The work by Dr. Michael Kesden, assistant professor of physics at UT Dallas, and his colleagues provides for the first time solutions to decades-old equations that describe conditions as two black holes in a binary system orbit each other and spiral in toward a collision.
The research is available online and in the Feb. 27 issue of the journal Physical Review Letters.
Kesden said the solutions should significantly impact not only the study of black holes, but also the search for gravitational waves in the cosmos. Albert Einstein’s general theory of relativity predicts that two massive objects orbiting in a binary system should move closer together as the system emits a type of radiation called gravitational waves.
“An accelerating charge, like an electron, produces electromagnetic radiation, including visible light waves. Similarly, any time you have an accelerating mass, you can produce gravitational waves,” Kesden said.
“The energy lost to gravitational waves causes the black holes to spiral closer and closer together until they merge, which is the most energetic event in the universe,” he said. “That energy, rather than going out as visible light, which is easy to see, goes out as gravitational waves, which are very weak and much more difficult to detect.”
While Einstein’s theories predict the existence of gravitational waves, they have not been directly detected. But the ability to “see” gravitational waves would open up a new window to view and study the universe.
Optical telescopes can capture photos of visible objects, such as stars and planets, and radio and infrared telescopes can reveal additional information about invisible energetic events. Gravitational waves would provide yet another medium through which to examine astrophysical phenomena, Kesden said.
“Using gravitational waves as an observational tool, you could learn about the characteristics of the black holes that were emitting those waves billions of years ago, information such as their masses and mass ratios,” he said. “That’s important data for more fully understanding the evolution and nature of the universe.”
This year, a large-scale physics experiment called the Laser Interferometer Gravitational-Wave Observatory (LIGO) aims to be the first to directly detect gravitational waves. LIGO is the largest project funded by the National Science Foundation.
“The equations that we solved will help predict the characteristics of the gravitational waves that LIGO would expect to see from binary black hole mergers,” Kesden said. “We’re looking forward to comparing our solutions to the data that LIGO collects.”
The equations Kesden solved deal specifically with the spin angular momentum of binary black holes and a phenomenon called precession.
Angular momentum is a measure of the amount of rotation a spinning object has. Spin angular momentum includes the rotation’s speed and the direction in which that spin points. For a simple object like a spinning figure skater, the direction of angular momentum would point up.
Another type of angular momentum, called orbital angular momentum, applies to a system in which objects are in orbit about one another. Orbital angular momentum also has a magnitude and a direction.
In an astrophysical setting like a binary black hole system, the directions of the individual types of angular momenta change, or precess, over time.
“In these systems, you have three angular momenta, all changing direction with respect to the plane of the orbit — the two spin angular momenta and the one orbital angular momentum,” Kesden said. “The solutions that we now have describe the orientations of the precessing black hole spins.”
In addition to solving existing equations, Kesden also derived equations that will allow scientists to statistically track spin precession from black hole formation to merger far more efficiently and quickly.
“We can do it millions of times faster than was previously possible,” he said. “With these solutions, we can create computer simulations that follow black hole evolution over billions of years. A simulation that previously would have taken years can now be done in seconds. But it’s not just faster. There are things that we can learn from these simulations that we just couldn’t learn any other way.”
Researchers from the University of Cambridge, the Rochester Institute of Technology and the University of Mississippi also contributed to the Physical Review Letterspaper. The researchers were supported in part by the National Science Foundation and UT Dallas.
- Michael Kesden, Davide Gerosa, Richard O’Shaughnessy, Emanuele Berti, Ulrich Sperhake. Effective Potentials and Morphological Transitions for Binary Black Hole Spin Precession. Physical Review Letters, 2015; 114 (8) DOI:10.1103/PhysRevLett.114.081103
University of Texas at Dallas. “New insight found in black hole collisions.” ScienceDaily. ScienceDaily, 26 February 2015. <www.sciencedaily.com/releases/2015/02/150226110448.htm>.
