October 19, 2016
David Geffen School of Medicine at UCLA
Using a recently developed technology for analyzing DNA, scientists have found dozens of genes and two major biological pathways that are likely involved in the development of the disorder but had not been uncovered in previous genetic studies of schizophrenia. The work provides important new information about how schizophrenia originates and points the way to more detailed studies — and possibly better treatments in the future. Schizophrenia is a chronic, disabling mental illness whose symptoms can include hallucinations, delusions and cognitive problems. The illness afflicts about 1 percent of the human population.
UCLA scientists have made a major advance in understanding the biology of schizophrenia.
Using a recently developed technology for analyzing DNA, the scientists found dozens of genes and two major biological pathways that are likely involved in the development of the disorder but had not been uncovered in previous genetic studies of schizophrenia. The work provides important new information about how schizophrenia originates and points the way to more detailed studies — and possibly better treatments in the future.
Schizophrenia is a chronic, disabling mental illness whose symptoms can include hallucinations, delusions and cognitive problems. The illness afflicts about 1 percent of the human population — more than 50 million people worldwide. Because the causes of schizophrenia are poorly understood, current medications can help diminish the symptoms but do not cure the disorder.
The study, which is published online in the journal Nature, is likely to have an impact beyond schizophrenia research because it demonstrates a general and potentially powerful new strategy for illuminating the mechanisms of human disease.
“This work provides a road map for understanding how common genetic variation associated with a complex disease affects specific genes and pathways,” said principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and professor of neurology and psychiatry at UCLA’s David Geffen School of Medicine at UCLA.
Schizophrenia has long been known to be highly genetic; it often runs in families. A large genome-wide association study of people with schizophrenia, published in 2014, linked the disorder to small DNA variations at more than 100 distinct locations on the human genome. However, most of those locations lie outside of actual genes, so their roles in schizophrenia have been unclear. Genome-wide study analyses of other major diseases have come up with similarly puzzling results.
In some cases, the non-gene locations identified in these studies have turned out to be what are known as “regulatory regions,” which serve to enhance or repress the activity of genes lying near them on the genome. But many of these disease-linked locations have no obvious gene target nearby on the genome.
One possibility is that these mysterious disease-linked locations are also regulatory regions that target genes lying relatively far away on the genome. They could do this if they are brought physically close to those “distant” genes by the complex twisting and looping that DNA undergoes when packaged into a chromosome, just as two opposite ends of a rope can end up close together when the rope is coiled.
To investigate that possibility, Geschwind and his team used a relatively new, high-resolution version of a technology called “chromosome conformation capture,” which chemically marks and then maps the locations where loops of chromosomal DNA come into contact.
Because each cell type in the body can have subtly different 3-D chromosome structures, the researchers applied the technique to immature human brain cells from the cortex — the large region across the top of the brain that handles higher cognitive tasks. Schizophrenia is believed to be a disorder of abnormal cortical development.
The mapping revealed that most of the more than 100 schizophrenia-linked sites from the 2014 study contact known genes during brain development. Many of these are genes that already have been linked to schizophrenia in previous studies. Others had been suspected of involvement, for example because their level of activity in schizophrenics is known to be abnormal in the cortex.
The genes newly linked to schizophrenia in the study include several for brain cell receptors that are activated by the neurotransmitter acetylcholine, implying that variations in the functions of these receptors can help bring about schizophrenia.
“There’s a lot of clinical and pharmacologic data suggesting that changes in acetylcholine signaling in the brain can worsen schizophrenia symptoms, but until now there’s been no genetic evidence that it can help cause the disorder,” Geschwind said.
The analysis also pointed for the first time to several genes that are involved in the early-life burst of brain cell production that gives rise to the cerebral cortex of humans.
In all, the researchers identified several hundred genes that may be abnormally regulated in schizophrenia but had not been linked to the disorder before. In further experiments and analyses of two dozen of those genes, they found additional evidence of abnormal regulation in schizophrenia.
As further studies clarify the roles of these genes in schizophrenia, scientists will get a more complete picture of how the disorder develops and persists, and should then be able to develop more effective treatments.
“In the near term we’re using the findings from this study to help us understand schizophrenia better, but we’re also planning to apply this same strategy to identify key genes in the development of autism and other neurodevelopmental disorders,” Geschwind said.
In principle, the 3-D chromosome mapping technology can be used to make sense of gene association data for any disease involving genetic risk. This same approach also can be used to discover relationships between genes and their regulatory regions in ordinary biological processes.
- Hyejung Won, Luis de la Torre-Ubieta, Jason L. Stein, Neelroop N. Parikshak, Jerry Huang, Carli K. Opland, Michael J. Gandal, Gavin J. Sutton, Farhad Hormozdiari, Daning Lu, Changhoon Lee, Eleazar Eskin, Irina Voineagu, Jason Ernst, Daniel H. Geschwind. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature, 2016; DOI:10.1038/nature19847
Source: David Geffen School of Medicine at UCLA. “Scientists find new genetic roots of schizophrenia.” ScienceDaily. ScienceDaily, 19 October 2016. <www.sciencedaily.com/releases/2016/10/161019160035.htm>.
October 14, 2016
Ohio State University
The same hotspot in Earth’s mantle that feeds Iceland’s active volcanoes has been playing a trick on the scientists who are trying to measure how much ice is melting on nearby Greenland. According to a new study, the hotspot softened the mantle rock beneath Greenland in a way that ultimately distorted their calculations for ice loss in the Greenland ice sheet. This caused them to underestimate the melting by about 20 gigatons (20 billion metric tons) per year.
The same hotspot in Earth’s mantle that feeds Iceland’s active volcanoes has been playing a trick on the scientists who are trying to measure how much ice is melting on nearby Greenland.
