Scientists provide first evidence that carbamates can upset circadian rhythms
January 19, 2017
University at Buffalo
Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks researchers have found.
Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks, University at Buffalo researchers have found. The research suggests that exposure to these insecticides adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes.
Published online on Dec. 27 in Chemical Research in Toxicology, the research combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. It was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.
Disruptions in human circadian rhythms are known to put people at higher risk for diabetes and other metabolic diseases but the mechanism involved is not well-understood.
“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors,” said Margarita L. Dubocovich, PhD, senior author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology and senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences at UB.
“No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows,” she said.
The current research focuses on two chemicals, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife.
“We found that both insecticides are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion,” said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB. “That means that exposure to them could put people at higher risk for diabetes and also affect sleeping patterns.”
The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something which is not currently being considered by federal regulators. The UB researchers are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.
The work is part of a larger effort by Dubocovich and her colleagues at UB to develop their Chem2Risk pipeline, combining UB’s expertise in computational biology and melatonin receptor pharmacology.
“Our approach seamlessly integrates the screening of environmental chemicals through computer simulation, in vitro and in vivo techniques to gauge the risk these chemicals present for various disease end points,” explained Raj Rajnarayanan, PhD, lead author and assistant professor of pharmacology and toxicology at UB.
The UB database contains about four million chemicals reported to have some level of toxicity. “From those, we identified hundreds of thousands of compounds that had readily available chemical structures so that we could study them,” Rajnarayanan explained. After grouping the chemicals in clusters according to their similarity, they found several with functional groups similar to melatonin.
Using predictive computational modeling and in vitro experiments with cells that express human melatonin receptors, they found that carbamates selectively interact with a melatonin receptor. That interaction can disrupt melatonin signaling and alter important regulatory processes in the body.
“By directly interacting with melatonin receptors in the brain and peripheral tissues, environmental chemicals, such as carbaryl, may disrupt key physiological processes leading to misaligned circadian rhythms, sleep patterns, and altered metabolic functions increasing the risk for chronic diseases such as diabetes and metabolic disorders,” said Dubocovich.
For example, she explained, there is a fine balance between the release of insulin and glucose in the pancreas at very specific times of day, but if that balance becomes disrupted over a long period of time, there is a higher risk of developing diabetes.
Dubocovich is an internationally renowned authority on the brain hormone melatonin and how melatonin receptors are regulated. Her work has significantly boosted the scientific understanding of how melatonin impacts circadian rhythms and human health in general, including sleep disorders, metabolic disease and drug addiction.
Popovska-Gorevski presented preliminary findings on this work at the 2014 Experimental Biology meeting in San Diego, receiving a Best Abstract Award from the Toxicology Division of the American Society for Pharmaceutical and Experimental Therapeutics and a Best Poster Award from the Upstate New York Pharmacology Society.
- Marina Popovska-Gorevski, Margarita L. Dubocovich, Rajendram V. Rajnarayanan. Carbamate Insecticides Target Human Melatonin Receptors. Chemical Research in Toxicology, 2017; DOI: 10.1021/acs.chemrestox.6b00301
Source: University at Buffalo. “Insecticides mimic melatonin, creating higher risk for diabetes: Scientists provide first evidence that carbamates can upset circadian rhythms.” ScienceDaily. ScienceDaily, 19 January 2017. <www.sciencedaily.com/releases/2017/01/170119120213.htm>.
January 18, 2017
University of Tromso (Universitetet i Tromsø – UiT)
A new model reconstruction shows in exceptional detail the evolution of the Eurasian ice sheet during the last ice age. This can help scientists understand how climate and ocean warming can affect the remaining ice masses on Earth.
A new model reconstruction shows in exceptional detail the evolution of the Eurasian ice sheet during the last ice age. This can help scientists understand how climate and ocean warming can affect the remaining ice masses on Earth.
The Eurasian ice sheet was the third largest ice mass during the Last Glacial Maximum some 22,000 years ago. Alongside the Antarctic and North American ice sheets it lowered the global sea level by more than 120 metres. In volume it was almost three times greater than the modern day Greenland ice sheet.
At its peak there was continuous ice cover from present-day Ireland, across Scandinavia and all the way through to western Siberia in the Russian High Arctic.
The results are published in Quaternary Science Reviews (Open access)
Three ice caps that merged
It all started some 37,000 years ago when the planet’s climate started getting colder. This process happened as part of the natural climate cycles on our planet, which are linked to Earth’s movements around the sun and around its own axis. For the last million years or so these cycles have repeated consistently every 100,000 years: 90,000 years of ice age followed by a roughly 10,000 year interglacial warm period.
“The Eurasian Ice Sheet started life off as a number of small and isolated ice caps scattered across Europe and the Arctic. Through time, and with the climate getting increasingly colder this ice grew, with the ice caps eventually merging together to form one coherent ice sheet. The weight of this ice was sufficient to warp Earth’s crust, making dramatic changes to the coastline.” says Patton.