Unlike other chemicals, agricultural pesticides are intentionally applied to the environment to help farmers control insects, weeds and other potentially harmful pests threatening agricultural production. They can therefore affect land ecosystems but also surface waters from runoff. According to estimates, ca. 4 million tons of agricultural pesticides are applied annually, equating to an average of 0.27 kilograms per hectare of the global land surface. “We know from earlier investigations for example that pesticides can reduce the biodiversity of invertebrates in freshwater ecosystems by up to 42 percent and that we can expect an increased application of pesticides as a result of climate change,” explains Prof. Dr. Matthias Liess from the UFZ, who was recently appointed to a term of five years on the scientific advisory board “National Action Plan on Sustainable Use of Plant Protection Products” where he advises the Federal Ministry of Food and Agriculture. Liess warns of an increase in the application of pesticides in many developing countries as farmers increasingly switch from traditionally extensive agricultural practices to more intensive ones. Until now the global extent of the potential water pollution from the application of insecticides has remained largely unknown.
The international team of scientists therefore came up with a global model with a raster of ca. ten kilometres, into which agricultural data from FAO and land use data from NASA among other data were entered. Annual average temperatures and monthly maximum precipitation measurements from around 77,000 weather stations were also taken into account. Following that, the researchers then estimated the so-called runoff potential (RP), in other words the amount of insecticides that enters streams and rivers through the rainwater from agricultural land. “In this respect, daily rainfall intensity, terrain slope, and insecticide application rate play an equally important role as well as the crops cultivated,” explains junior professor Dr. Ralf B. Schäfer from the University of Koblenz-Landau. “In order to test such complex models, we therefore carried out control measurements of insecticide contamination in freshwater ecosystems from four different regions.”
Several world maps were produced: the vulnerability map only takes into account the geographic and climatic background. The risk map on the other hand shows the risks from this natural vulnerability through anthropogenic land use. In Central Europe, scientists largely assessed the risk for water bodies as medium to high. In the northern hemisphere, insecticide runoff presented an overall more significant latitudinal gradient. “The risks of insecticide exposure to water bodies increased significantly the further South one travelled on a North-South gradient in Europe, North America and Asia, mainly driven by a higher insecticide application rate as a result of higher average temperatures,” Dr. Mira Kattwinkel reports, who is now conducting research at the Swiss Federal Institute of Aquatic Science and Technology (Eawag). Because the economy and the population are growing rapidly in many countries of the southern hemisphere, scientists expect a higher insecticide application rate in those countries in the future to cover an increase in agricultural production. The map could therefore still change colour considerably in other parts of the world. At the moment it is water bodies in the Mediterranean, the USA, Central America and Southeast Asia that are particularly vulnerable.
In Southeast Asia, countries such as the Philippines or Vietnam are greatly affected for example. UFZ researchers are looking into solutions for such regions within the framework of the LEGATO-project together with the International Rice Research Institute (IRRI), in an attempt to reduce pesticide application rates. One approach for example could be to revitalise the functioning of ecosystems so that the natural competitors of rice pests can help to avoid their mass reproduction and subsequent harvest yield losses.
“Our analysis provides a global map of hotspots for insecticide contamination that are a major risk for biodiversity in water bodies. To our knowledge this is the first study that assesses insecticide contamination of water bodies on a global scale,” Prof. Dr. Matthias Liess summarizes the significance of the new investigation. The researchers intend to use the global map to sensitize citizens and authorities about this issue in vulnerable regions and to incite local investigations. Buffer zones along the edge of water bodies can significantly reduce negative impacts for example. Efficient environmental management and conservation efforts in the future should focus on informing authorities and farmers about the costs, impacts and alternatives. Ultimately, mitigation and management takes place at the local level, determining the extent to which a water body will be affected under the application of such chemicals.