According to a new study in the journal Science Advances, the hotspot softened the mantle rock beneath Greenland in a way that ultimately distorted their calculations for ice loss in the Greenland ice sheet. This caused them to underestimate the melting by about 20 gigatons (20 billion metric tons) per year.
That means Greenland did not lose about 2,500 gigatons of ice from 2003-2013 as scientists previously thought, but nearly 2,700 gigatons instead — a 7.6 percent difference, said study co-author Michael Bevis of The Ohio State University.
“It’s a fairly modest correction,” said Bevis, the Ohio Eminent Scholar in Geodynamics, professor of earth sciences at Ohio State and leader of GNET, the Greenland GPS Network.
“It doesn’t change our estimates of the total mass loss all over Greenland by that much, but it brings a more significant change to our understanding of where within the ice sheet that loss has happened, and where it is happening now.”
Earth’s crust in that part of the world is slowly moving northwest, he explained, and 40 million years ago, parts of Greenland passed over an especially hot column of partially molten rock that now lies beneath Iceland. The hotspot softened the rock in its wake, lowering the viscosity of the mantle rocks along a path running deep below the surface of Greenland’s east coast.
During the last ice age, Greenland’s ice sheet was much larger than now, and its enormous weight caused Greenland’s crust to slowly sink into the softened mantle rock below. When large parts of the ice sheet melted at the end of the ice age, the weight of the ice sheet decreased, and the crust began to rebound. It is still rising, as mantle rock continues to flow inwards and upwards beneath Greenland.
The existence of mantle flow beneath Greenland is not a surprise in itself, Bevis said. When the Gravity Recovery and Climate Experiment (GRACE) satellites began measuring gravity signals around the world in 2002, scientists knew they would have to separate mass flow beneath Earth’s crust from changes in the mass of the overlying ice sheet.
“GRACE measures mass, period. It cannot tell the difference between ice mass and rock mass. So, inferring the ice mass change from the total mass change requires a model of all the mass flows within Earth. If that model is wrong, so is the ice mass change inferred from GRACE,” he explained.
Models of this rock flow depend on what researchers can glean about the viscosity of the mantle. The original models assumed a fairly typical mantle viscosity, but Greenland’s close encounter with the Iceland hot spot greatly changed the picture.
To the GNET team, the 7.6 percent discrepancy in overall ice loss is overshadowed by the fact that it concealed which parts of the ice sheet are most being affected by climate change. The new results reveal that the pattern of modern ice loss is similar to that which has prevailed since the end of the last ice age.
“This result is a detail, but it is an important detail,” Bevis continued. “By refining the spatial pattern of mass loss in the world’s second largest — and most unstable — ice sheet, and learning how that pattern has evolved, we are steadily increasing our understanding of ice loss processes, which will lead to better-informed projections of sea level rise.”
Computer models can give a good estimate of mantle flow and crustal uplift, he said, and GNET’s mission is to make those models better by providing direct observations of present-day crustal motion. That’s why the GNET team includes GRACE scientists and earth modelers as well as GPS experts and glaciologists.
The team used GPS to measure uplift in the crust all along Greenland’s coast. That’s when they discovered that two neighboring stations on the east coast were uplifting far more rapidly than standard models had predicted.
“We did not expect to see the anomalous uplift rates at the two stations that sit on the ‘track’ of the Iceland hot spot,” Bevis said. “We were shocked when we first saw them. Only afterwards did we make the connection.”
He added that the discovery holds big implications for measuring ice loss elsewhere in the world.
For instance, GNET has a sister network, ANET, that spans West Antarctica. It employs roughly similar numbers of GPS stations, but spread out over a vastly larger area. Unless more stations are added to ANET, anomalous rates of uplift may go undetected, Bevis cautioned, and analyses of GRACE data will lead to inaccurate estimates of ice loss in Antarctica.
- S. A. Khan, I. Sasgen, M. Bevis, T. van Dam, J. L. Bamber, J. Wahr, M. Willis, K. H. Kjaer, B. Wouters, V. Helm, B. Csatho, K. Fleming, A. A. Bjork, A. Aschwanden, P. Knudsen, P. K. Munneke. Geodetic measurements reveal similarities between post-Last Glacial Maximum and present-day mass loss from the Greenland ice sheet. Science Advances, 2016; 2 (9): e1600931 DOI:10.1126/sciadv.1600931
Source: Ohio State University. “Greenland ice is melting 7 percent faster than previously thought.” ScienceDaily. ScienceDaily, 14 October 2016. <www.sciencedaily.com/releases/2016/10/161014150655.htm>.
October 17, 2016
The first large-scale map of rainfall declines revealed by signatures in ancient soil could help researchers better understand profound regional and global climate transformation.
A new study chronicles how central Asia dried out over the last 23 million years into one of the most arid regions on the planet. The findings illustrate the dramatic climatic shifts wrought by the ponderous rise of new mountain ranges over geologic time.
Researchers have long cited the uplift of the Tibetan Plateau and the Himalayan Mountains around 50 million years ago for blocking rain clouds’ entry into central Asia from the south, killing off much of the region’s plant life.
The new study, published online in the journal Geology, paints a more nuanced picture of Central Asia’s desertification. It suggests that the relatively recent rise of lesser-known mountain ranges, such as the Tian Shan and the Altai, further sealed off moisture from the west and north. As a result, great stretches of what we now consider western China, southwestern Mongolia and eastern Tajikistan became barren earth or laced by sand dunes.
“While Central Asia was probably never lush and verdant, it was certainly greener 23 million years ago and probably even greener in the more distant past,” said Jeremy Kesner Caves, the lead author of the study and a doctoral student at Stanford’s School of Earth, Energy & Environmental Sciences.