It is a slow process from human perspective, but from a geological point of view things do happen quite quickly: within 6,000 years these individual ice sheets were large enough to develop fast-flowing ice streams, and within 13,000 years they merged into one continuous ice mass.
Twice the Mediterranean
“By itself it lowered global sea level by more than 17 metres. However, despite its global influence, attempts to understand the climatic and oceanographic drivers behind its growth have remained poorly resolved.” says postdoc Henry Patton from the Centre for Arctic Gas Hydrate, Environment and Climate (CAGE)
Until now, that is. Patton and colleagues have recently published comprehensive, high-resolution model experiments, detailing the inception and evolution of the Eurasian ice sheet from its first steps 37,000 years ago through to its maximum extent some 15,000 years later.
They calculated that by that time the ice sheet had grown to a massive volume of more than 7 million cubic kilometres — twice the volume of the Mediterranean Sea. It had an average ice thickness of more than 1.3 km.
“Our model allows us to appreciate the complexities and sensitivities of such a vast ice sheet. The climate that made this ice complex grow was significantly different to the climate we experience today. The issue is further complicated by the fact that once an ice sheet grows large enough, it also begins to heavily influence the regional climate patterns around it.”
Wet in the west, desert in the east
It takes more than just cold temperatures to make an ice sheet grow. It also depends a lot on the amount of snowfall, which enables the ice sheet to accumulate mass. Then, as today, Norway, Britain and Ireland were subject to relatively wet, maritime conditions, with the coastal mountains becoming the perfect setting for ice accumulation.
“Snowfall is a key factor for making an ice sheet grow. In the case of the Eurasian ice sheet complex, snowfall across the mountains of Western Europe was vital for allowing the various ice caps to initially expand.”
The Eurasian ice sheet had an enormous influence on the climate at the continental scale: it absorbed precipitation to such an extent that it created a rain-shadow effect effectively turning much of western Russia and Siberia into a frozen desert where glaciers could not grow.
“As the ice sheet grew thicker, less and less precipitation was able to reach the lee areas east of the complex. This created desert conditions similar to what we see in the Dry Valleys of Antarctica today.” Patton explains.
Traces on the ocean floor
Successfully reconstructing the evolution of an ice sheet through millennia depends on the quality and abundance of observational data available. Distributions of glacial sediments, radiocarbon dates, and geological features found on the landscape are all examples of data that can help guide modelling experiments. As the ice moved it also left traces on the ocean floor.
“Perhaps the most important advance to have aided this modelling work is the quantity and quality of geophysical data from beneath marine areas that we now have access too. Only 10-15 years ago we had a very limited understanding of what Eurasian ice was doing offshore, particularly in the Barents and Kara seas.”
Major portions of this ice sheet were grounded below sea level, just like in West Antarctica today. Understanding the climatic and oceanographic sensitivities of this Eurasian ice sheet, and how it impacted the environment, is thus important also for our present-day ice sheets.
The next step for Patton and colleagues will be to model the collapse of this Eurasian ice-sheet.
“One of the major questions facing us today is how the present ice sheets in Greenland and Antarctica will react to climate change. Simply put, the more we understand of the mechanisms that drove ice sheets to collapse in the past, the better we will be able to predict what will happen in the future.”
Materials provided by University of Tromso (Universitetet i Tromsø – UiT). Original written by Maja Sojtaric. Note: Content may be edited for style and length.
- Henry Patton, Alun Hubbard, Karin Andreassen, Monica Winsborrow, Arjen P. Stroeven. The build-up, configuration, and dynamical sensitivity of the Eurasian ice-sheet complex to Late Weichselian climatic and oceanic forcing. Quaternary Science Reviews, 2016; 153: 97 DOI: 10.1016/j.quascirev.2016.10.009
Source: University of Tromso (Universitetet i Tromsø – UiT). “New reconstruction of an ancient ice sheet.” ScienceDaily. ScienceDaily, 18 January 2017. <www.sciencedaily.com/releases/2017/01/170118082419.htm>.
January 17, 2017
European Southern Observatory – ESO
New images have revealed otherwise invisible details of our Sun, including a new view of the dark, contorted center of a sunspot that is nearly twice the diameter of the Earth. The images are the first ever made of the Sun with a facility where ESO is a partner. The results are an important expansion of the range of observations that can be used to probe the physics of our nearest star.
New images taken with the Atacama Large Millimeter/submillimeter Array (ALMA) in Chile have revealed otherwise invisible details of our Sun, including a new view of the dark, contorted centre of a sunspot that is nearly twice the diameter of the Earth. The images are the first ever made of the Sun with a facility where ESO is a partner. The results are an important expansion of the range of observations that can be used to probe the physics of our nearest star. The ALMA antennas had been carefully designed so they could image the Sun without being damaged by the intense heat of the focussed light.
Astronomers have harnessed ALMA’s capabilities to image the millimetre-wavelength light emitted by the Sun’s chromosphere — the region that lies just above the photosphere, which forms the visible surface of the Sun. The solar campaign team, an international group of astronomers with members from Europe, North America and East Asia , produced the images as a demonstration of ALMA’s ability to study solar activity at longer wavelengths of light than are typically available to solar observatories on Earth.