- Alessio Ippolito, Mira Kattwinkel, Jes J. Rasmussen, Ralf B. Schäfer, Riccardo Fornaroli, Matthias Liess. Modeling global distribution of agricultural insecticides in surface waters. Environmental Pollution, 2015; 198: 54 DOI:10.1016/j.envpol.2014.12.016
- J.H. Spangenberg, J.-M. Douguet, J. Settele, K.L. Heong. Escaping the lock-in of continuous insecticide spraying in rice: Developing an integrated ecological and socio-political DPSIR analysis. Ecological Modelling, 2015; 295: 188 DOI:10.1016/j.ecolmodel.2014.05.010
Helmholtz Centre For Environmental Research – UFZ. “Agricultural insecticides pose a global risk to surface water bodies, researchers find.” ScienceDaily. ScienceDaily, 25 February 2015. <www.sciencedaily.com/releases/2015/02/150225082836.htm>.
The work, led by Elizabeth Shank, an assistant professor of biology in the UNC-Chapel Hill College of Arts and Sciences as well as microbiology and immunology in the UNC-Chapel Hill School of Medicine, and Rachel Bleich, a graduate student in the UNC-Chapel Hill Eshelman School of Pharmacy, not only adds a new dimension to how we treat infections, but also might change our understanding of why bacteria produce antibiotics in the first place.
“For a long time we’ve thought that bacteria make antibiotics for the same reasons that we love them — because they kill other bacteria,” said Shank, whose work appears in the February 23 Early Edition of the Proceedings of the National Academy of Sciences. “However, we’ve also known that antibiotics can sometimes have pesky side-effects, like stimulating biofilm formation.”
Shank and her team now show that this side-effect — the production of biofilms — is not a side-effect after all, suggesting that bacteria may have evolved to produce antibiotics in order to produce biofilms and not only for their killing abilities.
Biofilms are communities of bacteria that form on surfaces, a phenomenon dentists usually refer to as plaque. Biofilms are everywhere. In many cases, biofilms can be beneficial, such as when they protect plant roots from pathogens. But they can also harm, for instance when they form on medical catheters or feeding tubes in patients, causing disease.
“It was never that surprising that many bacteria form biofilms in response to antibiotics: it helps them survive an attack. But it’s always been thought that this was a general stress response, a kind of non-specific side-effect of antibiotics. Our findings indicate that this isn’t true. We’ve discovered an antibiotic that very specifically activates biofilm formation, and does so in a way that has nothing to do with its ability to kill.”
Shank and her team previously reported that the soil bacterium Bacillus cereus could stimulate the bacterium Bacillus subtilis to form a biofilm in response to an unknown secreted signal. B. subtilis is found in soil and the gastrointestinal tract of humans.
Using imaging mass spectrometry, they subsequently identified the signaling compound that induced biofilm production as thiocillin, a member of a class of antibiotics called thiazolyl peptide antibiotics, which are produced by a range of bacteria.
At that point, Shank and her colleagues knew thiocillin had two very specific and different functions, but they didn’t know why — and wanted to know how it worked. That’s when they modified thiocillin’s structure in a way that eliminated thiocillin’s antibiotic activity, but did not halt biofilm production.
“That suggests that antibiotics can independently and simultaneously induce potentially dangerous biofilm formation in other bacteria and that these activities may be acting through specific signaling pathways,” said Shank. “It has generated further discussion about the evolution of antibiotic activity, and the fact that some antibiotics being used therapeutically may induce biofilm formation in a strong and specific way, which has broad implications for human health.”
- Rachel Bleich, Jeramie D. Watrous, Pieter C. Dorrestein, Albert A. Bowers, and Elizabeth A. Shank. Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis. PNAS, February 23, 2015 DOI: 10.1073/pnas.1414272112
University of North Carolina at Chapel Hill. “Antibiotics give rise to new communities of harmful bacteria.” ScienceDaily. ScienceDaily, 23 February 2015. <www.sciencedaily.com/releases/2015/02/150223164533.htm>.
The authors discuss how the birth of such neurons may help animals and humans adapt to their current environment and circumstances in a complex and changing world. They advocate for testing these ideas using naturalistic designs, such as allowing laboratory rodents to live in more natural social burrow settings and observing how circumstances such as social status influence the rate at which new neurons are born.
