Warren Pearlson Vacationed in Iceland and Wow!

 

Warren Pearlson, our esteemed Director of Business Development, visited Iceland recently and came back with some fantastic photos the he and a colleague took. Fortunately for Target Health, Dr. Mitchel will be presenting on the topic of EHR/EDC integration in Iceland in a few weeks at the Spring meeting of the eClinical Forum. Hope to see you there.

 

Iceland: Seljalandsfoss Waterfall (photo by Warren Pearlson

 

Iceland – Northern Lights (Photo by Tu Duong

 

 

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. Mitchel. 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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Can Genius be Linked to Uterine Exposure of Higher Levels of Hormones?

Formal portrait of Albert Einstein taken in 1935 at Princeton. The photo was published a few times, the earliest one found was in a newspaper in 1955 (A.P. Wirephoto). None of the sources indicate any copyright or other details. The original uncropped photo is inscribed to the photographer, Sophie Delar. A copyright search found nothing related was renewed for the period required based on the earliest known publication date of 1955. This is a Public Domain photo; Wikipedia Commons

 

A longstanding debate as to whether genius is a byproduct of good 1) ____ or good environment has an upstart challenger that may take the discussion in an entirely new direction. University of Alberta researcher Marty Mrazik says being bright may be due to an excess level of a natural hormone. Mrazik, a professor in the Faculty of Education’s educational psychology department, and a colleague from Rider University in the U.S., have published a paper in Roeper Review linking giftedness (having an IQ score of 130 or higher) to prenatal exposure of higher levels of testosterone. Mrazik hypothesizes that, in the same way that physical and cognitive deficiencies can be developed in 2) ___, so, too, could similar exposure to this naturally occurring chemical result in giftedness. “There seems to be some evidence that excessive prenatal exposure to 3) ___ facilitates increased connections in the brain, especially in the right prefrontal cortex,“ said Mrazik. “That’s why we see some intellectually gifted people with distinct personality characteristics that you don’t see in the normal population.“ Mrazik’s notion came from observations made during clinical assessments of gifted individuals. He and his fellow researcher observed some specific traits among the subjects. This finding stimulated a conversation on the role of early development in setting the foundation for giftedness. “It gave us some interesting ideas that there could be more to this notion of genius being predetermined from a biological perspective than maybe people gave it credit for,“ said Mrazik. “It seemed that the bulk of evidence from new technologies (such as Functional 4) ___ scans) tell us that there’s a little bit more going on than a genetic versus environmental interaction.“

 

Based on their observations, the researchers made the hypothesis that this hormonal “glitch“ in the in-utero neurobiological development means that gifted children are born with an affinity for certain areas such as the arts, math or science. Mrazik cautions that more research is needed to determine what exact processes may cause the development of the gifted 5) ___. He notes that more is known about what derails the brain’s normal development, thus charting what makes gifted people gifted is very much a new frontier. Mrazik hopes that devices such as the Functional MRI scanner will give them a deeper understanding of the role of neurobiology in the development of the gifted brain. “It’s really hard to say what does put the brain in a pathway where it’s going to be much more precocious,“ he said. “The next steps in this research lay in finding out what exact 6) ___ causes this atypical brain development.“  The group benefits of intelligence (including language, the ability to communicate between individuals, the ability to teach others, and other cooperative aspects) have apparent utility in increasing the survival potential of a group.

 

Higher cognitive functioning develops better in an environment with adequate nutrition. Diets deficient in iron, zinc, protein, iodine, B vitamins, omega 3 fatty acids, magnesium and other nutrients can result in lower intelligence either in the 7) ___ during pregnancy or in the child during development. While these inputs did not have an effect on the evolution of intelligence they do govern its expression. A higher intelligence could be a signal that an individual comes from and lives in a physical and social environment where nutrition levels are high, whereas a lower intelligence could imply a child, its mother, or both, come from a physical and social environment where nutritional levels are low. 8) ___ factors, especially meat and shellfish consumption, contribute to elevations of dopaminergic activity in the brain, which may have been responsible for the evolution of human intelligence since dopamine is crucial to working memory, cognitive shifting, abstract, distant concepts, and other hallmarks of advanced intelligence. There is no universally accepted definition of intelligence. One definition is “the ability to reason, plan, solve problems, think abstractly, comprehend ideas and language, and learn.“ The evolution of hominid intelligence can be traced over its course for the past 10 million years, and attributed to specific environmental challenges. It is a misunderstanding of evolutionary theory, however, to see this as a necessary process, and an even greater misunderstanding to see it as one directed to a particular outcome. There are primate species which have not 9) ___ any greater degree of intelligence than they had 10 million years ago: this is because their particular environment has not demanded this particular adaptation of them. Intelligence as an adaptation to the challenge of natural selection is no better or worse than any other adaptation, such as the speed of the cheetah or the venomous bite of the cobra. Human intelligence appears to be, however, the only adaptation which has allowed a species to establish complete domination over the rest of the natural world. Whether our species has yet acquired sufficient 10) ___ to manage this responsibility is a matter for debate. Source: University of Alberta; Martin Mrazik, Stefan Dombrowski. The Neurobiological Foundations of Giftedness. Roeper Review, 2010; 32 (4): 224 DOI: 10.1080/02783193.2010.508154; Wikipedia; ScienceDaily.com

 

ANSWERS: 1) genes; 2) utero; 3) testosterone; 4) MRI; 5) brain; 6) stimuli; 7) mother; 8) Nutritional; 9) evolved; 10) intelligence

 

Fuller Albright MD (1900-1969): Founder of Modern Endocrinology

(A) A photo of Fuller Albright as a young physician outside of Massachusetts General Hospital. (B) A photo probably from the late 1940s showing Albright with advanced Parkinson’s disease. Source: Clinical Journal of the American Society of Nephrology

 

 

Fuller Albright’s remarkable book Parathyroid Glands and Metabolic Bone Disease, a landmark publication in 1948, summarized Albright’s many contributions to mineral metabolism during the previous two decades.