Astronomers have studied the Sun and probed its dynamic surface and energetic atmosphere in many ways through the centuries. But, to achieve a fuller understanding, astronomers need to study it across the entire electromagnetic spectrum, including the millimetre and submillimetre portion that ALMA can observe.
Since the Sun is many billions of times brighter than the faint objects ALMA typically observes, the ALMA antennas were specially designed to allow them to image the Sun in exquisite detail using the technique of radio interferometry — and avoid damage from the intense heat of the focussed sunlight . The result of this work is a series of images that demonstrate ALMA’s unique vision and ability to study our Sun.The data from the solar observing campaign are being released this week to the worldwide astronomical community for further study and analysis.
The team observed an enormous sunspot at wavelengths of 1.25 millimetres and 3 millimetres using two of ALMA’s receiver bands. The images reveal differences in temperature between parts of the Sun’s chromosphere . Understanding the heating and dynamics of the chromosphere are key areas of research that will be addressed in the future using ALMA.
Sunspots are transient features that occur in regions where the Sun’s magnetic field is extremely concentrated and powerful. They are lower in temperature than the surrounding regions, which is why they appear relatively dark.
The difference in appearance between the two images is due to the different wavelengths of emitted light being observed. Observations at shorter wavelengths are able to probe deeper into the Sun, meaning the 1.25 millimetre images show a layer of the chromosphere that is deeper, and therefore closer to the photosphere, than those made at a wavelength of 3 millimetres.
ALMA is the first facility where ESO is a partner that allows astronomers to study the nearest star, our own Sun. All other existing and past ESO facilities need to be protected from the intense solar radiation to avoid damage. The new ALMA capabilities will expand the ESO community to include solar astronomers.
 The ALMA Solar Campaign team includes: Shin’ichiro Asayama, East Asia ALMA Support Center, Tokyo, Japan; Miroslav Barta, Astronomical Institute of the Czech Academy of Sciences, Ondrejov, Czech Republic; Tim Bastian, National Radio Astronomy Observatory, USA; Roman Brajsa, Hvar Observatory, Faculty of Geodesy, University of Zagreb, Croatia; Bin Chen, New Jersey Institute of Technology, USA; Bart De Pontieu, LMSAL, USA; Gregory Fleishman, New Jersey Institute of Technology, USA; Dale Gary, New Jersey Institute of Technology, USA; Antonio Hales, Joint ALMA Observatory, Chile; Akihiko Hirota, Joint ALMA Observatory, Chile; Hugh Hudson, School of Physics and Astronomy, University of Glasgow, UK; Richard Hills, Cavendish Laboratory, Cambridge, UK; Kazumasa Iwai, National Institute of Information and Communications Technology, Japan; Sujin Kim, Korea Astronomy and Space Science Institute, Daejeon, Republic of Korea; Neil Philips, Joint ALMA Observatory, Chile; Tsuyoshi Sawada, Joint ALMA Observatory, Chile; Masumi Shimojo (interferometry lead), NAOJ, Tokyo, Japan; Giorgio Siringo, Joint ALMA Observatory, Chile; Ivica Skokic, Astronomical Institute of the Czech Academy of Sciences, Ondrejov, Czech Republic; Sven Wedemeyer, Institute of Theoretical Astrophysics, University of Oslo, Norway; Stephen White (single dish lead), AFRL, USA; Pavel Yagoubov, ESO, Garching, Germany and Yihua Yan, NAO, Chinese Academy of Sciences, Beijing, China.
 Indeed, this lesson has been learned the hard way: the Swedish-ESO Submillimetre Telescope (SEST) had a fire in its secondary mirror assembly after the telescope was accidentally pointed at the Sun.
 A map of the whole disc of the Sun was also made with a single ALMA antenna, using a technique called fast-scanning, at a wavelength of 1.25 millimetres. The accuracy and speed of observing with a single ALMA antenna makes it possible to produce a map of the entire solar disc in just a few minutes. These maps show the distribution of temperatures in the chromosphere over the whole disc at low spatial resolution and therefore complement the detailed interferometric images of individual regions of interest.
Source: European Southern Observatory – ESO. “The sun in detail: Contorted center of sunspot nearly twice the size of Earth.” ScienceDaily. ScienceDaily, 17 January 2017. <www.sciencedaily.com/releases/2017/01/170117101835.htm>.
January 16, 2017
Université de Montréal
The timing of the first entry of humans into North America across the Bering Strait has now been set back 10,000 years, scientists report.
The timing of the first entry of humans into North America across the Bering Strait has now been set back 10,000 years.
This has been demonstrated beyond a shadow of a doubt by Ariane Burke, a professor in Université de Montréal’s Department of Anthropology, and her doctoral student Lauriane Bourgeon, with the contribution of Dr. Thomas Higham, Deputy Director of Oxford University’s Radiocarbon Accelerator Unit.
