Drug and Device Development for Orphan and Rare Diseases


As the number of drugs that can initially treat so called common diseases become generic and some even moving over-the-counter (OTC), and with new tools in molecular biology and drug screening for specific disease targets, there has become a focus on developing products for Orphan and Rare diseases. Recently, we were asked by a pharmaceutical company to share our strategic approaches to orphan and rare disease product development.  Here are some of the challenges and suggestions:


1. There is a small patient base for clinical trials

2. Multinational trials most likely be required

3. Efficacy endpoints may be difficult and may need to be negotiated

4. Patient organizations can be key to study recruitment

5. Good idea to use patient organizations in order to better understand the market

6. Make FDA a partner and invite Orphan Office personnel to any review division meeting


Target Health is pleased that our esteemed Regulatory Affairs group has obtained Orphan Drug Designations for our clients in the following indications:


1.   Alagille Syndrome

2.   Aplastic anemia

3.   Behcet’s disease

4.   Burn progression in hospitalized patients

5.   Caries prevention, head and neck cancer

6.   Cushing’s syndrome secondary to ectopic ACTH secretion

7.   Debridement in hospitalized patients with 3rd degree burns

8.   Edema-related effects in hospitalized patients with 3rd degree burns

9.   Fibrolamellar Carcinoma (FLC)

10. Gaucher Disease

11. Growth Hormone

12. Hereditary Angioedema

13. Invasive candidiasis

14. Multiple myeloma

15. Osteonecrosis of the jaw

16. Ovarian carcinoma

17. Rabies

18 Scleroderma


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


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchelor Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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A low dose of a chemical agent may trigger, from an organism, the opposite response to a very high 1) ___.


Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. It comes from Greek hormesis “rapid motion, eagerness“, itself from ancient Greek hormaein “to set in motion, impel, urge on“. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses. Hormetics is the term proposed for the study and science of hormesis. In toxicology, hormesis is a dose response phenomenon characterized by a low dose stimulation, high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response. Such environmental factors that would seem to produce positive responses have also been termed “eustress“.


The hormesis model of dose response is vigorously debated. The notion that hormesis is important for chemical risks regulations is not widely accepted. The biochemical mechanisms by which 2) ___ works are not well understood. It is conjectured that low doses of toxins or other stressors might activate the repair mechanisms of the body. The repair process fixes not only the damage caused by the toxin, but also other low-level damage that might have accumulated before without having triggered the repair mechanism. The term “hormesis“ was coined and used for the first time in a scientific paper by C.M. Southam and J. Ehrlich in 1943 in the journal: Phytopathology, volume 33, pp. 517-541. Recently, Edward Calabrese has revived the hormesis theory through his research on peppermint 3) ___. The evidence for and importance of hormesis in physiology and health was advanced by Mark Mattson, who elucidated cellular and molecular mechanisms by which the nervous system responds adaptively to mild bioenergetic stresses such as fasting and 4) ___. Cells respond to such challenges by increasing their production of neurotrophic factors, DNA repair proteins and antioxidant enzymes. Mattson also proposed that the reason that vegetables, fruits, tea and coffee can improve brain health is that they contain ?noxious’ chemicals that are produced by the plants to protect themselves from being eaten by insects and other organisms. Such phytochemicals trigger hormetic responses in brain 5) ___ which can improve brain function and may increase the resistance of neurons to injury and age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.


Individuals with low levels of physical activity are at risk for high levels of oxidative stress, as are individuals engaged in highly intensive exercise programs; however individuals engaged in moderately intensive, regular exercise experience lower levels of oxidative stress. High levels of oxidative stress have been linked by some with the increased incidence of a variety of diseases. It has been claimed that this relationship, characterized by positive effects at an intermediate dose of the stressor (exercise), is characteristic of hormesis. However, it is important to point out that there is evidence that the oxidative stress associated with intensive exercise may have long-term health benefits. This would imply that oxidative stress, itself, provides an example of hormesis (see section on Mitochondrial hormesis), but physical exercise does not. Alcohol is believed to be hormetic in preventing heart disease and stroke, although the benefits of light drinking may have been exaggerated.


In 2010, a paper published in the journal Environmental Toxicology & Chemistry showed that low doses of methylmercury, a potent neurotoxic pollutant, improved the hatching rate of mallard eggs. The author of the study, Gary Heinz, who led the study for the U.S. Geological Survey at the Patuxent Wildlife Research Center in Beltsville, Md., stated that other explanations are possible. For instance, it is possible that the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds.