 

Fuller Albright was born in Buffalo, New York, on January 12, 1900. His father was a wealthy industrialist and philanthropist. The major art museum in Buffalo is known today as the Albright-Knox Art Gallery. Albright attended the Nichols School in Buffalo, which was founded by his father. He not only excelled academically, but also was captain of the football team. During his childhood, the Albright family made frequent visits to Wilmurt Lake in the Adirondacks, where he became an avid fly fisherman and developed woodsman’s skills. During his academic years in Boston, Albright would spend summer vacations at Wilmurt Lake with his family. It was at Wilmurt Lake where he directed that his ashes be scattered after his death.

 

Fuller Albright attended Harvard College, but after only 18 months, he falsified his age and enlisted in the Army after America’s entry into World War I. It was also the time of the great influenza pandemic, which has been postulated to be a cause of Parkinson’s disease many years after recovery from influenza. Albright was to develop Parkinson’s disease in his mid-30s, and it was to progress relentlessly during the next two decades of his life. In 1921, Albright entered Harvard Medical School, where he excelled and was elected to Alpha Omega Alpha. On graduation, he did an internship and residency in Medicine at Massachusetts General Hospital. There he met Read Ellsworth, who became a close friend and collaborator. Both initially were mentored by Dr. Joseph Aub, a clinical scientist in endocrinology and metabolism. Albright and Ellsworth continued their research collaboration in mineral metabolism until the latter’s premature death from tuberculosis in 1937. Perhaps the most critical year in Albright’s training was that of 1928-1929, when he went to Vienna to study with Dr. Jacob Erdheim, a brilliant pathologist who in 1906 had established the relation between the parathyroid glands and calcium metabolism by showing that calcium is not deposited into growing teeth in the absence of parathyroid glands. Also, it was Erdheim who had first described compensatory hyperplasia of the parathyroid gland associated with osteomalacia. Albright often would later say of Erdheim that quite simply he knew more about human disease than any other living man and referred to him as the greatest of living pathologists.

 

Albright returned to Massachusetts General Hospital in 1929. There he would begin his long, productive career in clinical research, much of which emanated from the then recently established Ward 4, which was a 10-bed research unit where patients and healthy subjects could be intensively studied. On Ward 4, special diets could be prepared, biochemical measurements could be performed, and meticulous collections of urinary and fecal output could be obtained. The latter, when combined with measurement of dietary intake, constituted the balance study that became a major investigative tool for Albright. Albright married Claire Birge in 1932, and they had two sons. She became a major source of support for him as his Parkinson’s disease progressed. By the early 1940s, Albright could no longer write, and by the mid-1940s his speech had become difficult to understand. In an article written in 1946 for the twenty-fifth anniversary of his medical school class enrollment, Albright wrote, I have had the interesting experience of observing the course of Parkinson’s syndrome on myself. It disturbs every movement and gives a certain rigidity that makes small talk look strained. The condition does have its compensations: one is not taken away from interesting work to be sent to Burma, one avoids all forms of deadly committee meetings, etc.

 

The patients for Albright’s studies came from his three weekly clinics: the Ovarian Dysfunction Clinic on Tuesdays, the Stone Clinic on Wednesdays (also known as the Quarry), and the general Endocrine Clinic on Saturdays. Even when not involved in a study, every patient would return to the respective clinic at least once per year. If a patient failed to return, a visiting nurse would be sent to find the patient. In 1939, Anne Forbes became his physician administrative chief and collaborator. She assumed much of the administrative and organizational burden for his studies. In 1942, Albright became an Associate Professor of Medicine at Harvard, but not wanting any administrative burden, he refused to become a full professor. In the 1950s, the medical student taking an elective with Albright would be given the family’s second car with the assigned task of transporting Albright to the hospital and looking after him at work. These students included such future well-known investigators as Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher, and Stan Franklin. By the early 1950s, Anne Forbes has said that Albright was convinced that the Parkinson’s disease was affecting his intellect. In 1952, a noted New York neurosurgeon, Dr. Irving Cooper, had reported that Parkinson’s patients could be improved by a surgical procedure, chemopallidectomy, in which small amounts of alcohol were injected into the areas of the brain responsible for the tremor and rigidity. Despite expert advice to the contrary from his Harvard colleagues and even from Dr. Cooper, Albright was determined to undergo the procedure because of his inability to speak comprehensively and a severely impaired capacity to dress, eat, and write. The surgery was performed in June 1956. After the intervention on the right side, a marked improvement in symptoms was observed. However, the operation on the left side was followed by a major cerebral hemorrhage, from which Albright would never recover. For the next 13 years, he lived in a vegetative state. In a ceremony in 1961, Fuller Albright was officially retired from the Faculty of Medicine at Harvard as Professor, Emeritus. Fuller Albright died on December 8, 1969.