The earliest settlement date of North America, until now estimated at 14,000 years Before Present (BP) according to the earliest dated archaeological sites, is now estimated at 24,000 BP, at the height of the last ice age or Last Glacial Maximum.
The researchers made their discovery using artifacts from the Bluefish Caves, located on the banks of the Bluefish River in northern Yukon near the Alaska border. The site was excavated by archaeologist Jacques Cinq-Mars between 1977 and 1987. Based on radiocarbon dating of animal bones, the researcher made the bold hypothesis that human settlement in the region dated as far back as 30,000 BP.
In the absence of other sites of similar age, Cinq-Mars’ hypothesis remained highly controversial in the scientific community. Moreover, there was no evidence that the presence of horse, mammoth, bison and caribou bones in the Bluefish Caves was due to human activity.
To set the record straight, Bourgeon examined the approximate 36,000 bone fragments culled from the site and preserved at the Canadian Museum of History in Gatineau — an enormous undertaking that took her two years to complete. Comprehensive analysis of certain pieces at UdeM’s Ecomorphology and Paleoanthropology Laboratory revealed undeniable traces of human activity in 15 bones. Around 20 other fragments also showed probable traces of the same type of activity.
“Series of straight, V-shaped lines on the surface of the bones were made by stone tools used to skin animals,” said Burke. “These are indisputable cut-marks created by humans.”
Bourgeon submitted the bones to further radiocarbon dating. The oldest fragment, a horse mandible showing the marks of a stone tool apparently used to remove the tongue, was radiocarbon-dated at 19,650 years, which is equivalent to between 23,000 and 24,000 cal BP (calibrated years Before Present).
“Our discovery confirms previous analyses and demonstrates that this is the earliest known site of human settlement in Canada,” said Burke. It shows that Eastern Beringia was inhabited during the last ice age.”
Beringia is a vast region stretching from the Mackenzie River in the Northwest Territories to the Lena River in Russia. According to Burke, studies in population genetics have shown that a group of a few thousand individuals lived in isolation from the rest of the world in Beringia 15,000 to 24,000 years ago.
“Our discovery confirms the ‘Beringian standstill [or genetic isolation] hypothesis,'” she said, “Genetic isolation would have corresponded to geographical isolation. During the Last Glacial Maximum, Beringia was isolated from the rest of North America by glaciers and steppes too inhospitable for human occupation to the West. It was potentially a place of refuge.”
The Beringians of Bluefish Caves were therefore among the ancestors of people who, at the end of the last ice age, colonized the entire continent along the coast to South America.
The results of Lauriane Bourgeon’s doctoral research were published in the January 6 edition of PLoS One under the title “Earliest Human Presence in North America Dated to the Last Glacial Maximum: New Radiocarbon Dates from Bluefish Caves, Canada.” The article is co-authored by Professor Burke and by Dr. Thomas Higham of Oxford University’s Radiocarbon Accelerator Unit, in the U.K.
- Lauriane Bourgeon, Ariane Burke, Thomas Higham. Earliest Human Presence in North America Dated to the Last Glacial Maximum: New Radiocarbon Dates from Bluefish Caves, Canada. PLOS ONE, 2017; 12 (1): e0169486 DOI: 10.1371/journal.pone.0169486
Source: Université de Montréal. “First humans arrived in North America a lot earlier than believed.” ScienceDaily. ScienceDaily, 16 January 2017. <www.sciencedaily.com/releases/2017/01/170116091428.htm>.
The Paperless Clinical Trial – New Publication in Applied Clinical Trials
On 4 January 2017, Applied Clinical Trials published an online paper, entitled, Regulatory Considerations when Designing and Running 21st Century Paperless Clinical Trials. The paper is coauthored by Jonathan Helfgott, MS, former the Associate Director for Risk Science at FDA CDER OSI and the main author of FDA’s eSource Guidance, and Jules Mitchel, MBA, PhD, President, Target Health Inc. Jonathan is currently the Coordinator of the Regulatory Science Graduate Program at Johns Hopkins University.
The following are some excerpts from the paper which is meant to be both informative and evocative.
Introduction: The regulatory push to the paperless clinical trial has occurred despite a pharmaceutical industry that has been risk-averse in adopting modern-day technology tools that could support clinical trials. This risk aversion is in part due to fear by sites and sponsors of receiving a FDA Form 483. What if the FDA turns down an application if it discovers that, for example, a patient was born in 1982, when in the study database it is recorded as 1983, even when there is no impact on the study results? The clinical sites are also fearful of losing business as a result of any FDA Form 483 finding, however minor.
Risk Assessments: A quality by design (QbD) methodology, which includes a risk assessment and risk mitigation strategies, is a critical exercise when building software. Using a Boeing 787 analogy, a plane has several electrical systems that control the engine and the coffee machine. We should not assign the same risk to the coffee machine not delivering hot coffee as we do to the engine failing on takeoff.