One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging. Since the basic survival capacity of any biological system depends on its homeodynamic (homeostatic) ability, biogerontologists proposed that exposing cells and organisms to mild 6) ___ should result in the adaptive or hormetic response with various biological benefits. This idea has now gathered a large body of supportive evidence showing that repetitive mild stress exposure has anti-aging effects. Exercise is a paradigm for hormesis in this respect. Some of the mild stresses used for such studies on the application of hormesis in aging research and interventions are heat shock, irradiation, prooxidants, hypergravity and food restriction. Some other natural and synthetic molecules, such as celasterols from medicinal herbs and curcumin from the spice turmeric have also been found to have hormetic beneficial effects. Such compounds which bring about their health beneficial effects by stimulating or by modulating stress response pathways in cells have been termed “hormetins“. Hormetic interventions have also been proposed at the clinical level, with a variety of stimuli, challenges and stressful actions, that aim to increase the dynamical complexity of the biological systems in humans.


Mitochondria are sometimes described as “cellular power plants“ because they generate most of the cell’s supply of adenosine triphosphate (ATP), a source of chemical 7) ___. Reactive oxygen species (ROS) have been regarded as unwanted by-products of oxidative phosphorylation in mitochondria by the proponents of the free-radical theory of aging promoted by Denham Harman. The free-radical theory suggests that the use of compounds which inactivate ROS, such as antioxidants, would lead to a reduction of oxidative stress and thereby produce an increase in lifespan. ROS may perform an essential and potentially lifespan-promoting role as redox signaling molecules which transduce signals from the mitochondrial compartment to other compartments of the cell. Increased formation of ROS within the mitochondria may cause an adaptive reaction which produces increased stress resistance and a long-term reduction of oxidative stress. This kind of reverse effect of the response to ROS stress has been named mitochondrial hormesis or mitohormesis and is hypothesized to be responsible for the respective lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise. Hormesis may also be induced by endogenously produced, potentially toxic agents. For example, mitochondria consume oxygen which generates free radicals (reactive oxygen species) as a by-product. It was previously proposed on a hypothetical basis that such free radicals may induce an endogenous response culminating in increased defense capacity against exogenous radicals (and possibly other toxic compounds). Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends life span of a model organism. Most importantly, this extension of life span is prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects. Since mitochondrial activity was found to be increased in the previously mentioned studies, this effect cannot be explained by an excess of free radicals that might mark mitochondria for destruction by lysosomes, with the free radicals acting as a signal within the cell to indicate which mitochondria are ready for destruction, as proposed by Nick Lane.


Whether this concept applies to humans remains to be shown, although recent epidemiological findings support the process of mitohormesis, and even suggest that some antioxidant supplements may increase disease prevalence in humans. Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. In Taiwan recycled radio contaminated steel was inadvertently used in the construction of over 100 apartment buildings causing the long-term (10 years) exposure of 10,000 people. The average dose rate was 50 mSv/year and a subset of the population (1,000 people) received a total dose of over 4,000 mSv over ten years. In the widely used Linear No Threshold (LNT) theory used by regulatory bodies, the expected cancer deaths in this population would have been 302 with 70 caused by the extra ionizing radiation with the remainder caused by natural background radiation. However the observed cancer rate was quite low at 7 cancer deaths when 232 would be predicted by the LNT theory. Ionizing radiation hormesis appears to be at work. Described by Professor Charles L. Sanders, Korea Advanced Institute of Science and Technology.


Taiwan’s National Cancer Registry (first study)

Cancer risks in a population with prolonged low dose-rate gamma-radiation exposure in radiocontaminated buildings, 1983-2002. The results suggest that prolonged low dose-rate radiation exposure appeared to increase risks of developing certain cancers in specific subgroups of this population in Taiwan.


Taiwan’s National Cancer Registry (second study, two years later)

A significant radiation risk was observed for leukemia excluding chronic lymphocytic leukemia (HR(100mGy) 1.19). Breast cancer exhibited a marginally significant dose response (HR(100mGy) 1.12). The results further strengthen the association between protracted low-dose radiation and cancer risks, especially for breast cancers and leukemia, in this unique cohort population.