“One way to think about this change is that when viewed from space today, Central Asia appears very brown because of its expansive deserts,” Caves said. “If viewed from space 23 million years ago, though, Central Asia would have looked somewhat darker, simply due to there being considerably more leaves and vegetation.”
Caves and his co-authors arrived at their conclusions after measuring the carbon isotope values in buried, ancient soil samples. A particular isotope, or version, of carbon found in the samples speaks to the dryness of conditions at the time of the soil’s deposition. Wetter, rainier conditions allow for greater numbers of organisms, including plants and soil-dwelling bacteria, to thrive and pull carbon out of their surroundings to fuel their growth and metabolism, leaving telltale carbon isotopes in their environment.
Previously, scientists had relied on these sorts of soil sample measurements primarily to study plant types and atmospheric carbon dioxide levels. Caves and colleagues instead looked at samples over extensive geographic and temporal spans in order to draw a fuller portrait of the climatic changes influencing soil composition.
“Our paper is the first-ever attempt to present maps of carbon isotopes over a geologic time frame of more than a million years,” Caves said.
He and several co-authors traveled to Mongolia, eastern Kazakhstan and northern China to collect the bulk of 171 new soil samples, while Russian co-authors collected samples near Lake Baikal. The new specimens were considered alongside more than 2,200 previously collected samples. Because most of those existing samples originated from the Tibetan Plateau, the research team plugged a gap in the geographical coverage by going to little-studied northern central Asia.
The samples themselves “are honestly pretty boring,” Caves admitted. “Basically, they look and feel like dirt.” But the rocky outcrops exposing the old, hardened soil chunks can dazzle. “The outcrops are striped deep purple, red and green, and they often erode in crazy patterns,” Caves said. “Imagine Badlands National Park in South Dakota or the Painted Desert in Arizona.”
Overall, the samples were well-distributed from 23 million to 2.6 million years ago during a geological period known as the Neogene. Earth’s climate cooled off substantially as the Neogene wore on, setting the stage for an Ice Age when glaciers crept from polar regions into lower latitudes.
Upon analysis, the samples’ carbon isotope values revealed an exceptionally arid region deep in Asia’s interior going back 23 million years, initially ringed by areas of higher rainfall. Starting about five million years ago, however, that dry region expanded to the north and west, as new mountain ranges reached heights sufficient to block westerly winds from delivering moisture.
The findings will help researchers disentangle how much of Central Asia’s de-greening occurred in response to localized geological changes versus global shifts happening during the Neogene.
Investigating North America
With this compelling demonstration of using ancient soil samples as proxies for regional climate in Asia, Caves now plans to extend his investigations elsewhere on the globe. “I hope to be able to apply this method to other continents, such as North America, where there are large datasets of carbon isotopes,” Caves said.
Doing so could illuminate impacts on western North America’s climate due to the uplift of the Sierra Nevada in eastern California, as well as the Rocky Mountains further east, which reached near their present elevations around 40 million and 50 million years ago, respectively.
“Only by making these continental-scale maps, like Jeremy has done for Central Asia, can you further understand how the uplift of mountain ranges controlled rainfall patterns against this backdrop of global cooling in the Neogene,” said Page Chamberlain, co-author of the study and a professor of Earth system science at Stanford. “North America is really ripe for this kind of research.”
- Jeremy K. Caves, Danielle Y. Moragne, Daniel E. Ibarra, Bolat U. Bayshashov, Yuan Gao, Matthew M. Jones, Aizhan Zhamangara, Anastasia V. Arzhannikova, Sergey G Arzhannikov, C. Page Chamberlain. The Neogene de-greening of Central Asia. Geology, 2016; G38267.1 DOI:10.1130/G38267.1
Source: Stanford University. “Making of a desert: Central Asia over the ages.” ScienceDaily. ScienceDaily, 17 October 2016. <www.sciencedaily.com/releases/2016/10/161017125949.htm>.
Orphan Drug Development at Target Health Inc.
Target Health’s esteemed regulatory team which provides regulatory strategic planning, FDA representation and regulatory operation services for 47 of our clients, is also very active in the Orphan Drug space.
Here is the list of Orphan Drug Designations obtained by Target Health on behalf of its clients. Also included is the the status of the drug products:
- Alagille Syndrome
- Behcet’s disease
- Burn progression in hospitalized patients
- Caries prevention, head and neck cancer
- Cushing’s syndrome secondary to ectopic ACTH secretion
- Debridement in hospitalized patients with 3rd degree burns (EMA Approved 2012)
- Edema-related effects in hospitalized patients with 3rd degree burns
- Fibrolamellar Carcinoma (FLC)
- Fungal Infections
- Gaucher Disease (sold to Pfizer; NDA Approved 2012)
- Growth Hormone (Licensed to Pfizer)
- Hereditary angioedema (sold to Shire; NDA Approved 2011)
- Hodgkin’s Lymphoma
- Intradialytic Hypotension (Symptomatic hypotension in the immediate post-dialysis)
- Invasive Aspergillus Infections
- Multiple Myeloma
- Osteonecrosis of the jaw
- Ovarian Cancer
Hope to see you at the NORD meeting in Washington DC this week. Dr. Jules Mitchel will be on a panel entitled Collaborations Across Borders-Addressing Rare Diseases as a Global Public Health Challenge, discussing global drug development challenges for orphan diseases.