Discussion and Conclusion: For more than a decade, technologies and processes allowing for the paperless clinical trial have been substantiated and encouraged from both the business and regulatory perspectives. The time is ripe to put away fears of regulatory sanctions when using modern technology, and make changes to modernize and optimize the drug and device development processes that will ultimately, positively, support the regulatory approval process.
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.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Azithromycin Structure: Source: By Giorgiogp – Own work, Wikimedia Commons
Azithromycin is an antibiotic indicated for the treatment of a number of bacterial infections. A team of researchers at the pharmaceutical company Pliva, located in Zagreb, 1) ___, (Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburasev, led by Dr. Slobodan Dokic), discovered azithromycin in 1980. It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991. Pfizer’s exclusive rights have since lapsed and Pliva-manufactured azithromycin is also marketed in the United States by generic drug maker Teva Pharmaceuticals (which now owns Pliva).
Indications for use of azithromycin include middle ear infections, strep 2) ___, pneumonia, traveler’s diarrhea, and certain other intestinal infections. It may also be used for a number of sexually transmitted infections including chlamydia and gonorrhea infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day. Common side effects include nausea, vomiting, diarrhea and upset 3) ___. An allergic reaction or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with its use during pregnancy. Its safety during breastfeeding is not confirmed, but it is likely safe. Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thus stopping bacterial growth.
Azithromycin is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic 4) ___ system. It is available as a generic medication and is sold under many trade names worldwide. The wholesale cost in the developing world is about 0.18 to 2.98 USD per dose. In the United States it is about 33 USD for a course of treatment.
Azithromycin is used to treat many different infections, including:
1. Prevention and treatment of acute bacterial exacerbations of chronic obstructive 5) ___ disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.
2. Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.
3. Community-acquired pneumonia’ due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
4. Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.
5. Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
6. Uncomplicated skin and skin structure infections due to S. aureus, S. pyogenes, or S. agalactiae
7. Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae
8.Genital ulcer disease (chancroid) in men due to H. ducreyi
9. In combination with ceftriaxone, 6) ___ is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci.
Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative 7) ___, and many atypical bacteria. A strain of gonnorhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin, but the drug is not widely used as monotherapy due to a low barrier to resistance development.
No harm has been found with use during pregnancy. However, there are no adequate well-controlled studies in 8) ___ women. Safety of the medication during breastfeeding is unclear. It has been reported that because only low levels are found in breastmilk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects. Nevertheless, it is recommended that the drug be used with caution during breastfeeding.
Most common side effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to change in advice comes because to date, no evidence conclusively demonstrates antibiotics (other than rifampicin or rifabutin) affect these contraceptives. Occasionally, patients have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy. Clostridium difficile has been reported with use of azithromycin.
In 2013 the FDA issued a warning that azithromycin, can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm. The FDA noted in the warning a 2012 study that found the drug may increase the risk of 9) ___, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.
Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.
Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility. Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days. Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours. Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.
After several years, the U.S. Food and Drug Administration approved AzaSite, an ophthalmic formulation of azithromycin, for the treatment of 10) ___ infections. AzaSite is marketed in the U.S. and Canada by Inspire Pharmaceuticals, a wholly owned subsidiary of Merck. Sources: Wikipedia; WebMD
ANSWERS: 1) Croatia; 2) throat; 3) stomach; 4) health; 5) pulmonary; 6) azithromycin; 7) bacteria; 8) pregnant; 9) death; 10) eye
100 Years Later, Death Theories of Healer, Grigori Rasputin Remain a Mystery
Grigori Rasputin 1869-1916: Photo source: Public Domain, Wikipedia Commons
Grigori Yefimovich Rasputin was a Russian peasant, an experienced traveler, a mystical faith healer, and trusted friend of the family of Nicholas II, the last Tsar of the Russian Empire. He became an influential figure in Saint Petersburg, especially after August 1915 when Nicholas took command of the army fighting in World War I. Advising his wife, Alexandra Feodorovna, in countless spiritual and political issues, Rasputin became an easy scapegoat for Russian nationalists, liberals and aristocrats. There is uncertainty over much of Rasputin’s life and the degree of influence that he exerted over the extremely shy Tsar and the strong-willed Tsarina. Accounts are often based on dubious memoirs, hearsay, and legend. While his influence and position may have been exaggerated by society gossip and his own drunken boasting his presence played a significant role in the increasing unpopularity of the Imperial couple. It is believed that Rasputin was murdered by monarchists who hoped to save Tsarism by ending his sway over the royal family. The end of December 2016, marked the 100th anniversary of the death of Rasputin, the mad monk of Russia, or lover of the Russian queen.
Grigori Yefimovich Rasputin, a mystic and spiritual healer born in Pokrovskoe in Siberia, wielded huge influence over the Russian royal family, particularly Alexandra, the Tsarina, who looked to the spiritual healer to cure her hemophiliac son, heir, Tsesarevich Alexei.