Chemical and Ionizing Radiation combined

No experiment can be performed in perfect isolation. Thick lead shielding around a chemical dose experiment to rule out the effects of ionizing radiation is built and rigorously controlled for in the laboratory, and certainly not the field. Likewise the same applies for ionizing radiation studies because by definition ionization radiation creates a cascade of new chemicals in the body which combine with whatever other environmental exposure is occurring during the measurement period. The resulting confusion in the low dose exposure field (radiation and chemical) arise from lack of consideration of this concept as described by Mothersill and Seymory. Mothersill and Seymory state “Most of the arguments about whether radiation is ?good for you’ or ?bad for you’ fail due to lack of consideration of the hierarchical level at which the effect occurs and because most of the arguments are anthropocentric. For example cell death is seen as a ?bad’ effect but if it removes a potentially carcinogenic cell from the population of cells in a tissue it could prevent cancer starting and could be seen as ‘good.“


Whether hormesis is common or important is controversial. At least one peer-reviewed article accepts the idea, claiming that over 600 substances show a U-shaped dose-response relationship. Calaberese and Baldwin wrote: “One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria.“ The idea that low dose effects may be (sometimes strikingly) different is accepted, but that the low dose effect is positive is questionable. The hypothesis of hormesis has generated the most controversy when applied to ionizing radiation. This theory is called radiation hormesis. For policy making purposes, the commonly accepted model of dose response in radiobiology is the linear no-threshold model (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and 8) ___dose. The United States National Research Council (part of the National Academy of Sciences), the National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress) and the United Nations Scientific Committee on the Effects of Ionizing Radiation (UNSCEAR) all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses. A report commissioned by the French National Academy concluded that there is sufficient evidence for hormesis occurring at low doses and that LNT should be reconsidered as the methodology used to estimate risks from low level sources of radiation, like deep geological repositories for nuclear waste. On the other hand, the United States-based National Council on Radiation Protection and Measurements states that there is insufficient evidence for radiation hormesis and that radiation protection authorities should continue to apply the LNT model for purposes of risk estimation.


Regulatory agencies such as the EPA 9) ___ ___ ___, the Food and Drug Administration (FDA), and the Nuclear Regulatory Commission(NRC) traditionally use a linear no-threshold model for carcinogens (including radiation). In the linear model, the assumption is that there is no dosage that has no risk of causing cancer. While this linear approach remains the default, with sufficient mechanistic evidence suggesting a non-linear dose-response, EPA allows for the derivation of a threshold dose (also known as reference dose) below which it is assumed that there is no risk for cancer. While proponents of hormesis argue that changing to a hormesis model would likely change exposure standards for these toxicants in air, water, food and soil, making the standards less strict, other scientists point out that low dose stimulation can have extremely adverse effects. Similarly, low doses of the phthalate, DEHP cause increased allergic responses to allergens, while higher doses have no effect. Wider use of the hormesis model would affect how scientists design and conduct studies and the selection of models that estimate risk. In all likelihood, recognizing that low dose effects can’t be predicted from high dose experiments would force a strengthening of public 10) ___ standards, not their weakening, as hormesis proponents would argue.


Hormesis remains largely unknown to the public. Any policy change ought to consider hormesis first as a public health issue. This would include the assessment of the public concern regarding exposure to small toxic doses. In addition, impact of hormesis policy change upon the management of industrial risks should be studied.


ANSWERS: 1) dose; 2) hormesis; 3) plants; 4) exercise; 5) cells; 6) stress; 7) energy; 8) radiation; 9) Environmental Protection Agency; 10) health


Medical Collaborators: Drs. Rudolf Arndt, Hugo Schulz, Edward Calabrese (1835 – Present)