Target Health Inc. Cultural Liaison Goes To Scandinavia House in New York City
A rapidly warming Arctic is threatening Arctic Communities through coastal erosion, thawing of the permafrost and changing ecosystems. As the Arctic faces a critical moment in history, US special representative for the Arctic Admiral Robert J. Papp shared his thoughts last month at Scandinavia house, which is located just a block away from Target Health. The topic was Cooperation In the Arctic – Reflections on the U.S. Chairmanship of the Artic at its halfway Point. (click on the link to hear the lecture)
Admiral Robert J. Papp is the state department’s special representative for the Arctic Region, and with a focus on climate change, economic, and environmental issues. The Unites Sates holds the chairmanship of the Arctic Council from 2015-2017. He gave a lovely speech outlining the progress and key accomplishments of the U.S. Chairmanship of the Arctic council. He spoke about many relevant issues such as the council’s work on energy and water security to try to improve economic and living conditions in the communities through the coastal region. He also address the impact of climate change in the Artic region where people, animals and plants have thrived for thousands of years. Climate change is threatening these communities and their way of life, as well as the ecosystems that the communities depend on.
Fortunately, the Arctic Council recognizes the impacts of climate change and tries to raise awareness of the Arctic by promoting the development of climate change tools such as high-resolution mapping and by targeting short-lived climate pollutants through reduction of black carbon and methane emissions. General Papp hopes to partner with the Nordic countries and their partners to increase scientists, communities, policy makers and the general public’s understanding of the impacts of climate change. He spoke about his travels with Secretary John Kerry through the Northern Hemisphere and describe his job as gratifying since he gets to travel to other countries and speak to other UN Councils while promoting sustainable development and environmental protection. He also hopes to get people into long term involvement in working together to promote Arctic ocean safety, security & stewardship.
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 or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Credit: Blausen.com staff. Blausen gallery 2014. Wikiversity Journal of Medicine.
Hypertension, also known as high blood pressure (HBP), is a long term medical condition in which the 1) ___ pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long term high blood pressure, however, is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss, and chronic kidney disease. High blood pressure is classified as either primary (essential) high blood pressure or secondary high blood pressure. About 90-95% of cases are primary, defined as high blood pressure due to nonspecific lifestyle and genetic factors. Lifestyle factors that increase the risk include excess salt, excess body weight, smoking, and alcohol. The remaining 5-10% of cases are categorized as secondary high blood pressure, defined as high blood pressure due to an identifiable cause, such as chronic kidney disease, narrowing of the kidney arteries, an endocrine disorder, or the use of birth control pills.
Blood pressure is expressed by two measurements, the systolic and 2) ___ pressures, which are the maximum and minimum pressures, respectively. Normal blood pressure at rest is within the range of 100-140 millimeters mercury (mmHg) systolic and 60-90 mmHg diastolic. High blood pressure is present if the resting blood pressure is persistently at or above 140/90 mmHg for most adults. Different numbers apply to children. Ambulatory blood pressure monitoring over a 24-hour period appears more accurate than office best blood pressure measurement. Lifestyle changes and medications can lower blood pressure and decrease the risk of health complications. Lifestyle changes include weight loss, decreased salt intake, physical 3) ___, and a healthy diet. If lifestyle changes are not sufficient then blood pressure medications are used. Up to three medications can control blood pressure in 90% of people. The treatment of moderately high arterial blood pressure (defined as >160/100 mmHg) with medications is associated with an improved life expectancy. The effect of treatment of blood pressure between 140/90 mmHg and 160/100 mmHg is less clear, with some reviews finding benefit and others not finding benefit. High blood pressure affects between 16 and 37% of the population globally. In 2010 hypertension was believed to have been a factor in 18% (9.4 million) deaths.
Hypertension is rarely accompanied by symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. Some with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as light-headedness, vertigo, tinnitus (buzzing or hissing in the 4) ___), altered vision or fainting episodes. These symptoms, however, might be related to associated anxiety rather than the high blood pressure itself. On physical examination, hypertension may be associated with the presence of changes in the optic fundus seen by ophthalmoscopy. The severity of the changes typical of hypertensive retinopathy is graded from I-IV; grades I and II may be difficult to differentiate. The severity of the retinopathy correlates roughly with the duration and/or the severity of the hypertension. Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110) is referred to as a hypertensive crisis. Hypertensive crisis is categorized as either hypertensive urgency or hypertensive emergency, according to the absence or presence of end organ damage, respectively. In hypertensive urgency, there is no evidence of end organ damage resulting from the elevated blood 5) ___. In these cases, oral medications are used to lower the BP gradually over 24 to 48 hours. In hypertensive emergency, there is evidence of direct damage to one or more organs. The most affected organs include the brain, kidney, heart and lungs, producing symptoms which may include confusion, drowsiness, chest pain and breathlessness. In hypertensive emergency, the blood pressure must be reduced more rapidly to stop ongoing organ damage, however, there is a lack of randomized controlled trial evidence for this approach.
Hypertension results from a complex interaction of genes and environmental factors. Numerous common genetic variants with small effects on blood pressure have been identified as well as some rare genetic variants with large effects on blood pressure. Blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable. Several environmental factors influence blood pressure. High 6) ___ intake raises the blood pressure in salt sensitive individuals; lack of exercise, obesity, and depression can play a role in individual cases. The possible role of other factors such as caffeine consumption, and vitamin D deficiency are less clear. Insulin resistance, which is common in obesity and is a component of syndrome X (or the metabolic syndrome), is also thought to contribute to hypertension. Events in early life, such as low birth weight, maternal smoking, and lack of breast feeding may be risk factors for adult essential hypertension, although the mechanisms linking these exposures to adult hypertension remain unclear. An increased rate of high blood urea has been found in untreated people with hypertension, in comparison with people with normal blood pressure, although it is uncertain whether the former plays a causal role or is subsidiary to poor 7) ___ function. Many mechanisms have been proposed to account for the rise in peripheral resistance in hypertension. Most evidence implicates either disturbances in the kidneys’ salt and water handling (particularly abnormalities in the intrarenal renin-angiotensin system) and/or abnormalities of the sympathetic nervous system. These mechanisms are not mutually exclusive and it is likely that both contribute to some extent in most cases of essential hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension.