 

Albright, the Clinical Investigator Par Excellence

Mineral Metabolism

 

Albright’s work on serum calcium and phosphorus regulation, primary hyperparathyroidism, and the renal excretion of calcium and phosphorus became the foundation of our understanding of mineral metabolism. His description and study of vitamin D resistant rickets became the basis for the study of renal phosphate transport. Starting in the late 1920s and continuing through the mid-1930s, Albright’s primary focus was studying how differences in dietary calcium and phosphate affected calcium and phosphate balance in healthy subjects and in patients with primary hyperparathyroidism and with hypoparathyroidism. Healthy subjects and patients with hypoparathyroidism were studied with the newly available parathyroid extract (PTE). Because the balance studies were remarkably consistent, only a small number of subjects needed to be studied to provide the results, which remain true today. Albright was the first to provide a comprehensive framework for understanding the regulation of calcium and phosphate in normal subjects and in patients with parathyroid disorders. The report of the seventeen patients operated on for primary hyperparathyroidism published by Albright in 1934 was the largest series until then. The number of patients in that series diagnosed with primary hyperparathyroidism had been greatly expanded when Albright had the insight to measure serum calcium values in patients with kidney stones. At diagnosis, primary hyperparathyroidism was a much more severe disease than now. The average preoperative serum calcium value was 13.9 mg/dl and the average weight of the removed parathyroid adenoma was >11 g. Parathyroidectomy was an entirely new operation for surgeons and required intensive training with autopsy material. Two remarkable findings characterized the first 17 parathyroidectomies. Two patients had ectopic locations of their parathyroid adenoma, one of whom was the famous Captain Martell, who required seven operations before the ectopic gland was discovered. Cases 15 through 17 had parathyroid hyperplasia and not an adenoma as the cause of the hyperparathyroidism.

 

In a discussion of a case of renal osteitis fibrosa cystica in 1937, Albright suggested that the reason for parathyroid hyperplasia was the phosphate retention in renal failure. He added that in the absence of parathyroid hyperplasia, there would be greater phosphate retention and a further lowering of the blood calcium. Also in 1937, Albright described a patient with rickets that was resistant to treatment with vitamin D. This patient was intensively studied and clearly differentiated from patients with rickets from vitamin D deficiency. The name given to the disorder by Albright, vitamin D resistant rickets, was in use for many years until it was renamed X-linked hypophosphatemic rickets. This disorder also became the basis for the study of abnormal renal phosphate transport. Finally, in 1937, Albright reported five cases of another unusual bone disorder, polyostotic fibrous dysplasia, which was associated with hyperpigmented lesions of the skin and endocrine dysfunction. Today the disorder is called the McCune-Albright syndrome. In 1941 at a clinicopathological conference, Albright asked why a patient presenting with a destructive bone lesion in the right ilium from renal cell carcinoma should have hypercalcemia and hypophosphatemia. A neck exploration for presumed hyperparathyroidism was performed, but no abnormality was found. Albright questioned whether the tumor might be responsible for ectopic production of parathyroid hormone. In the same year, Albright described a case of hypercalcemia in a 14 year old boy who fractured his femur through a bone cyst in an athletic accident. After casting and bed rest, the patient developed severe hypercalcemia. Because of the hypercalcemia and the presence of a bone cyst, a parathyroid exploration was performed but no abnormalities were seen. Albright was the first to recognize that immobilization could cause hypercalcemia. A similar report of hypercalcemia following immobilization in Paget’s disease was published in 1944. In 1942 Albright described pseudohypoparathyroidism. In this disorder, the important concept of end-organ resistance to a hormone (PTH) was first shown. Albright chose the name, Seabright-Bantam, because this male fowl has feathers similar to the female despite having normal functioning testes. Other highlights of Albright’s investigation into disorders of calcium and phosphorus included his publication in 1946 of osteomalacia, rickets, and nephrocalcinosis in association with renal tubular acidosis. In 1948, Albright reported the occurrence of band keratopathy of the cornea in 19 patients with diverse causes of hypercalcemia. In 1949, Albright reported several patients with the chronic form of the milk alkali syndrome. These patients had chronic renal failure, hypercalcemia, soft tissue calcium deposits, band keratopathy, and nephrocalcinosis from the chronic ingestion of calcium- containing antacids. In 1953, Albright reported 35 patients with idiopathic hypercalciuria associated with kidney stones, hypophosphatemia, and normal serum calcium values.

 

Pituitary, Adrenal and Gonadal Axis

 