“New neurons may serve as a means to fine-tune the hippocampus to the predicted environment,” Opendak says. “In particular, seeking out rewarding experiences or avoiding stressful experiences may help each individual optimize his or her own brain. However, more naturalistic experimental conditions may be a necessary step toward understanding the adaptive significance of neurons born in the adult brain.”
In recent years, it has become increasingly clear that environmental influences have a profound effect on the adult brain in a wide range of mammalian species. Stressful experiences, such as restraint, social defeat, exposure to predator odors, inescapable foot shock, and sleep deprivation, have been shown to decrease the number of new neurons in the hippocampus. By contrast, more rewarding experiences, such as physical exercise and mating, tend to increase the production of new neurons in the hippocampus.
The birth of new neurons in adulthood may have important behavioral and cognitive consequences. Stress-induced suppression of adult neurogenesis has been associated with impaired performance on hippocampus-dependent cognitive tasks, such as spatial navigation learning and object memory. Stressful experiences have also been shown to increase anxiety-like behaviors that are associated with the hippocampus. In contrast, rewarding experiences are associated with reduced anxiety-like behavior and improved performance on cognitive tasks involving the hippocampus.
Although scientists generally agree that our day-to-day actions change our brains even in adulthood, there is some disagreement on the adaptive significance of new neurons. For instance, the literature presents mixed findings on whether new neurons generated under a specific experimental condition are geared toward the recognition of that particular experience or if they provide a more naive pool of new neurons that enable environmental adaptation in the future.
Gould and her collaborators recently proposed that stress-induced decreases in new neuron formation might improve the chances of survival by increasing anxiety and inhibiting exploration, thereby prioritizing safety and avoidant behavior at the expense of performing optimally on cognitive tasks. On the other hand, reward-induced increases in new neuron number may reduce anxiety and facilitate exploration and learning, leading to greater reproductive success.
“Because the past is often the best predictor of the future, a stress-modeled brain may facilitate adaptive responses to life in a stressful environment, whereas a reward-modeled brain may do the same but for life in a low-stress, high-reward environment,” says Gould, a professor of psychology and neuroscience at Princeton University.
However, when aversive experiences far outnumber rewarding ones in both quantity and intensity, the system may reach a breaking point and produce a maladaptive outcome. For example, repeated stress produces continued reduction in the birth of new neurons, and ultimately the emergence of heightened anxiety and depressive-like symptoms.
“Such a scenario could represent processes that are engaged under pathological conditions and may be somewhat akin to what humans experience when exposed to repeated traumatic stress,” Opendak says.
Because many studies that investigate adult neurogenesis use controlled laboratory conditions, the relevance of the findings to real-world circumstances remains unclear. The use of a visible burrow system–a structure consisting of tubes, chambers, and an open field–has allowed researchers to recreate the conditions that allow for the production of dominance hierarchies that rats naturally form in the wild, replicating the stressors, rewards, and cognitive processes that accompany this social lifestyle.
“This more realistic setting has revealed individual differences in adult neurogenesis, with more new neurons produced in dominant versus subordinate male rats,” Gould says. “Taking findings from laboratory animals to the next level by exploring complex social interactions in settings that maximize individual variability, a hallmark of the human experience, is likely to be especially illuminating.”
- Maya Opendak, Elizabeth Gould. Adult neurogenesis: a substrate for experience-dependent change. Trends in Cognitive Sciences, 2015; DOI:10.1016/j.tics.2015.01.001
Cell Press. “Newborn neurons in adult brain may help us adapt to environment.” ScienceDaily. ScienceDaily, 21 February 2015. <www.sciencedaily.com/releases/2015/02/150221192244.htm>.