Hypertension is diagnosed on the basis of a persistently high blood pressure. Traditionally, the National Institute of Clinical Excellence recommends three separate sphygmomanometer measurements at monthly intervals. The American Heart Association recommends at least three measurements on at least two separate health care visits. Ambulatory blood pressure monitoring over 12 to 24 hours is the most accurate method to confirm the diagnosis. Once the diagnosis of hypertension has been made, healthcare providers should attempt to identify the underlying cause based on risk factors and other symptoms, if present. Secondary hypertension is more common in preadolescent children, with most cases caused by kidney disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension. Laboratory tests can also be performed to identify possible causes of secondary hypertension, and to determine whether hypertension has caused damage to the heart, eyes, and kidneys. Additional tests for diabetes and high cholesterol levels are usually performed because these conditions are additional risk factors for the development of 8) ___ disease and may require treatment. Serum 9) ___ is measured to assess for the presence of kidney disease, which can be either the cause or the result of hypertension.
The first chemical for hypertension, sodium thiocyanate, was used in 1900 but had many side effects and was unpopular. Several other agents were developed after the Second World War, the most popular and reasonably effective of which were tetramethylammonium chloride, hexamethonium, hydralazine and reserpine (derived from the medicinal plant Rauwolfia serpentina). None of these were well tolerated. A major 10) ___ breakthrough was achieved with the discovery of the first well-tolerated orally available agents. The first was chlorothiazide, the first thiazide diuretic and developed from the antibiotic sulfanilamide, which became available in 1958. Subsequently beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors were developed as antihypertensive agents.
For Home Use: Automated arm blood pressure meter showing arterial hypertension (shown a systolic blood pressure 158 mmHg, diastolic blood pressure 99 mmHg and heart rate of 80 beats per minute)
ANSWERS: 1) blood; 2) diastolic; 3) exercise; 4) ears; 5) pressure; 6) salt; 7) kidney; 8) heart; 9) creatinine; 10) pharmaceutical
Scipione Riva-Rocci (1863-1937), Physician & Inventor
By Hans Christophersen – Danish National Archive,
Public Domain, https://commons.wikimedia.org
Scipione Riva Rocci was an Italian physician, born August 1863 in Almese, Piedmont. He was an internist, pathologist and pediatrician; and is best known for the invention of an easy-to-use cuff-based version of the mercury sphygmomanometer for the measurement of blood pressure.
Riva Rocci graduated in medicine and surgery in 1888 from the University of Turin. From 1888 to 1898 he acted as assistant lecturer at the propaedeutic medical clinic in Turin under the guidance of Carlo Forlanini and assisted him in the application of iatrogenic pneumothorax for treatment of pulmonary tuberculosis. In 1894 he graduated in pathology and in 1907 in pediatrics. In 1898, he followed Forlanini to the University of Pavia where he continued to contribute to the development of Forlanini’s method by showing that the technique did not have a major adverse effect on lung function. From 1900 until 1928 was chief clinician and director of the civic hospital in Varese, and helped to modernize the hospital by opening sanatorium wings and introducing vaccination, radiology and other methods to fight tuberculosis. From 1909 to 1916, he occupied the first chair of pediatrics at Pavia University.
Illustration of Riva-Rocci’s spygmomanometer in use.
Source: Wikipedia Commons
In 1928 he retired from his medical positions due to a neurological condition, probably encephalitis letharica, which he may have contracted from a patient or an autopsy during an epidemic in 1921. He spent the last years of his life in ill-health with paralysis agitans, and died on 15 March 1937 in Rapallo. He was buried in the small cemetery of San Michele di Pagana.
Riva Rocci’s major contribution to medicine was the invention of an easy-to-use version of the mercury sphygmomanometer which measured brachial blood pressure. The key element of this design was the use of a cuff that encircled the arm – previous designs had used rubber bulbs filled with water or air to manually compress the artery or other technically difficult methods to measure pressure. In 1896, Riva Rocci published his work describing the new sphygmomanometer in the Gazzetta Medica di Torino. In total he published four papers on the design and usage of the device between 1896 and 1897. His design included every-day objects such as an inkwell, some copper pipe, bicycle inner tubing and a quantity of mercury. Riva Rocci measured the peak (systolic) blood pressure by observing the cuff pressure at which the radial pulse was no longer palpable. This approach did not allow the measurement of diastolic blood pressure, although it was possible to estimate mean arterial pressure with the device, albeit with some difficulty.
The American neurosurgeon, Harvey Cushing (1869-1939) visited Riva Rocci at Pavia in 1901 and made drawings and was given an example of his device. On his return to the US he made a similar device with some improvements and used it successfully in Johns Hopkins Hospital, most notably in intracranial surgery. Cushing, with support from Theodore Janeway in New York City and George Crile in Cleveland, played a major role in popularizing Riva Rocci’s mercury sphygmomanometer. Subsequent improvements to the device included the use of a wider cuff (the original was only 5cm wide) and the use of Korotkoff sounds to determine systolic and diastolic blood pressure. Riva Rocci always refused to patent his invention and did not make any financial gains from its widespread use.
Sustained SIV Remission In Monkeys
When a SIV-infected monkey or an HIV-infected person receives antiretroviral therapy (ART), the therapy can suppress the virus to undetectable levels. Yet the virus still lurks silently in the genetic material of infected immune cells, known as viral reservoirs, even when suppressed. If ART is discontinued, SIV or HIV rapidly rebounds to high levels within a few weeks. Thus, treatment for HIV today involves taking ART every day for life. Although ART dramatically improves health overall and prolongs life, daily ART can be a challenge to stick to and also can have side effects over time.