While much of Albright’s first decade as a clinical investigator was devoted to studies of mineral metabolism and the diagnosis and treatment of primary hyperparathyroidism, studies of adrenal and gonadal disorders assumed greater importance in the 1940s. His elegant studies of the Cushing syndrome were highlighted in three papers published in 1941. These studies were previously reviewed in detail by Schwartz, but will be summarized here. In the first paper, Albright showed that glucose intolerance and resistance to insulin were characteristic findings of the Cushing syndrome. In the second paper, Albright showed that besides cortisol excess, the Cushing syndrome was also characterized by androgen excess. The 24 h urine excretion of 17-ketosteroids was used as a measure of androgens. Because urinary excretion of 17-ketosteroids was greater in men than in women (14 versus 9 mg), Albright reasoned that 9 mg was the daily androgen output from the adrenals. His hypothesis was confirmed by studying patients with Addison’s disease in whom the excretion of 17-ketosteroids was 5 mg in men and absent in women. Albright also showed that adrenal excess was the cause of all forms of the Cushing syndrome whether of primary adrenal origin or due to a pituitary adenoma. In the third paper, Albright treated patients with the Cushing syndrome with testosterone, asking the question whether such treatment would counteract the catabolic effects seen in this syndrome. The testosterone treatment resulted in a strikingly positive nitrogen balance, a gain in weight and strength, thickening of the skin, and a reduction in abdominal protuberance. However, because of the availability of adrenal surgery, the use of testosterone treatment never gained widespread use. Albright also performed several studies that helped elucidate the etiology of congenital adrenal hyperplasia, which was called the adrenogenital syndrome by Albright. The paper in which Klinefelter’s syndrome was first described was published in 1942. The story is that the syndrome was discovered because the Draft Board in Boston sent recruits with prominent breasts to Albright’s clinic where small testes were noted and biopsied, and follicle stimulating hormone (FSH) levels were measured and found to be increased. Also in 1942, Albright further defined Turner’s syndrome by showing it was not of pituitary origin, but rather due to primary ovarian failure in which elevated FSH values were present. Finally, it has been stated that Albright first described or contributed to the description of 14 major clinical syndromes.

 

Albright, Through the Eyes of Coworkers and his Presidential Address

 

Fuller Albright’s 1944 presidential address to the annual meeting of the American Society for Clinical Investigation, Some of the Do’s and Do-Not’s in Clinical Investigation, is important because in it he provides his personal road map for performing clinical and laboratory investigation. In his introduction, Albright states that the clinical investigator must avoid the danger that he or she, as the clinician, be swamped with patients and the equal danger that he or she, as an investigator, be segregated entirely from the bedside. Even though his advice to the investigator is shown as a road map leading to the Castle Of Success (Figure 1), Albright refuses to define success, except to say that it is more than academic recognition and self-satisfaction. The reader is strongly encouraged to read this remarkable address in which Albright provides the investigator with the gift of his wisdom. It is readily available in the archives of the Journal of Clinical Investigation.

 

Figure 1.: A schematic diagram of the Do’s and Do Not’s Leading to the Castle of Success. The diagram is from Albright’s presidential address to the 36thAnnual Meeting of the American Society for Clinical Investigation in 1944 in which advice was given to the clinical investigator.

 

The following colleagues’ appreciations from several physicians who worked with Albright, are cited: William Parson worked with Albright during the late 1930s and early 1940s and later became Chairman of Medicine at the University of Virginia. In 1995, Parson wrote of Albright’s creative genius and his engaging personal qualities of unpretentiousness, good humor and wit. He went on to say that Albright was the first to conceptualize two important concepts in Endocrinology, end-organ unresponsiveness to a hormone (pseudohypoparathyroidism) and hormone or hormone-like production by nonendocrine tissue (ectopic production). Parson continued, Albright never had an interest in bench work. He felt that he could always get someone to make the measurements. The trick was to know what to measure and how to interpret the results. It was fun and exciting to work with a genius whose talent was to see relationships between facts universally considered to be unrelated. During the study of the first patient with pseudohypoparathyroidism, Parson relates that Albright was intrigued by her unusual appearance and the failure of a good batch of parathyroid extract to work. Albright refused to move on, even though others wanted to substitute dihydrotachysterol treatment and drop the project. Frederic Bartter worked with Albright in the 1940s and later became Chief of Clinical Endocrinology at the NIH. After Albright’s death in 1969, Bartter wrote a homage to Albright in which he said of Albright that clinical experiments of nature were the substrate for almost all of the inspired and systematic investigation that constituted his enormous contribution. He continued that Albright’s real delight was in formulating a theory to explain the unknown elements that remained, and Albright had no use for the “learned tradition. Rather, Albright believed that progress could only be made by formulation of a precise theory and challenge of that theory. Finally, Gilbert Gordan, who did a fellowship with Albright in the late 1940s and later became Professor of Medicine at the University of California at San Francisco, wrote in 1981 that “when Albright was working on a problem he virtually lived it every day, and he would discuss his ideas with anyone who was interested. Albright was completely self-assured and never concerned that someone less gifted would steal his ideas. Gordan continued, For every problem there were what Albright called ?measuring sticks’ – either chemical or bioassay, or the weight of axillary hair, or displacement of water by acromegalic hands and feet, or measurement of height to determine the growth rate, etc. One of his ?Do’s’ was – do measure something. In his presidential address in 1944, Albright stated that Oliver Wendell Holmes divides intellects into one-story, two-story, and three-story. The latter idealize, imagine, predict; their best illumination comes from above through the skylight. His coworkers and peers appreciated that Albright received illumination through the skylight. Albright also had the capacity to refute accepted dogma and to formulate a working hypothesis of clinical disorders, which he would continuously challenge. Finally, as in the recognition of hormone failure in pseudohypoparathyroidism, Albright understood that when all other possible explanations are eliminated, the remaining explanation no matter how improbable must be true.