Rudolf Gottfried Arndt MD (1835 – 1900) Public Domain: Wikipedia Commons


The Arndt-Schulz rule or Arndt-Schulz law is a claimed law concerning the effects of pharmaca or poisons in various concentrations. It states that: “For every substance, small doses stimulate, moderate doses inhibit, large doses kill.“ That is to say, highly diluted pharmaca or poisons enhance life processes, while strong concentrations may inhibit these processes and even terminate them. The rule was named after Rudolf Arndt MD and Dr. Hugo Paul Friedrich Schulz. The latter originally formulated it in 1888. However, the exceptions to the rule are so numerous that it cannot be considered a general law. For instance, many paralyzing substances have no effect in weak doses, and what constitutes a weak, medium or strong stimulus is highly individual, as pointed out by Arndt himself. The rule is no longer cited in modern pharmacology texts, having been supplanted by the theory of hormesis. What’s so interesting in the history of medicine, is how one generation hands knowledge to the next, and so on. Early studies of how living systems react to stimuli showed that physiological responses could be obtained with some regularity upon exposure to defined doses. Devising a mechanism for these observations proved difficult, and a significant amount of scientific effort was expended on the subject. The work of Arndt and Schultz, along with that of Ernst Heinrich Weber and Gustav Theodor Fechner, was called upon to provide some explanation for observed relationships between dose and response during the early days of pharmacology. However, other concepts such as Hormesis and Receptor Theory eventually supplanted such “laws” as a more complete and well-defined means of describing how chemicals and physiological systems interact.


Rudolf Gottfried Arndt MD (1835 – 1900) was a German psychiatrist from Bialken, district of Marienwerder. Arndt studied in Greifswald and Halle. As a student, his instructors included Felix von Niemeyer (1820-1871), Heinrich Adolf von Bardeleben (1819-1895), and Heinrich Philipp August Damerow (1798-1866). He was conferred doctor of medicine on 20 February 1860. From 1861 he maintained a private practice, and also participated in the Second Schleswig War (1864), Austro-Prussian War (1866) and Franco-Prussian War (1870-71). In 1867 he obtained his habilitation, subsequently serving as director of the Irren-Heil- und Pflege-Anstalt in Greifswald. In 1873 he became an associate professor of psychiatry at Greifswald. He died of angina pectoris.


Dr. Hugo Paul Friedrich Schulz (1853 – 1932) was a German pharmacologist from Wesel, Rhenish Prussia. He studied medicine in the universities of Heidelberg and Bonn, where he did scientific work in the physiological institute of Eduard Friedrich Wilhelm Pfluger (1829-1910). In 1877 he earned his doctorate, and afterwards worked in the pharmacological institute of Karl Binz (1832-1913) at Bonn. In 1883 he was appointed professor of pharmacology at the University of Greifswald. Schulz is known for his research of a phenomenon known as hormesis, showing that toxins can have the opposite effect in small doses than in large doses. This he demonstrated in experiments using chemical compounds on yeast cells. From his research came the “Arndt-Schulz rule”, a law concerning dosages in toxicology; named along with Dr. Rudolf Arndt. Schultz published a number of works in the field of pharmacology, including the well-regarded Pharmakotherapie (1898), a treatise that was included in Albert Eulenburg’s Handbuch der allgemeinen Therapie und der therapeutischen Methodik. Hugo Schulz first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician Rudolph Arndt, who studied animals given low doses of drugs, eventually giving rise to the Arndt-Schulz rule. Arndt’s advocacy of homeopathy contributed to the rule’s diminished credibility in the 1920s and 1930s. The term “hormesis” was coined and used for the first time in a scientific paper by C.M. Southam and J. Ehrlich in 1943 in the journal: Phytopathology.


Recently, Edward Calabrese has revived the hormesis theory through his research on peppermint plants. The evidence for and importance of hormesis in physiology and health was advanced by Mark Mattson, who elucidated cellular and molecular mechanisms by which the nervous system responds adaptively to mild bioenergetic stresses such as fasting and exercise. Cells respond to such challenges by increasing their production of neurotrophic factors, DNA repair proteins and antioxidant enzymes. Mattson also proposed that the reason that vegetables, fruits, tea and coffee can improve brain health is that they contain ?noxious’ chemicals that are produced by the plants to protect themselves from being eaten by insects and other organisms. Such phytochemicals trigger hormetic responses in brain cells which can improve brain function and may increase the resistance of neurons to injury and age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.