According to an article online in Science (14 October 2016) experimentally induced sustained remission of SIV, the simian form of HIV, has been obtained in infected monkeys. The animals’ immune systems have been suppressing the virus to undetectable levels for as long as 23 months since the monkeys completed an investigational treatment regimen. In addition, the regimen has led to the near-complete replenishment of key immune cells that SIV had destroyed, something unachievable with ART alone.
According to the NIH, the data suggest that the immune systems of these animals are controlling SIV replication in the absence of antiretroviral therapy, and that the experimental treatment regimen appears to have given the immune systems of the monkeys the necessary boost to put the virus into sustained remission. The precise mechanisms of this effect are unclear and will be actively pursued since they could have important implications for the control of HIV infection in humans in the absence of ART.
The investigational treatment regimen consisted of 90 days of ART combined with 23 weeks of treatment with a laboratory-derived monkey antibody against a cellular receptor called a4b7 integrin. This antibody is similar to the human drug vedolizumab (trade name Entyvio), a monoclonal antibody developed by Millennium Pharmaceuticals, Inc. (a subsidiary of Takeda Pharmaceuticals), which is approved by the FDA for treating ulcerative colitis and Crohn’s disease. Vedolizumab consists of an antibody to a4b7 integrin, a receptor that is present at high levels on the immune-system cells that SIV and HIV preferentially infect. One function of this antibody is to prevent these immune cells from homing to gastrointestinal tissues, a major site of SIV and HIV replication and viral reservoir formation early in infection. A critical unanswered question, and the subject of ongoing research, is precisely how treatment with the a4b7 antibody led to the regulation of SIV replication in the study monkeys. According to the authors, If we could figure out how the antibody works, then an effective HIV vaccine could be modeled on that mechanism.
For the study, 18 rhesus macaques housed at the NIH-supported Yerkes Research Center were infected with a disease-causing clone of SIV. Five weeks after infection, all the animals began receiving a 90-day course of daily ART. In addition, nine weeks after infection, 11 monkeys began receiving infusions of the investigational treatment antibody every three weeks while the other seven monkeys began receiving infusions of a placebo antibody. The infusions continued for 23 weeks. At the 32nd week after infection, all treatment ceased. Results showed that all 18 monkeys fully suppressed SIV by their third week on ART. Once the infusions began, three monkeys developed antibodies against the investigational treatment antibody and were excluded from further study. After the 15 remaining monkeys stopped receiving ART, SIV rebounded to high levels in the seven control animals within two weeks and remained high. Among the eight monkeys who received the investigational antibody infusions, SIV rebounded temporarily in six of them, but they regained control of the virus within four weeks. The virus never rebounded in the other two animals. These eight monkeys have continued to suppress SIV to undetectable levels in both the blood and gastrointestinal tissues for as long as 23 months since all treatment ended.
Since it is unclear whether the findings of this monkey study will translate into a clinical benefit for HIV-infected people, NIAID researchers recently began an effort to determine whether short-term treatment with vedolizumab in combination with ART can generate sustained HIV remission in such individuals. Sustained HIV remission, also known as a functional cure, refers to the outcome of a treatment or therapeutic vaccination that induces prolonged, undetectable levels of HIV viremia without ART. The study investigators are hopeful that combining short-term vedolizumab treatment with ART will be as effective at suppressing HIV replication following withdrawal of ART in people as it appears to be at suppressing SIV replication in monkeys. A small, early-phase clinical trial testing the treatment regimen in HIV-infected people has already begun at the NIH Clinical Research Center in Bethesda, Maryland. The study is testing whether a 30-week course of vedolizumab is safe and tolerable and allows study participants’ immune systems to control the virus when they temporarily stop taking ART. Preliminary results are expected by the end of 2017 with further data becoming available into 2018.
Study Finds Ebola Treatment Zmapp Holds Promise
Editor’s note: If a cancer drug with a small number of patients had a mortality rate of 22% vs. 37% in comparison with placebo, with no other treatment available, we would all be ecstatic. We should think about whether there should be times when a P value <0.05 should not necessarily be the gold standard. Imagine if a drug’s probability of a correct outcome was 90% of the time (P < 0.1) vs. 95% of the time (p < 0.05), how much money and time we will all save. Someone should do the calculation.
A clinical trial to evaluate the experimental Ebola treatment ZMapp found the treatment to be safe and well-tolerated; however, because of the waning Ebola epidemic, the study enrolled too few people to determine definitively whether it is a better treatment for Ebola virus disease (EVD) than the best available standard of care alone. The findings from the randomized, controlled trial known as PREVAIL II appear in the Oct. 13, 2016 issue of The New England Journal of Medicine. Initial trial findings were reported in February 2016, at the Conference on Retroviruses and Opportunistic Infections in Boston.
According to the NIH, although there is no definitive evidence that ZMapp is superior to the optimized standard of care, the results of the PREVAIL II trial are promising and provide valuable scientific data. Importantly, the study establishes that it is feasible to conduct a randomized, controlled trial during a major public health emergency in a scientifically and ethically sound manner.
ZMapp, developed by Mapp Biopharmaceutical, Inc., based in San Diego, is composed of three different laboratory-made proteins called monoclonal antibodies. The treatment is designed to prevent the progression of EVD within the body by targeting the main surface protein of the Ebola virus. Earlier studies in nonhuman primates demonstrated that ZMapp had strong antiviral activity and prevented death when administered as late as five days after experimental infection with Zaire ebolavirus. The study launched through a collaboration between the Liberian Ministry of Health and NIAID, known as the Partnership for Research on Ebola Virus in Liberia (PREVAIL). It later expanded to include research partners within the countries of Sierra Leone and Guinea and the French medical research organization INSERM.