On 13 October 1906, Rasputin paid a visit to the Imperial family and presented an icon. On request of the Tsar, he then visited the next prime minister, Pyotr Stolypin. A few weeks before, 29 people had been killed on Aptekarsky Island in a bomb attack by the Maximalists and two of Stolypin’s children were wounded. Rasputin was invited to pray. On 6 April 1907, Rasputin was invited to Alexander Palace in Tsarskoe Selo, this time to see Tsesarevich Alexei, the heir. The boy had suffered an injury which caused him painful bleeding. By then, it was not known that Alexei had a rare form of hemophilia. The doctors could not supply a cure, and the desperate Tsarina invited Rasputin. He was able to calm the parents and their son, standing at the foot of the bed and praying. From that moment, Alexandra believed Rasputin was Alexei’s savior. Pierre Gilliard, the French historian Helene Carrere d’Encausse, and journalist Diarmuid Jeffreys speculated that Rasputin’s healing practice included halting the administration of aspirin, a pain-relieving analgesic available since 1899. Aspirin is an anticoagulant and has blood-thinning properties; the mechanism of action of aspirin is that it prevents clotting and promotes bleeding, which could have caused the hemarthrosis at the root of Alexei’s joints swelling and pain. On September 1912, the Romanovs were visiting their hunting retreat in the Bialowieza Forest; on 5 September, the careless Tsesarevich jumped into a rowboat and hit one of the oarlocks. A large bruise appeared within minutes. Within a week the hematoma reduced in size. In mid-September, the family moved to Spala (then in Russian Poland). On 2 October, after a drive in the woods, the juddering of the carriage had caused still healing hematoma in his upper thigh to rupture and start bleeding again. Alexei had to be carried out in an almost unconscious state. His temperature rose and his heartbeat dropped, caused by a swelling in the left groin; Alexandra barely left his bedside. A constant record was kept of the boy’s temperature. On 10 October, a medical bulletin appeared in the newspapers, and Alexei received the last sacrament. His condition then improved at once, according to the Tsar. The positive trend continued throughout the next day. According to Nelipa, Robert K. Massie was correct to recommend that psychological factors do play a part.
It is not exactly clear on which day, either 9, 10, or 11 October, the Tsarina turned to her lady-in-waiting and best friend, Anna Vyrubova, to secure the help of the peasant healer, who at that time was out of favor. According to his daughter, Rasputin received the telegram on 12 October. If Maria Rasputin was right about the day, the telegram was sent the longstanding claim that Rasputin had somehow alleviated Alexei’s condition is simply fictitious, according to Nelipa. The next day he seems to have responded, with a short telegram, including the prophecy: The little one will not die. Do not allow the doctors [c.q. Eugene Botkin and Vladimir Derevenko] to bother him too much. On 19 October, Alexei’s condition was considerably better and the hematoma disappeared, but he had to undergo orthopedic therapy to straighten his left leg. The court physician, Botkin, believed that Rasputin was a charlatan and his apparent healing powers arose from his use of hypnosis, but Rasputin was not interested in this practice before 1913 and his teacher Gerasim Papnadato was expelled from St. Petersburg in 1914. Felix Yusupov, one of Rasputin’s enemies, suggested that he secretly drugged Alexei with Tibetan herbs which he had obtained from a quack doctor. For Fuhrmann, these ideas on hypnosis and drugs flourished because the imperial family lived such isolated lives. For Moynahan, There is no evidence that Rasputin ever summoned up spirits, or felt the need to; he won his admirers through force of personality, not by tricks. For Maria Rasputin and Vladimir Sukhomlinov, it was magnetism. For Shelley, the secret of his power lay in the sense of calm, gentle strength, and shining warmth of conviction.
What is known about the death of Rasputin, December, 1916, one hundred years ago, is that one evening Rasputin went to the Yusupov Palace in St Petersburg at the invitation of Prince Felix Yusupov. Rasputin’s dead body was recovered from the frozen Neva River days later. No one is completely sure what happened in between these two events. The most well-known account of the events comes from Prince Yusupov himself in his memoirs Lost Splendour. This autobiography reads more like a boy’s own adventure story than a reliable historical document and many doubt the authenticity of what he wrote. According to Yusupov, when Rasputin arrived at the palace he was taken down to the cellar where he was given cake and madeira wine. Upstairs, a gramophone played Yankee Doodle Dandy to fool the monk in to believing there was a party in full swing. Yusupov and his accomplices had planned things carefully. The cakes offered to Rasputin had been laced with enough potassium cyanide to slay a monastery full of monks. But Rasputin just kept eating them. Incredulous at the monk’s survival, Prince Yusupov poured madeira into a cyanide-laced wine glass and handed it to Rasputin. Instead of collapsing into unconsciousness within seconds, as would be expected from a massive dose of cyanide, Rasputin continued to sip the wine like a connoisseur. A second lethal glass disappeared into the monk’s mouth with little apparent effect other than some difficulty swallowing. Asked if he was feeling unwell he replied Yes, my head is heavy and I’ve a burning sensation in my stomach. A third glass of tainted wine only seemed to revive him. Having ingested their whole stock of cyanide, the group of assassins were somewhat at a loss as to what to do next. So they shot him. The bullet appeared to have entered the body near the heart – certain death, or so they thought. But, soon after, Rasputin’s eyes opened and, clearly upset at the turn of events, he attacked Yusupov. There was a ferocious struggle before the prince could free himself and run away up the stairs. Rasputin followed. The group finally emerged into a courtyard, where four more shots were fired into Rasputin’s body before he slumped to the ground. To make sure they wouldn’t be troubled again, the assassins wrapped and tied the body with a piece of heavy linen, bundled it into a car and drove to Petrovski Island, where it was dropped from a bridge into the frozen river below.