DIA Annual Meeting 2015 Symposium – How Risk-Based Monitoring and eSource Methodologies are Impacting Clinical Sites, Patients, Regulators and Sponsors
Target Health is pleased to announce that the Symposium, entitled How Risk-Based Monitoring and eSource Methodologies are Impacting Clinical Sites, Patients, Regulators and Sponsors, chaired by Dr. Jules Mitchel, will take place on Tuesday, June 16, 3:30PM – 5:00PM, at the DIA Annual Meeting, being held this year June 14-18, in Washington, DC.
The symposium will show how risk-based monitoring (RBM) and eSource methodologies are impacting the way clinical trials are being conducted and managed. The symposium participants will discuss results and experience from completed and ongoing clinical trials and identify how eSource and risk-based monitoring methodologies are impacting the clinical research enterprise including clinical research sites, patients, regulators, quality assurance, clinical research associates (CRAs), and project, safety and data managers. The esteemed panel will address the following:
The Time Is Now for Risk-Based Monitoring:
Frances E. Nolan, VP, Quality and Regulatory Affairs Medidata Solutions Worldwide
Overcoming Clinical Trial Data Collection Challenges with eSource Solution and Leveraging Mobile Technologies:
Avik Kumar Pal, CEO CliniOps
Innovation by Design: Using eSource to Maximize Clinical Development Productivity and Efficiency:
Edward Stephen Seguine, CEO Clinical Ink
Barred Owl Living Near TransTech Pharma, High Point, NC
Another spectacular nature photo from our friend and colleague, James Farley, Director, Data Management and Programming.
Barred Owl Living Near TransTech Pharma, High Point, NC ©JFarley Photography
ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Diets From Roman Gladiators to Present
From left, a disarmed and surrendering retiarius and his secutor opponent, a thraex and murmillo,
a hoplhus and murmillo (who is signaling his surrender), and the referee (Zliten mosaic, 200 AD); Wikipedia
Around 250 BC, Roman gladiators ate a mostly 1) ___ diet and drank ashes after training as a tonic. These are the findings of anthropological investigations carried out on bones of warriors found during excavations in the ancient city of Ephesos. Historic sources report that gladiators had their own diet. This comprised beans and grains. Contemporary reports referred to them as hordearii (barley eaters).
Roman Gladiator Mosaic 5th Century Palace in what is now, Turkey; Wikipedia
In a study by the Department of Forensic Medicine at the MedUni Vienna in cooperation with the Department of Anthropology at the Institute of Forensic Medicine at the University of Bern, bones were examined from a gladiator cemetery uncovered in 1993 which dates back to the 2nd or 3rd century BCE in the then Roman city of Ephesos (now in modern-day Turkey). At the time, Ephesos was the capital of the Roman province of Asia and had over 200,000 inhabitants. Using spectroscopy, stable isotope ratios (carbon, nitrogen and sulphur) were investigated in the collagen of the bones, along with the ratio of strontium to calcium in the bone mineral. The result shows that gladiators mostly ate a vegetarian diet. There is virtually no difference in terms of nutrition from the local normal population. Meals consisted primarily of grain and 2) __-free meals. The word barley eater relates in this case to the fact that gladiators were probably given grain of an inferior quality.
Build-Up Drink Following Physical Exertion
The difference between gladiators and the normal population is highly significant in terms of the amount of strontium measured in their bones. This leads to the conclusion that the gladiators had a higher intake of minerals from a strontium-rich source of calcium. The ash drink quoted in literature probably really did exist. Plant ashes were evidently consumed to fortify the body after physical exertion and to promote better bone healing, explains study leader Fabian Kanz from the Department of Forensic Medicine at the MedUni Vienna. Things were similar then to what we do today — we take magnesium and calcium (in the form of effervescent tablets, for example) following physical exertion. 3) ___ is essential for bone building and usually occurs primarily in milk products. A further research project is looking at the migration of gladiators, who often came from different parts of the Roman Empire to Ephesos. The researchers are hoping that comparison of the bone data from gladiators with that of the local fauna will yield a number of differences.