Dr. J. Edward Calabrese (1946-Present)


In 2009, Edward Calabrese, a professor in the School of Public Health and Health Sciences at the University of Massachusetts Amherst, was awarded the Marie Curie Prize for “outstanding achievements in research on the effects of low and very low doses of ionizing radiation on human health and biotopes.“ At an international conference in 2009, at UMass Amherst, Andre Maisseu, president of the Paris-based World Council of Nuclear Workers, announced that Calabrese is the council’s 2009 Curie Prize winner. Maisseu saluted Calabrese during the annual meeting of the International Dose-Response Society, of which Calabrese, an environmental toxicologist, is a founder and current director. Maisseu said the prize recognizes an entire body of research that has improved scientific knowledge of low-dose ionizing radiation effects on human beings and biological communities. A formal award ceremony was held in Rio de Janeiro, Brazil. Calabrese is the foremost expert in the world on a chemical dose-response phenomenon known as hormesis. Hormesis describes the fact that low doses of some chemicals are stimulative or promote growth but higher doses are toxic or inhibit growth, for example. The theory’s proponents suggest that low doses of minerals in multivitamin pills such as chromium and selenium, for example, boost health not because they provide required nutrients but because low doses of many toxins stimulate biological systems with beneficial mild stress, while higher doses are toxic. By contrast, the prevailing linear threshold model of toxin behavior says the absence of harmful effects below the threshold assumes there are no effects relevant to health. Calabrese and colleagues’ work on chemical hormesis has sparked vigorous scientific debate and a special section in the journal, Science, in 1989. Challenged to subject hormesis experiments to more rigorous statistical standards, Calabrese and his longtime UMass Amherst collaborator, Linda Baldwin, created a database of 21,000 papers. In 2003, they reported in a ground-breaking paper that the low-dose stimulatory effect of chemicals is typically about 40% enhanced growth, for example. Everyday implications of hormesis for risk assessment are significant. If chemical hormesis is a basic biological principle, Calabrese says, society is needlessly over-regulating the environment to protect against low exposures that are not dangerous, and we’re missing possible benefits. “The traditional threshold model is not very good at explaining or accounting for data that’s below the toxic threshold, and that’s where we live. But hormesis is quite good at that.“ Mark Mattson, chief of the Laboratory of Neurosciences at the National Institute on Aging, one of Calabrese’s past co-authors, agrees that the findings for which Calabrese is being recognized with the Marie Curie Prize “have major implications for public health policy regarding environmental ?toxins,’ for the design of biomedical studies, and for the discovery of new therapeutic interventions for a range of diseases.“ Mattson adds that the UMass Amherst research clearly reveals that “hormesis as a widespread feature of biological systems (cells, tissues, organisms and populations) that was previously either unrecognized or ignored by scientists in the fields of biology, biomedical research and toxicology. Calabrese and colleagues have shown that biological systems very often respond adaptively to low amounts of toxins and other stresses (radiation, heat, etc.) so as to increase their resistance to more severe stress and disease.“


Maisseu says it’s unfortunate that most research on ionizing radiation conducted since nuclear weapons were developed has focused on its harmfulness. This has prevented valuable work on possible beneficial low-dose effects, including adaption and repair mechanisms, he feels. Further, anti-hormesis prejudice has deprived the scientific community of fundamental knowledge which might be uncovered, and which is needed to pursue the fight against the different forms of cancer, Maisseu adds.


Calabrese grew up in Bridgewater, Massachusetts. He received his B.S. from Bridgewater State College in 1968 and his M.A. and Ph.D. from the University of Massachusetts Amherst in 1972 and 1973, respectively. Calabrese began working at the University of Massachusetts Amherst in 1976. Early in his career, Calabrese conducted research on carcinogens. However, he is best known for his research into, and championing of, hormesis, which he has called “the fundamental dose-response model”. In 2003, Calabrese told the Wall Street Journal that the view that there is a threshold of dose below which substances have no adverse effects, as has been stated in scientific textbooks, was “an error of historic proportions.” He credits his interest in hormesis to an experiment he performed as an undergraduate in 1966. In the experiment, his instructor told Calabrese and his classmates to treat a peppermint plant with a growth-inhibiting substance, Phosfon, but when they did so, the plant responded by growing approximately 40% taller and leafier than plants not treated with the substance, the opposite of what had been expected. The class later discovered that they had accidentally used a highly diluted form of Phosfon.


Prevention May Be Essential to Reduce Racial Disparities in Stroke


There has been a decline of almost 70% in stroke mortality rates overall in the past 50 years, making stroke the fifth leading cause of death in the United States. The reduction is attributed to improved stroke prevention due largely to better control of stroke risk factors including hypertension, diabetes, smoking cessation, and advances in post-stroke care.


According to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which looked at stroke incidence and mortality of nearly 30,000 participants over the age of 45 from an ethnically and demographically diverse sample of the U.S. population, blacks between the ages of 45 and 54 die of strokes at a rate that is three times greater than their white counterparts,. The findings suggest that the higher risk of death from strokes in blacks is due mostly to the higher incidence in this population, and not to worse outcomes following stroke. The REGARDS study was funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) and the results appear in the journal Stroke (2 June 2016).