 

Gabe Mirkin MD, who specializes in sports medicine, did an internship at Massachusetts General when Fuller Albright occupied a private room, where he lay in a coma. Mirkin saw Albright at this time and like many physicians held Albright in the highest respect; a role model for all physicians. Mirkin and Fuller Albright’s son, Birge Fuller, were in the same class at Harvard. The following was written by Gabe Mirkin MD:

 

Fuller Albright discovered more new diseases and their causes than any other person in the history of medicine. He was the founder of modern endocrinology, the study of how glands work in your body. In his time, many chairmen of the departments of endocrinology in North American medical schools were men who had studied under him. He was one of the most brilliant and innovative doctors who ever lived. He was also an outstanding athlete who captained his high school football team and was one of the better senior tennis players in New England even though he spent most of his time in his lab at the Mass General Hospital. His life of accomplishment ended with an experimental treatment for Parkinson’s disease that left him in a coma for his last thirteen years.

 

Albright left Harvard after 18 months to enlist in the Army to fight in World War I. During the 1918 pandemic, he was infected with influenza which can cause Parkinson’s disease many years later. In 1921, he went to Harvard Medical School and finished at the top of his class. He took his internship and residency at the Massachusetts General Hospital. In 1928, he went to Vienna to study with Dr. Jacob Erdheim. In 1929, Albright returned to the Massachusetts General Hospital and established the world-famous Ward 4, a 10-bed research unit where over the next 15 years, he described many new diseases and was one of the most loved and followed teachers at Harvard Medical School. His students remember this wonderful teacher always dressed in an old tweed jacket, baggy trousers, and a bright-colored bow tie. Married to Claire Birge in 1932, they had two sons. One of his sons, Birge Albright was named after his wife’s maiden name, just as his father had named him Fuller after his mother’s maiden name. Birge was a classmate of mine (of Gabe Mirkin) at Harvard.

 

List of Firsts

Try to imagine how one person could make so many breakthroughs in our understanding of how the human body functions. Fuller Albright was the first person to:

–        describe the functions of the parathyroid gland,

–        associate an overactive parathyroid gland with kidney stones,

–        explain the modern diagnosis and treatment of kidney stones,

–        develop a method for measuring sex hormones in the urine,

–        explain what causes women to have irregular periods or even stop menstruating,

–        describe various male sex hormone deficiencies,

–        show how certain types of diarrhea cause vitamin deficiencies,

–        describe renal tubular acidosis and its treatment,

–        show how menopause weakens bones,

–        use estrogen to prevent a woman from releasing an egg, setting the stage for the first birth control pills,

–        show that progesterone can prevent uterine cancer in women who lack that hormone,

–        demonstrate the cause of overactive adrenal glands (Cushing’s syndrome),

–        warn how dangerous adrenal steroids can be.

–        He was the first to describe or characterize the following syndromes, tests and treatments:

Forbes-Albright syndrome (breast milk and absence of periods caused by a brain tumor)

Jaffe-Lichtenstein syndrome (painful, swollen deformity in one bone that fractures easily)

Klinefelter’s syndrome (a genetic disorder that causes males to be tall and have small testes with low testosterone, delayed puberty, breast enlargement, reduced facial and body hair, and infertility)

Lightwood-Albright syndrome (acidic blood caused by a kidney defect)

Martin-Albright syndrome (inability to respond to the parathyroid hormone, short stature, short fingers, round face, and mental retardation)

McCune-Albright syndrome (a genetic disease characterized by deformed, easily broken bones, premature sexual maturity, enlargement of the adrenal glands and the overproduction of cortisol)

Morgagni-Turner-Albright syndrome (partial or complete absence of one X-chromosome, ovaries fail to respond to pituitary hormones so they do not produce adequate estrogen, short stature, absence of secondary sexual characteristics, webbing of the neck and inconsistent heart problems)

Ahumada-del Castillo syndrome (women with breast milk not associated with nursing and the absence of menstrual periods due to not releasing an egg each month)

Albright’s anemia (anemia in advanced overactive parathyroidism)

Albright’s prophecy (in 1945 Albright wrote that preventing ovulation prevents pregnancy and explored the possibility of birth control by hormone therapy)

Albright’s syndrome II (Albright hereditary osteodystrophy in which a person has normal levels of parathyroid hormone, but cannot respond to that hormone)

Albright’s test (a kidney function test to see how much acid kidneys can clear)

Albright-Butler-Bloomberg disease (a metabolic syndrome marked by dwarfism and other severe developmental anomalies)

Albright-Hadorn syndrome (softening and bending of bones associated with abnormally low concentrations of blood potassium levels)

Chiari-Frommel syndrome (over-production of breast milk and absence of periods for more than six months after giving birth.)

 

Progression of Parkinson’s Disease

 

In 1937, at age 37, when he was one of the most productive, respected and well known physicians in the world, Albright noticed that his hands started to shake and would become even more shaky when he used them. For example, when he raised a glass of water to his mouth to drink, the shaking would increase as the glass came closer to his mouth. He noticed a progressive slurring of his words as he talked. This former athlete had to walk more slowly because the faster he walked, the more he would lose control of his legs and start to fall. These symptoms progressed very slowly over the next 20 years. He appeared to accept the challenges and did everything he could to overcome his increasing disability. He forced himself to work even harder and discovered many new syndromes and basic mechanisms of how hormones work during this period.

 

By his early forties, he could not write, and by his mid-forties, he could no longer speak clearly. In his fifties he could not drive a car, so the medical students assigned to him were given the family’s second car to drive him to and from the hospital. They also wrote notes for him at work. Many of these students became famous researchers themselves: Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher and Stan Franklin.