ROMAN GLADIATOR MOSAIC, 320 CE; Wikipedia
Roman Gladiators with Net and Trident; 79 CE
Source: Medical University of Vienna; Sandra L?sch, Negahnaz Moghaddam, Karl Grossschmidt, Daniele U. Risser, Fabian Kanz. Stable Isotope and Trace Element Studies on Gladiators and Contemporary Romans from Ephesus (Turkey, 2nd and 3rd Ct. AD) – Implications for Differences in Diet. PLoS ONE, October 15, 2014
What’s Next in 2015 Diets: Chili Peppers?
Chili Peppers Growing in Thailand; Wikipedia
Chili peppers have been a part of the human diet in the Americas since at least 7500 BC. The most recent research shows that chili peppers were domesticated more than 6000 years ago in Mexico, in the region that extends across southern Puebla and northern Oaxaca to southeastern Veracruz, and were one of the first self-pollinating crops cultivated in Mexico, Central and parts of South America. Christopher Columbus was one of the first Europeans to encounter them (by then they were in the Caribbean), and called them peppers because they, like black and white pepper of the Piper genus known in Europe, have a spicy hot taste.
Peppers each day, keep obesity away. Credit: Thyagarajan
There may be hope for 2015 dieters in those fiery little Native American fruits, chili peppers. Now we come full circle from Columbus to 2015, where a large percentage of the world’s population — fully one third, by the World Health Organization’s estimates — is currently overweight or 4) ___. These staggering statistics have made finding ways to address obesity a top priority for many scientists around the globe, and now a group of researchers at the University of Wyoming has found promise in the potential of capsaicin — the chief ingredient in chili peppers — as a diet-based supplement. The temptation to eat fatty foods is often so strong that, for many, it can override or overpower any dietary restrictions. As a solution to this problem, a group of researchers at the University of Wyoming developed a novel approach to stimulate energy 5) ___ — without the need to restrict calorie intake.
During the Biophysical Society’s 59th Annual Meeting in Baltimore, Md., Feb. 7-11, 2015, the researchers from the laboratory of Dr. Baskaran Thyagarajan, University ofWyoming described how dietary capsaicin may stimulate thermogenesis and energy burning by activating its receptors, which are expressed in white and 6) ___ fat cells. This may help to prevent and manage obesity and other related health complications such as Type 2 diabetes, high blood pressure, and cardiovascular diseases — though this effect has not yet been demonstrated in carefully-controlled clinical trials. Obesity is caused by an imbalance between calorie intake and energy dissipation, explained Vivek Krishnan, a graduate student working in Baskaran Thyagarajan’s laboratory at the University of Wyoming’s School of Pharmacy — a research group known as Baskilab. In our bodies, white fat cells store 7) ___ and brown fat cells serve as thermogenic (heat produced by burning fat) machinery to burn stored fat. Eating calorie-rich food and a lack of physical activity cause an imbalance in metabolism that leads to obesity. While pursuing a strategy for obesity management, our group’s laboratory data revealed that dietary capsaicin — a chief ‘agonist’ (initiator of a response) of transient receptor potential vanilloid 1 (TRPV1) channel protein — suppresses high-fat-diet-induced obesity, Krishnan said. Baskilab has found that high-fat-diet obesity and dietary capsaicin — 0.01 percent of capsaicin in the total high fat diet — prevented high-fat-diet-induced 8) ___ gain in trials with wild type mice, but not in mice that genetically lacked TRPV1. Further, dietary capsaicin didn’t modify food or water intake in these mice, although it did significantly increase the metabolic activity and energy expenditure in wild type mice fed a high-fat diet, but not for mice that genetically lack TRPV1 Krishnan noted. So, Baskilab’s overarching hypothesis is that dietary capsaicin induces browning of 9) ___ adipose tissue and stimulates thermogenesis to counteract obesity. The main goal of our work is to expand the knowledge of the mechanism by which capsaicin antagonizes obesity, as well as to advance the proof of principle of the anti-obesity potential of dietary capsaicin. Next, we’ll focus on our longer-term goal of developing TRPV1 agonists as new drug molecules to prevent and treat obesity, said researchers from Baskilab.