However, despite the national trends showing declining stroke incidence and mortality, data from the REGARDS study confirm persistence of disparities between blacks and whites in the occurrence of stroke and mortality due to stroke. The difference in stroke incidence is believed to be due in part to differences in the prevalence of such potent risk factors as hypertension and diabetes, which are more common in blacks. However, the magnitude of the disparity in stroke mortality diminishes as the population ages, with no difference in the stroke mortality rate for those age 85 and older.


The study authors say that the key to reducing the disparity in stroke incidence and mortality is increased efforts in stroke prevention, particularly control of high blood pressure and diabetes, which affect blacks disproportionately. Interestingly, the prevalence of hypertension is higher in blacks, but its impact is even greater in the black population. An increase of 10mmHg in blood pressure is associated with an 8% increase in stroke risk among whites but a 24% increase in stroke risk in blacks.


Earlier this year, the NINDS launched a stroke prevention campaign called Mind Your Risks, designed to educate people aged 45-65 about the link between uncontrolled high blood pressure and the risk of developing dementia later in life. The campaign messaging launched in the Stroke Belt, an area of the southeastern U.S. where stroke incidence is high and REGARDS has focused its efforts.


Visual Impairment, Blindness Cases in U.S. Expected to Double By 2050


According to projections based on the most recent census data and from studies funded by the National Eye Institute, part of the National Institutes of Health, with the youngest of the baby boomers hitting 65 by 2029, the number of people with visual impairment or blindness in the United States is expected to double to more than 8 million by 2050. Another 16.4 million Americans are expected to have difficulty seeing due to correctable refractive errors such as myopia (nearsightedness) or hyperopia (farsightedness) that can be fixed with glasses, contacts or surgery. The findings, published online in JAMA Ophthalmology (19 May 2016), suggest that there is a need for increased screening and interventions to identify and address treatable causes of vision loss. The authors estimate that 1 million Americans were legally blind (20/200 vision or worse) in 2015. Having 20/200 vision means that for clear vision, you would have to be 20 feet or closer to an object that a person with normal vision could see from 200 feet away. Meanwhile, 3.2 million Americans had visual impairment in 2015 – meaning they had 20/40 or worse vision with best possible correction. Another 8.2 million had vision problems due to uncorrected refractive error.


Over the next 35 years, the authors project that the number of people with legal blindness will increase by 21% each decade to 2 million by 2050. Likewise, best-corrected visual impairment will grow by 25% each decade, doubling to 6.95 million. The greatest burden of visual impairment and blindness will affect those 80 years or older as advanced age is a key risk factor for diseases such as age-related macular degeneration and cataract.


The authors analyzed data on visual impairment and blindness from six large studies: the Beaver Dam Eye Study (Beaver Dam, Wisconsin), Baltimore Eye Survey and Salisbury Eye Evaluation Study (Maryland), the Chinese American Eye Study (Monterey Park, California), Los Angeles Latino Eye Study, and Proyecto VER (Nogales and Tucson, Arizona). They used the 2014 census and population growth projections to estimate the nationwide prevalence of vision impairment and blindness now and in 2050. According to the authors, in terms of absolute numbers, non-Hispanic whites, particularly white women, represent the largest proportion of people affected by visual impairment and blindness, and their numbers will nearly double. By 2050, 2.15 million non-Hispanic white women are expected to be visually impaired and 610,000 will be blind. African Americans currently account for the second highest proportion of visual impairment, but that is expected to shift to Hispanics around 2040, as the Hispanic population – and particularly the number of older Hispanics – continues to grow. Hispanics have particularly high rates of diabetes, which is associated with diabetic eye disease, a treatable cause of visual impairment. African Americans, meanwhile, are expected to continue to account for the second highest proportion of blindness. African Americans are at disproportionately high risk for developing glaucoma, a potentially blinding eye disease that typically causes the loss of peripheral, but not central vision, so people tend to not realize that they are losing their vision and do not seek treatment.