 

Experimental Treatment Disaster

 

In 1952 Irving Cooper, a New York University neurosurgeon, reported that he could reduce the symptoms of Parkinson’s disease by injecting small amounts of alcohol into a part of the brain called the globus pallidus. Because Albright knew that he was losing his ability to reason in addition to losing his ability to eat, dress, write or speak, he went ahead and had the treatment in June 1956. Virtually all of his Harvard colleagues and even Dr. Cooper himself had discouraged him from having the procedure done. After his right side was injected, he noticed less rigidity and better control. He was able to walk comfortably and use his left hand more effectively. He was so encouraged that he had his left side injected, but this procedure resulted in extensive bleeding into his brain. He never recovered and was unable ever to speak again. He spent the next 13 years in a coma, living in a private room at the Massachusetts General Hospital. He was unable to respond to anyone. He died on December 8, 1969.

 

What is Parkinson’s Disease?

 

When you decide to move a muscle, your brain sends electrical messages between nerves and muscle fibers. When an electrical message reaches the end of a nerve, it releases chemicals called neurotransmitters that travel to the next nerve or muscle fiber to continue the message. Your fine muscle movements are controlled by a neurotransmitter called dopamine that sends messages by passing primarily between two brain areas called the substantia nigra and the corpus striatum.

 

Most of the movement-related symptoms of Parkinson’s disease are caused by a lack of dopamine due to loss of dopamine-producing cells in the substantia nigra. The lower the level of dopamine, the less control you have of your muscles.

 

We do not know the cause of the loss of dopamine-producing cells. A small percentage of Parkinson patients have other members of their family with the same disease. However, more than 90 percent of people with Parkinson’s disease do not have any family history of that disease. Thus most cases of Parkinson’s disease appear to be caused by something in the environment, not by a genetic condition.

 

Risk factors for Parkinson’s disease include:

 

–        Toxins: Exposure to manganese, carbon monoxide, cyanide and other chemicals. Some pesticides and herbicides inhibit dopamine production. Farmers are at increased risk for Parkinson’s disease.

–        Declining estrogen levels: Post-menopausal women and women who have had their ovaries removed are at increased risk.

–        Viruses: For example, people who survived exposure to influenza in the 1918 flu pandemic were at increased risk for Parkinson’s disease many years later.

–        Structural problems: Strokes and fluid buildup in the brain may increase risk of Parkinson’s disease.

–        Low levels of folic acid: A few studies suggest that folic acid deficiency may cause some cases of Parkinson’s disease.

–        Head trauma: Any damage to the head, neck, or upper spine increases risk. Boxer Muhammad Ali developed Parkinson’s disease very early in life, in his forties.

–        Advancing age: Parkinson’s disease affects one percent of people over 60 years of age. Risk increases with age.

–        Gender: Men are more likely to suffer from Parkinson’s than women, possibly because they have greater exposure to other risk factors such as toxins or head trauma.

–        Genetic factors: A Mayo-Clinic-led international study revealed that the gene alpha-synuclein may play a role in the likelihood of developing the disease. Studies showed that individuals with a more active gene had a 1.5 times greater risk of developing Parkinson’s. These findings support the development of alpha-synuclein suppressing therapies, which may in the long run slow or even halt the disease.

Sources: http://cjasn.asnjournals.org; Gabe Mirkin MD; nih.gov; Wikipedia

Genetic Basis For Drug Response In Childhood Absence Epilepsy

 

Childhood absence epilepsy (CAE), also known as pyknolepsy, is an idiopathic generalized epilepsy which occurs in otherwise normal children. CAE is characterized by absence seizures, in which children stare into space, unaware of their surroundings. The seizures are brief, often lasting less than 20 seconds, although children may have up to 100 of them per day. The disease usually begins in children who are between 4 and 8 years old. About one third of children with CAE also have problems with attention. Mild automatisms are frequent, but major motor involvement early in the course excludes this diagnosis. The EEG demonstrates characteristic “typical 3Hz spike-wave“ discharges. Prognosis is excellent in well-defined cases of CAE with most patients “growing out“ of their epilepsy. Thus, while many children will stop experiencing absence seizures by the time they reach adolescence, others go on to develop more severe seizures.

 

Consider two children who have CAE. They both take the same drug — one child sees an improvement in their seizures, but the other does not. A new study, published online in the Annals of Neurology (25 March 2017) identified the genes that may underlie this difference in treatment outcomes, suggesting there may be potential for using a precision medicine approach to help predict which drugs will be most effective to help children with CAE. For the study, the authors investigated whether there may be a genetic basis for different responses to three drugs used for CAE (ethosuximide, valproic acid, and lamotrigine). The experiments focused on three genes that code for T-type calcium channels that are involved in CAE and one gene that codes for a transporter that shuttles the drugs out of the brain. T-type calcium channels help control the firing rate of brain cells. The current study is part of a 32-center, randomized, controlled clinical trial that compared the effects of the three most commonly used drugs in 446 children who were recently diagnosed with CAE.

 

The results suggest knowledge of specific gene variants in children with CAE may help predict what drugs would work best for them. For example, two specific forms of the calcium channel genes appeared more often in children for whom ethosuximide did not work. Two other variants of the calcium channel genes were found in children for whom lamotrigine did work, but one form of the drug transporter gene was associated with a continuation of seizures. The authors conducted additional experiments using the form of calcium channel gene that was associated with ethosuximide failure in patients. When cells in a dish containing this calcium channel variant were treated with ethosuximide, the drug had less effect on inhibiting the channel, suggesting that the genetic form of calcium channel may determine patients’ response to the drug. According to the authors, they were able to identify a potential link between genes and the children’s’ responses to certain treatments, and they were also able to clearly show that one variant caused a change in how a key calcium channel responded to ethosuximide, thus confirming what was found in the clinical trial. The authors added that more research is needed to learn about the specific genes involved in CAE and the ways that they influence the effect of anti-epileptic drugs, and that there is a need to determine which factors, other than genetics, may play a role in treatment response.