The trial enrolled 72 participants of any age with confirmed Ebola virus infection from March 2015 through November 2015. The participants came from Sierra Leone (54 patients), Guinea (12 patients), Liberia (five patients) and the United States (one patient, a health care worker evacuated from Sierra Leone). The average age of the participants was 24 years, and slightly more than half were women. Investigators closed the study in January 2016 because they could not enroll additional patients, up to the targeted 200, because of the decline in the number of new Ebola cases as the outbreak diminished. The study sought to determine if the experimental drug ZMapp plus the optimized standard of care for treating EVD — 1) providing intravenous fluids, 2) balancing electrolytes needed to maintain bodily functions, and 3) maintaining healthy oxygen and blood pressure levels — was superior to the optimized standard of care alone in reducing deaths caused by EVD. All participants received the optimized standard of care, and half were randomly assigned to also receive three intravenous infusions of ZMapp administered three days apart.
Investigators compared the number of deaths in each group at 28 days after enrollment. Thirteen deaths (37% mortality) were reported in the group of 35 patients who received the optimized standard of care only, while eight deaths (22% mortality) occurred in the ZMapp group of 36 patients. One patient left treatment early and was not included in the analysis. Although the difference between the two groups translates to a 40% lower risk of death for those who received ZMapp, the difference did not reach statistical significance.
Should new cases of Ebola arise, Mapp Biopharmaceutical has received funding from the U.S. Biomedical Advanced Research and Development Authority to offer ZMapp to patients with confirmed EVD in the four countries where the trial occurred under an expanded access protocol (EAP). Expanded access is a U.S. regulatory mechanism that enables an investigational drug to be made available to treat a serious or life-threatening disease for which no comparable or satisfactory alternative therapy is available. The EAP was reviewed and considered safe to proceed in the United States by the U.S. Food and Drug Administration. The company will make appropriate regulatory applications on the three West African countries that participated in PREVAIL II as well.
Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices
There has been a lot of misunderstanding by non-software quality assurance professionals about the definition of software validation. The definition Target Health Inc. was taught, by experts, at the time we started software development in the late 1990’s, was that validated software acts as intended. Fortunately, FDA has defined validation in the draft guidance and it is as follows.
One component of design validation is software validation. Software validation refers to establishing, by objective evidence, that the software conforms with the user needs and intended uses of the device. Software validation is a part of design validation of the finished device. It involves checking for proper operation of the software in its actual or simulated use environment, including integration into the final device where appropriate. Software validation is highly dependent upon comprehensive software testing and other verification tasks previously completed at each stage of the software development life cycle. Planning, verification, traceability, configuration management, and many other aspects of good software engineering are important activities that together help to support a conclusion that software is validated.
FDA has issued a draft guidance entitled Content of Premarket Submissions for Software Contained in Medical Devices. The draft Guidance provides information to industry regarding the documentation that FDA recommends that companies include in premarket submissions for software devices, including stand-alone software applications and hardware-based devices that incorporate software. This document is a result of ongoing efforts to state FDA’s recommendations more clearly and ensure they remain current as technology advances. This document supersedes Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, issued May 29, 1998, and Reviewer Guidance for a Premarket Notification Submission for Blood Establishment Computer Software, issued January 13, 1997.
For the purposes of this document, FDA refers to devices that contain one or more software components, parts, or accessories, or are composed solely of software as software devices, including:
1. Firmware, the permanent software programmed into a read-only memory, as well as other means for software-based control of medical devices
2. Stand-alone software applications
3. Software intended for installation in general-purpose computers
4. Dedicated hardware/software medical devices.
5. Accessories to medical devices when those accessories contain or are composed of software.
This guidance applies to software devices regardless of the means by which the software is delivered to the end user, whether factory-installed, installed by a third-party vendor, or field-installed or -upgraded. Software not covered by this guidance includes software designed for manufacturing or other process-control functions but not intended for use as a device.
Pasta with Fresh Corn, Basil, Pine Nuts & Parmesan
Oh-h, this is so-o good! With or without chicken, fish or seafood, you won’t be able to stop eating this delicious dish. ©Joyce Hays, Target Health Inc.
Pinch Kosher or sea salt
12 ounces dry farfalle (bow tie pasta, made in chicken broth)
1 Tablespoon olive oil
3 Tablespoons truffle oil, (black or white) drizzle before serving
10 scallions, trimmed and thinly sliced (keep the whites and greens separate)
6 garlic cloves, sliced thin
1 cup pine nuts, toasted
5 large or 6 medium ears corn, shucked & kernels removed (approximately 4-5 cups kernels)
Pinch black pepper
1 teaspoon turmeric
Pinch chili flakes (no more than 1 pinch)
3 Tablespoons unsalted butter
1/2 cup grated Parmesan cheese, more to taste
1/2 cup fresh basil leaves, finely chopped
1/2 cup fresh mint leaves, finely chopped
1/2 cup fresh dill, finely chopped
Handful fresh parsley, finely chopped for garnish
Zest of 1/2 fresh lemon
Juice of 1/2 fresh lemon
I forgot to put the truffle oil in this photo of ingredients, but if you make this recipe be sure to use it. ©Joyce Hays, Target Health Inc.
1. Toast pine nuts, then set aside.
First toast the pine nuts, then set aside. ©Joyce Hays, Target Health Inc.
2. Cook pasta 1 minute less than usual (according to the package directions). Cook in chicken stock or broth, instead of water.
3. When pasta is done, remove it from pot with slotted spoon and put into a separate bowl, to drain. Save all the pasta liquid left in the pot.
I always make pasta (and rice) by boiling in chicken stock or broth, then save the liquid for other uses. Above the pasta has been cooked and is now draining. ©Joyce Hays, Target Health Inc.