First Blood Test to Detect Gene Mutation Associated with Non-Small Cell Lung Cancer


Lung cancer is the leading cause of cancer-related death among men and women in the U.S. and, though more common in men, the number of deaths from lung cancer in women is increasing. According to the National Cancer Institute, an estimated 221,200 Americans will be diagnosed with lung cancer, and 158,040 will die from the disease this year. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC tumors may shed tumor DNA into a patient’s blood, thus making it possible to detect specific mutations in blood samples. Testing for tumor DNA using a blood sample is also called a “liquid biopsy.“


The FDA has approved the cobas EGFR Mutation Test v2, a blood-based companion diagnostic for the cancer drug Tarceva (erlotinib). This is the first FDA-approved, blood-based genetic test that can detect epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer patients. Such mutations are present in approximately 10-20% of NSCLCs.


With the cobas EGFR Mutation Test v2, the presence of specific NSCLC mutations [exon 19 deletion or exon 21 (L858R) substitution mutations] detected in patients’ blood samples aids in selecting those who may benefit from treatment with Tarceva. However, if such mutations are not detected in the blood, then a tumor biopsy should be performed to determine if the NSCLC mutations are present. Insofar as the test provides positive results, it may benefit patients who may be too ill or are otherwise unable to provide a tumor specimen for EGFR testing. The efficacy of the cobas EGFR Mutation Test v2 using blood samples was determined by using the test to identify the EGFR mutation status in patients enrolled into a clinical trial whose tumor biopsies were previously confirmed positive for the EGFR exon 19 deletion or L858R mutations as determined by the cobas EGFR Mutation Test v1.


The FDA approved Tarceva in 2004 to treat patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen, and in 2013, the FDA approved it for  the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors having EGFR exon 19 deletions or L858R substitution mutations as detected by an FDA-approved test. The most common side effects of Tarceva are rash, diarrhea, anorexia, fatigue, difficulty breathing (dyspnea), cough, nausea and vomiting. Tarceva is not recommended for use in combination with platinum-based chemotherapy and the drug has not been evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or L858R substitution mutations.


The cobas EGFR Mutation Test v2 is manufactured by Roche Molecular Systems in Pleasanton, California. Tarceva is manufactured by Astellas Pharma Technologies, Inc. of Norman, Oklahoma and distributed by Genentech Inc., of South San Francisco, California.


Green Bean, Arugula, and Walnut Salad


We’re going to be dining on a lot more salads, this summer. Although we have air conditioning in our kitchen, with the oven on, it’s still hard to keep cool. Salads are healthy, easy and cool. Serve along with pita, hummus, and a chilled Pouilley-Fuisse. Mangoes are in season now. Put some ripe mango slices in the fridge and serve this sweet juicy fruit for dessert, once it’s gotten nicely chilled.




3/4 to 1 pound green and/or yellow string beans (or both), trimmed

3 Tablespoons extra-virgin olive oil

Pinch Kosher salt

Pinch black pepper

Pinch chili flakes

2 cloves garlic, juiced

2 cups baby or regular arugula

1/2 cup walnuts, toasted and coarsely chopped

1 teaspoon finely grated lemon zest

1/2 or 1 onion, well chopped

1/2 cup freshly grated parmesan cheese, for garnish




1. In a large bowl, mix the 3 Tablespoons of olive oil, chopped onion and garlic. Add the salt, pepper, chili flakes and stir.

2. To the bowl, add the beans and toss them with the contents of the bowl. Let the beans marinate for 10 minutes or so.

3. In a wok or frying pan, stir-fry the beans over medium-high heat, along with the olive oil marinade, for 3-4 minutes or until tender but still crisp. Then remove from heat.

4. Let the beans cool for a few minutes.

5. With a spatula, scrape the contents (beans and marinade) of the frying pan, into a salad bowl.

6. To the salad bowl, add the arugula, walnuts, lemon zest, (optional) more salt, and/ or pepper to your taste. Toss until the arugula is wilted, 2 to 3 minutes.

7. Sprinkle the freshly grated Parmesan cheese over the salad, and serve.



We’re still trying out various Pouilly-Fuisse and always come back to our favorite to date, the Louis Jadot. This smooth icy white, went very well with the green bean salad. ©Joyce Hays, Target Health Inc.


My brother-in-law, from Germany is staying with us and having a great time in the Big Apple, where he grew up and attended lower school, high school, then went away to MIT, where he got a PhD in engineering. In Germany, he is Herr Doctor Professor.


Have a great week, everyone!




From Our Table to Yours !


Bon Appetit!