed that could be used next to a dying animal.


Until recently, it was assumed that rinderpest existed as long ago as 10,000 BCE, when cattle were domesticated in the Indus Valley in what is now Pakistan. It was blamed for an epidemic in Egypt in 3,000 BCE (the fifth plague of Moses fell on the pharaoh’s herds) and for the widespread die-offs that starved the Roman Empire in the face of fourth-century invaders. In the ninth century, it was the chief suspect in the “mortality upon the horned animals“ in the British Isles. Last year, however, Japanese geneticists studying rinderpest’s mutation patterns estimated that until about 1000 CE, it was virtually identical to measles – making it likely that pandemics that killed only animals before that time had other causes, like anthrax or possibly an ancestor virus from which both measles and rinderpest evolved.


Some experts now believe the disease arose in the gray oxen of the Central Asian steppes and was swept forward in the trains of baggage and beasts that followed the Mongol armies in the 1200s as they conquered Eurasia from China to Poland. (The Mongols are also suspected of importing bubonic plague from South Asia in flea-bitten rats hiding in grain sacks.)
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FDA Approves Arcapta Neohaler to Treat Chronic Obstructive Pulmonary Disease


Chronic obstructive pulmonary disease (COPD) is a serious lung disease that makes breathing difficult. Symptoms can include breathlessness, chronic cough and excessive phlegm. Cigarette smoking is the leading cause of COPD, and is the fourth leading cause of death in the United States, according to the Centers for Disease Control and Prevention.


The FDA has approved Arcapta Neohaler (indacaterol inhalation powder) for the long term, once-daily maintenance bronchodilator treatment of airflow obstruction in people with COPD including chronic bronchitis and/or emphysema. Arcapta Neohaler is a new molecular entity in the beta2-adrenergic agonist class that helps muscles around the airways of the lungs stay relaxed to prevent symptoms of COPD, such as wheezing and breathlessness. Arcapta Neohaler is not intended to treat asthma or sudden, severe symptoms of COPD.


The safety and efficacy of Arcapta Neohaler was demonstrated in six confirmatory clinical trials that included 5,474 patients ages 40 and older with a clinical diagnosis of COPD. Those treated had a smoking history of at least one pack a day for 10 years and exhibited moderate-to-severe decreases in lung function. Arcapta Neohaler carries a boxed warning that long-acting beta2 adrenergic agonists (LABA) increase the risk of asthma-related death. All LABA, including Arcapta Neohaler, should not be used in patients with asthma, unless used with a long-term asthma control medication.


The FDA approved Arcapta Neohaler with a medication guide that includes instructions for use and information about the potential risks of taking the drug. The most common side effects reported by those using Arcapta Neohaler include runny nose, cough, sore throat, headache and nausea.


Arcapta Neohaler is marketed by Novartis Pharmaceuticals Corp. of East Hanover, N.J.


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