 

Origin of Blood-Brain Barrier ‘Sentry Cells’

 

The blood-brain barrier is the layer of cells that line the blood vessels of the brain. The inner cell layer that lines vessels, known as the endothelium, is present in all the blood vessels of the body. Within the blood vessels of the brain, endothelial cells and other adjacent cells form a tight barrier that helps to prevent toxins and microbes from entering the brain. Although their function is not completely understood, a special population of cells covering the blood vessels on the brain’s surface is thought to contribute to the organ’s protection. The cells act as sentries, engulfing toxins, cellular wastes and microbes and then encasing them in sphere-like structures called vesicles. These sentry cells are called fluorescent granular perithelial cells (FGPs) because the vesicles they contain give off a yellow glow in the presence of light. FGPs are thought to be important in a variety of human brain disorders and conditions. These cells appear to be a major entry point for HIV infection of the brain. Age-related decline in cognitive function is associated with a decline in the scavenging function of FGPs. According to the authors, learning more about how FGPs function may lead to a greater understanding of dementia and other conditions.

 

A study using zebrafish, published online in eLife (11 April 2017), has shown that a population of cells that protect the brain against diseases and harmful substances are not immune cells, as had previously been thought, but instead likely arise from the lining of the circulatory system. This basic science finding may have implications for understanding age-related decline in brain functioning and how HIV infects brain cells. The study showed that FGPs are present on the surface of the zebrafish brain and that these blood vessel-associated FGPs do not arise from the immune system, as had been previously thought, but from endothelial cells themselves. The research lab performing this study uses zebrafish to understand how the blood and lymphatic systems develop. Because the young fish are transparent, it is possible to see the developing circulatory system while observing the fish under a light microscope. As part of this effort, the authors inserted a gene for a protein that turns green into the cells that line the endothelium of selected embryonic veins and in the lymphatic system — the network of vessels through which immune cells travel in the body. In addition to seeing green lymphatic cells in the zebrafish embryos, the authors noticed that green cells also covered the surface of the tiny fish’s brains.

 

Upon closer inspection, the authors tentatively identified these cells as FGPs. Because they turned green, it was apparent that they arose from endothelial cells. Until the current study, FGPs were thought to be macrophages, a type of immune cell. The authors conducted additional experiments to confirm the origins of the FGPs, including analyzing what proteins were being made by their DNA. These proteins most closely resembled those made by endothelial cells in the lymphatic system, not the proteins made by macrophages or other immune cells. In another series of experiments, they inserted a green fluorescent protein into the tissues that give rise to blood and lymph vessels in embryonic zebrafish. Using time lapse photography, images were captured of FGPs arising from the vessels’ endothelium. When zebrafish with the green fluorescing endothelial gene matured, green FGPs were observed on the surface of the fish’s brains — confirming that these cells arose from endothelial tissue.

 

The authors hope to conduct further studies of how FGPs interact with blood vessels and the blood-brain barrier. The researchers noted that, unlike mammals, embryonic zebrafish can be observed under a microscope as they develop, providing an easy means for studying the role of FGPs in protecting the brain.

 

An NICHD time lapse video on the development of zebrafish embryos is available.

 

New Warnings About the Use of Codeine and Tramadol in Children & Nursing Mothers

 

The following is FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on New Warnings About The Use Of Codeine And Tramadol In Children & Nursing Mothers:

 

The health and safety of children is a top priority at the FDA, which is why today we are requiring a series of changes to the labeling of two types of opioid medications in order to help better protect children from serious risks associated with these medicines – codeine (found in some prescription pain and cough medicines and some over-the-counter cough medicines) and tramadol (found in some prescription pain medicines).

 

We are requiring these changes because we know that some children who received codeine or tramadol have experienced life-threatening respiratory depression and death because they metabolize (or break down) these medicines much faster than usual (called ultra-rapid metabolism), causing dangerously high levels of active drug in their bodies. This is especially concerning in children under 12 years of age and adolescents who are obese or have conditions that may increase the risk of breathing problems, like obstructive sleep apnea or lung disease. Respiratory depression can also occur in nursing babies, when mothers who are ultra-rapid metabolizers take these types of medicines and pass it along to their children through their breast milk.

 

This isn’t the first time we have taken action on codeine to better ensure the safety of our children. Since 2013, prescription codeine labeling has contained a Boxed Warning and Contraindication for children up to age 18 years of age regarding the risk of life-threatening respiratory depression following the use of codeine for pain management after the removal of the tonsils (tonsillectomy) and/or adenoids (adenoidectomy). Now, labels for both codeine and tramadol are being updated to include additional Contraindications and Warnings; among the updates are Contraindications for use of codeine or tramadol in all children younger than 12 years of age, warnings about their use in children 12-18 years of age with certain medical conditions, and a stronger warning recommending against their use in nursing mothers. In addition to these labeling changes, labeling for tramadol-containing products will also get a Contraindication for post-operative pain management in children up to age 18 years of age who have undergone tonsillectomy and/or adenoidectomy, which is already in labeling for codeine products.