The whole account sounds fanciful from start to finish, but remarkable things do happen. Human beings have achieved incredible physical feats in spite of horrible injuries. Maybe Rasputin really was still alive after the first shot and capable of a fight. But what about the poison? Surely no one could eat so much cyanide with so little effect? The theories as to why the cyanide didn’t kill Rasputin are almost as numerous as the theories of how he really died. What is surprising is that the theories are scientifically credible. The first theory is that the poisoners were not the supposed strength. Either they didn’t use enough, or the cyanide they had was old stock that had decayed into something far less toxic. Though plausible, a century after the events it is impossible to tell if this is true. The second theory is that Rasputin, aware that someone might be trying to kill him (he had survived at least one assassination attempt already), had decided to protect himself against poison. Perhaps he was inspired by Mithridates, king of Pontus in the first century BCE, who, fearful of poisoners, concocted an antidote or preventative. By ingesting sub-lethal amounts of every known poison he developed an immunity. When Mithridates was under threat from the local populace he tried to kill himself with poison, but the attempt failed and he had to request that a guard kill him with a sword. It is true that the body can develop a natural immunity or tolerance to some very toxic substances by administering very small doses over a period of time. Some of these toxic compounds include snake venom, ricin and opiates, to name but a few. Unfortunately, cyanide isn’t one of those substances. You simply cannot build up a natural tolerance to cyanide by using this method. The third theory is that Rasputin had alcoholic gastritis, which can lead to having less stomach acid. Without acid in the stomach, the potassium cyanide can’t be converted into hydrogen cyanide, and is therefore considerably less toxic. It’s another plausible explanation, but no one really knows if Rasputin suffered from this complaint or not. The fourth theory is that his poisoners unintentionally gave him the antidote along with the poison. Studies have shown that rats fed sugar with cyanide fare a lot better than those fed cyanide without it. The theory, though not proven, is that the sugar binds to the cyanide in a way that allows its excretion before it can be fully absorbed into the body. The assassins therefore may have chosen poorly when they elected to deliver the cyanide in sugary cakes and wine. The final theory is that Yusupov made the whole thing up, and Rasputin was simply shot shortly after he arrived at the palace by a person or persons unknown. This is probably much nearer the truth – but it isn’t nearly as interesting as stories of an unkillable monk.
Rasputin was an extraordinary but minor figure. He contributed little to the tragedy that engulfed Russia in the first two decades of the 20th century. Far more important were a grossly incompetent monarch in the shape of Nicholas II, a ruthless revolutionary in the form of Lenin, and a world war that the Russian government was no more able to avert than any other. All combined to bring down a nation that, if left to itself, might perhaps have become what so many Russians have hoped for, a normal and prosperous country. Sources: The Guardian (Kathryn Harkup); Wikipedia
Blood Biomarker May Predict Recovery From Concussions
Athletes who return to play before full recovery from concussions are at high risk for long-term symptoms like headaches, dizziness, and cognitive deficits with subsequent concussions. About half of college athletes see their post-concussive symptoms resolve within 10 days, but in others, the symptoms become chronic. Despite the millions of sports-related concussions that occur annually in the United States, there is no reliable blood-based test to predict recovery and an athlete’s readiness to return to play. Now, according to an article published online in Neurology (6 January 2017), NIH researchers have identified a blood biomarker that could better identify athletes who need more recovery time before safely returning to play after a sports-related concussion. The new study shows that measuring tau levels could potentially be an unbiased tool to help prevent athletes from returning to action too soon and risking further neurological injury. Tau is also connected to development of Alzheimer’s and Parkinson’s diseases, and is a marker of neuronal injury following severe traumatic brain injuries.
The new study evaluated changes in tau following a sports-related concussion in male and female collegiate athletes to determine if higher levels of tau relate to longer recovery durations. To measure tau levels, a group of 632 soccer, football, basketball, hockey, and lacrosse athletes from the University of Rochester first underwent pre-season blood plasma sampling and cognitive testing to establish a baseline. They were then followed during the season for any diagnosis of a concussion, with 43 of them developing concussions during the study. For comparison, a control group of 37 teammate athletes without concussions was also included in the study, as well as a group of 21 healthy non-athletes. Following a sports-related concussion, blood was sampled from both the concussed and control athletes at six hours, 24 hours, 72 hours, and seven days post-concussion.