Hold each cob at the base, then use a medium sharp knife to cut/scrape the kernels off. Set aside. ©Joyce Hays, Target Health Inc.
4. Do all the chopping, you need to do for this recipe. Chop everything on the same board, and do as much as you can at the same time.
Chopping all the herbs at once. Use same cutting board to chop scallions, garlic. In the top left, you can see the lemon zest, done and set aside. ©Joyce Hays, Target Health Inc.
While the pasta is boiling, grate the parmesan. ©Joyce Hays, Target Health Inc.
I’m using one of my favorite pans for this recipe. It’s a heavy iron pan with a cover. The two handles makes it easy to move and carry. It goes from stovetop to oven to table and cooks everything really well. I bought it on Amazon. ©Joyce Hays, Target Health Inc.
5. Meanwhile, heat oil in a large oven-proof, pan, (that can also be used for serving on the table) over medium heat. Add scallions, garlic cloves sliced, pinch of salt and cook until soft, 3 minutes. Add 1/4 cup of the pasta liquid (that you saved), and all the corn except for, 1/4 cup corn. Set aside ? cup of corn.
This is step 4, starting the cooking. ©Joyce Hays, Target Health Inc.
6. Simmer until corn is heated through and almost tender, 3 to 5 minutes. Add pinch black pepper and the turmeric.
Add most of the corn and stir to combine. Put aside the ? cup of kernels, you saved. ©Joyce Hays, Target Health Inc.
7. Transfer the saut?ed corn mixture, to a blender, or food processor and pur?e mixture until smooth, adding a little extra pasta liquid, if needed, to get a thick but pourable texture. Let it sit, while you do the next step.
From pan to food processor. ©Joyce Hays, Target Health Inc.
Pulse until you puree the contents. ©Joyce Hays, Target Health Inc.
8. Using the same pan, (over high heat), don’t rinse it out. Add butter and let melt. Add the 1/4 cup corn, that you saved, and cook until tender, 1 minute. (It’s O.K. if the butter browns; that deepens the flavor.)
To the same pan, add butter and the saved corn kernels. ©Joyce Hays, Target Health Inc.
9. Add the corn pur?e that you left in the blender, to the white pan with larger pieces of corn. Cook, only, for 30 seconds to heat and combine the flavors.
Add the contents of the blender or food processor, to the whole kernels in the pan. ©Joyce Hays, Target Health Inc.
10. Reduce heat to medium. Add all the pasta that was draining in a bowl. Add the lemon zest and stir it in, then add the lemon juice and stir it in.
Here, I’m adding the pasta and the lemon zest. ©Joyce Hays, Target Health Inc.
After stirring the pasta in, I’m adding all the chopped herbs. ©Joyce Hays, Target Health Inc.
11. Add half (not all) the pasta liquid still left, to the pan with corn. Toss everything to coat all the pasta. Cook for 1 minute. If you think the mixture is too thick, add a little more of the left-over pasta liquid. If not too thick and just right, go to the next step.
12. Stir in 1/4 cup of the scallion greens, the Parmesan, the herbs, the chili flakes and the toasted pine nuts.
Adding the toasted pine nuts. ©Joyce Hays, Target Health Inc.
Finally, adding some parmesan and the chili flakes. Will stir well and toss to combine everything well. ©Joyce Hays, Target Health Inc.
13. For the final few minutes, before serving, dust with more freshly grated parmesan, and drizzle over the parmesan, the 2 Tablespoons of truffle oil and with a cover on, warm for a few more minutes.
14. Also, consider, putting this in a preheated 400 degree oven for 10 minutes, so the parmesan melts. No cover, if you put in the oven.
Here is the finished dish, waiting for the final touches of truffle oil and parmesan, before going into the oven. ©Joyce Hays, Target Health Inc.
Just sprinkled with truffle oil and parmesan. Now, going into 400 degree oven for 10 minutes. ©Joyce Hays, Target Health Inc.
15. Bring to table and set down on an attractive trivet, the warm pasta. Sprinkle with extra well chopped fresh parsley and serve.
Here’s the done deal! Smells wonderful! Will not disappoint, ©Joyce Hays, Target Health Inc.
First a refreshing salad, with cucumber, tomatoes, endive, avocado, and green olives, in a simple dressing of extra virgin olive oil and fresh lemon juice. ©Joyce Hays, Target Health Inc.
A new icy white Italian, La Scolca. ©Joyce Hays, Target Health Inc.
This is another wine from the Piedmont area. Grapes from Cortese vines, vines which average over 60 years of age. As you see, this delicious wine is pale straw in color with flavors of Intense lemon citrus fruit, plus floral and has a flinty layer, comparable to the best wines from Chablis. Some say medium body, for us it was full bodied, as white wines go. The finish is crisp, refreshing and long. This wine was delicious with the new Pasta Recipe above, as well as the salad we started with. If you purchase this wine yourself, it will run in the $40 range; however, in a restaurant it will cost over $100 per bottle.
Simple dessert: Grapes, cheese & wine, followed by the last piece of last week’s
Apple Marzipan Cake. ©Joyce Hays, Target Health Inc.
We are devoted cat people so when one of our beloved cats died this weekend, we stayed home. Just too sad for us to go out. This was our beautiful boy, BillyBob. Because the tiny kitten was born right after 9/11 and because I was emailing back and forth with the cat breeder about Persians, right after we bought BillyBob, the breeder out on Long Island got a visit from the CIA. That’s right; the CIA. A red flag must have gone up for those who evesdrop and/or hack into, phone lines, when there was so much talk of Persians.
Such a sweet face. BillyBob on the right, on my home office desk, and Dodi curled up on the left. ©Joyce Hays, Target Health Inc.
From Our Table to Yours !