 

We urge health care providers, stakeholders and the public to read the Drug Safety Communication that we issued today, which provides more detailed information regarding the new Warnings and Contraindications, and the data that informed them. We also encourage parents to review the ingredients of pain medicines to see whether they include codeine or tramadol, and cough medicines to see if they contain codeine. It’s also important to check non-prescription cough and cold medicines that may be sold over the counter, as some of these medicines also include codeine. In all cases, if the medicine contains codeine or tramadol, parents should consult a health care provider before giving their children the medicines or taking them when nursing.

 

We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe.

Salmon-Avocado Appetizer

We love salmon in our house: sauteed salmon, baked salmon, Nova Scotia salmon (Nova), salmon mousse, salmon salad. You name it; we love it. So, it was a no-brainer to come up with this recipe. What’s amazing is that I didn’t think of it sooner. This has got to be the world’s easiest, most delicious fish recipe. It came to me, after we decided to cut calories and not have weekend bagels piled high with Tofutti (soy cream cheese) and Nova, with steaming mugs of coffee. We grind our own beans because of the influence of our son Alex and because Dean Gittleman told us we were missing out on great coffee by not doing grinding our own beans! ©Joyce Hays, Target Health Inc.

 

This recipe went from a more complex, salmon ceviche with 16 ingredients to what you see here, a two-ingredient recipe with no marinade, no seasoning, no cilantro, no sake. It eliminated all the extra work, without a loss of flavor. Who could ask for anything more? ©Joyce Hays, Target Health Inc.

 

 

Ingredients For Two People

 

6 ounces of special ahi salmon, sold especially to be eaten raw, like sushi and/or sashimi

2 ripe, but not mushy avocados

1 bag of bamboo picks, 6 inches long

 

World’s easiest appetizer with only two ingredients. Or, to be precise, if you count the bamboo picks, then three items to buy. ©Joyce Hays, Target Health Inc.

 

I got this Ahi Salmon from Whole Foods. It’s in the frozen section and is especially for eating raw salmon as in my recipe and as in making sushi and/or sashimi. You want to get the very best salmon, cut and flash frozen for the purpose of eating raw fish. ©Joyce Hays, Target Health Inc.

 

 

Directions

 

1. Cut the salmon into small pieces (cube like if possible) on a cutting board. Put on a plate.

 

If from your freezer, thaw out the salmon. Then cut it into small cube-like pieces.  Keep in mind that you want to have three cubes of salmon for about 10 to 13 bamboo picks, so try to get at least a total of 30 of these small pieces of salmon. ©Joyce Hays, Target Health Inc.

 

2. Cut the avocados in half and pull out the pit the best you can, without damaging the flesh.

3. With a knife, crisscross each avocado half, so you have little squares. Then with a knife, run the blade all around the avocado half to loosen the flesh. With a small spoon take out each cube of avocado, carefully, so it stays intact. Put on a plate.

4. Get out your bamboo picks and alternately put a piece of salmon, then avocado on each stick, so that you have a total of 3 small pieces of salmon and 3 small pieces of avocado

5. Arrange the salmon picks on a serving platter and devour.

6. I suppose you could add wedges or circles of lemon and/or lime on the serving plate, which would look lovely. I didn’t think of it when I served this the last time, but will do it next time. If you have any leftover avocado, serve that on the table, or on the serving platter.

7. A white wine (icy if possible) goes well with this recipe, including champagne or prosecco.

 

So-o colorful and inviting to serve your guests! ©Joyce Hays, Target Health Inc.

 

We had icy Pouilly Fuisse with the salmon appetizers. ©Joyce Hays, Target Health Inc.

 

Pretty and Easy, not to mention delicious. Happy Spring! ©Joyce Hays, Target Health Inc.

 

This is the beautiful high ceiling of the Metropolitan Opera, after all the Swarovski crystal chandeliers slowly, have been raised up. ©Joyce Hays, Target Health Inc.

 

The breathtakingly beautiful Metropolitan Opera chandeliers, by Swarovski from Austria. Photo source: Genista – http://www.flickr.com/photos/genista/3491661640/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=9756704

 

We’ve seen our last opera for this season. We usually go to 10 to 12 operas each year. The MetOpera season went so fast this year, can’t believe it’s almost over. My three favorite operas this year were Bellini’s I Puritani, Verdi’s Rigoletto and Wagner’s Tristin and Isolde (yes, 5 hours). For those operas lovers reading this, I am posting one aria from each opera, for you to enjoy.

 

I Puritani: Tenor Aria, Act 1

Rigoletto: Quartet, Final Act

Tristan and Isolde: Final Act: Isolde’s aria, sung by Nina Stemme, who sang at the Met in this year’s production – an epic version. At the end of this five hour opera, I stood up with tears streaming down my face – finally looked around me – the people in front of me and those next to me, were the same, moved to tears. A transcendental experience, is what we all agreed. I will never forget this particular production and I’ve seen it several times before this. Bravo to all involved and to the audience so deeply moved.

Vladimir Horowitz plays Wagner-Liszt Isolde’s Liebestod: Editor’s note: It took the legendary pianist three separate days to record this piece to his satisfaction, and he died four days after its completion on November 5, 1989.

WAGNER – Tristan und Isolde – Prelude and Liebestod (Georg Solti – Chicago Symphony Orchestra)

 

 

From Our Table to Yours !

 

Bon Appetit!