Results showed that concussed athletes who needed a longer amount of recovery time before returning to play, (more than 10 days post-concussion) had higher tau concentrations overall at six, 24, and 72-hours post-concussion compared to athletes who were able to return to play in 10 days or less. These observed changes in tau levels occurred in both male and female athletes, as well as across the various sports studied. According to the authors, these findings indicate that changes in tau measured in as short a time as within six hours of a sports-related concussion may provide objective clinical information to better inform athletes, trainers, and team physicians’ decision-making about predicted recovery times and safe return to play. The authors added that further research will test additional protein biomarkers and examine other post-concussion outcomes.
Parental Obesity Linked to Delays in Child Development
Research indicates that about 1 in 5 pregnant women in the United States is overweight or obese.
According to an article published in Pediatrics (January 2017), children of obese parents may be at risk for developmental delays and were more likely to fail tests of fine motor skill — the ability to control movement of small muscles, such as those in the fingers and hands. Children of obese fathers were more likely to fail measures of social competence, and those born to extremely obese couples also were more likely to fail tests of problem solving ability.
For the study, authors reviewed data collected from the Upstate KIDS study, which originally sought to determine if fertility treatments could affect child development from birth through age 3. More than 5,000 women enrolled in the study roughly 4 months after giving birth in New York State (excluding New York City) between 2008 and 2010. To assess development, parents completed the Ages and Stages Questionnaire after performing a series of activities with their children. The test isn’t used to diagnose specific disabilities, but serves as a screen for potential problems, so that children can be referred for further testing. Children in the study were tested at 4 months of age and retested 6 more times through age 3. When they enrolled, mothers also provided information on their health and weight — before and after pregnancy — and the weight of their partners.
Results showed that compared to children of normal weight mothers, children of obese mothers were nearly 70% more likely to have failed the test indicator on fine motor skill by age 3. Children of obese fathers were 75% more likely to fail the test’s personal-social domain — an indicator of how well they were able to relate to and interact with others by age 3. Children with two obese parents were nearly 3x more likely to fail the test’s problem solving section by age 3.
According to the authors, it is not known why parental obesity might increase children’s risk for developmental delay. The authors note that animal studies indicate that obesity during pregnancy may promote inflammation, which could affect the fetal brain. Less information is available on the potential effects of paternal obesity on child development. The authors added that some studies have indicated that obesity could affect the expression of genes in sperm. If the link between parental obesity and developmental delays is confirmed, the authors wrote, physicians may need to take parental weight into account when screening young children for delays and early interventional services.
New NCI Drug Formulary Will Expedite Use of Agents In Clinical Trials
The National Cancer Institute (NCI) has launched a new drug formulary (the “NCI Formulary”) that will enable investigators at NCI-designated Cancer Centers to have quicker access to approved and investigational agents for use in preclinical studies and cancer clinical trials. The NCI Formulary could ultimately translate into speeding the availability of more-effective treatment options to patients with cancer.
The NCI Formulary is a public-private partnership between NCI and pharmaceutical and biotechnology companies. It is also one of NCI’s efforts in support of the Cancer Moonshot, answering Vice President Biden’s call for greater collaboration and faster development of new therapies for patients. The availability of agents through the NCI Formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process — sometimes up to 18 months — that has been required for investigators to access such agents on their own.
The NCI Formulary launched today with 15 targeted agents from six pharmaceutical companies:
— Bristol-Myers Squibb
— Eli Lilly and Company
— Kyowa Hakko Kirin
— Loxo Oncology
— Xcovery Holding Company LLC
The establishment of the NCI Formulary will enable NCI to act as an intermediary between investigators at NCI-designated Cancer Centers and participating pharmaceutical companies, facilitating and streamlining the arrangements for access to and use of pharmaceutical agents. Following company approval, investigators will be able to obtain agents from the available formulary list and test them in new preclinical or clinical studies, including combination studies of formulary agents from different companies. The NCI Formulary leverages lessons learned through NCI’s Cancer Therapy Evaluation Program (CTEP) and the NCI-MATCH trial, a study in which targeted agents from different companies are being tested alone or in combination in patients with genetic mutations that are targeted by these drugs. As the use of genomic sequencing data becomes more common in selecting cancer therapies, requests for access to multiple targeted agents for the conduct of clinical trials are becoming more common.
By the end of 2017, NIH expects to have doubled the number of partnerships and drugs available in the NCI Formulary and CTEP staff continue to discuss the NCI Formulary with pharmaceutical companies to make additional proprietary agents available for studies initiated by investigators at NCI-designated Cancer Centers.
The Formulary will complement NIH’s plans for another new public-private partnership in oncology, the Partnership to Accelerate Cancer Therapies (PACT). Through PACT, the NIH, U.S. Food and Drug Administration, biopharmaceutical groups in the private sector, foundations, and cancer advocacy organizations will come together to support new research projects to accelerate progress in cancer research as part of the Cancer Moonshot. PACT research will center on the identification and validation of biomarkers of response and resistance to cancer therapies, with special emphasis on immunotherapies. PACT will also establish a platform for selecting and testing combination therapies. PACT is expected to launch in 2017.