Developing a natural dietary supplement as a strategy to combat obesity can be easily advanced to human clinical trials, according to the researchers. We envision a nanoparticle-based, sustained-release formulation of 10) ___, which is currently under development in our laboratory, added researchers from Baskilab. In turn, this will advance a novel dietary supplement-based approach to prevent and treat one of the life-threatening diseases, obesity and its associated complications — in humans. The group’s strategy to counteract obesity is expected to form a major focus of future healthcare priorities for both the National Institutes of Health and Department of Defense. Baskilab has already submitted a patent application for the drug delivery aspect of the discovery. Sources: Biophysical Society; The University of Wyoming; What’s next in diets: Chili peppers?. ScienceDaily, 8 February 2015.
ANSWERS: vegetarian; 2) meat-; 3) Calcium; 4) obese; 5) metabolism; 6) brown; 7) energy; 8) weight; 9) white; 10) capsaicin
Dried chili peppers; Wikipedia
Roman Gladiator Forensics
Painting of fighting gladiator from Merida amphitheatre, Spain; Wikipedia
A gladiator (Latin: gladiator, swordsman, from gladius, sword) was an armed combatant who entertained audiences in the Roman Republic and Roman Empire in violent confrontations with other gladiators, wild animals, and condemned criminals. Some gladiators were volunteers who risked their legal and social standing and their lives by appearing in the arena. Most were despised as slaves, schooled under harsh conditions, socially marginalized, and segregated even in death. Irrespective of their origin, gladiators offered spectators an example of Rome’s martial ethics and, in fighting or dying well, they could inspire admiration and popular acclaim. They were celebrated in high and low art, and their value as entertainers was commemorated in precious and commonplace objects throughout the Roman world.
The origin of gladiatorial combat is open to debate. There is evidence of it in funeral rites during the Punic Wars of the 3rd century BCE, and thereafter it rapidly became an essential feature of politics and social life in the Roman world. Its popularity led to its use in ever more lavish and costly games. The gladiator games lasted for nearly a thousand years, reaching their peak between the 1st century BCE and the 2nd century CE. The games finally declined during the early 5th century after the adoption of Christianity as state church of the Roman Empire in 380, although beast hunts (venationes) continued into the 6th century.
Although their final outcomes may have been brutal, ancient Roman gladiators fought like gentlemen, according to scientific research.
Forensic analysis of remains from a gladiator cemetery in Turkey indicates that gladiators followed a strict set of rules, never letting the fight descend into the type of mutilation common on battlefields of the day. What’s more, the new findings suggest, is that when a gladiator was close to death, he would be put out of his misery by a backstage executioner with one swift hammer strike to the side of the head. Fabian Kanz from the Austrian Archaeological Institute and Karl Grosschmidt from the Medical University of Vienna, Austria, analyzed the injuries of 67 gladiators. All the men had been buried in a gladiator cemetery dating back to 2CE in the ancient city of Ephesus in Turkey, which was then part of the Roman Empire. Archaeologists first discovered the cemetery in 1993. Fighters depicted on the tombstones gave it away as a burial ground for gladiators.
Using microscope analysis and CT scans of bones, Kanz and Grosschmidt were able to determine how and when the gladiators received their wounds. Wounds that occur at or near the time of death are distinguished by lack of healing and [by] fracture margins characteristic of fresh bone breaks, Kanz said. By contrast, old battle scars in the bone have a more knitted-together appearance, because they had time to heal. All but one of the gladiators studied had only one wound associated with his death. In addition, injuries to the back of the head were rare. These findings back up ancient Roman accounts that gladiator fights had strict rules of combat, with no sneaky blows from behind. It is wonderful evidence, and it reenforces what we know from other sources. Gladiators were not just beating each other into the ground, said Steven Tuck, a gladiator expert from Miami University in Oxford, Ohio, who was not involved in the study.
Kanz and Grosschmidt also describe evidence of 16 nonfatal injuries in their paper, which was published in the journal Forensic Science International. Most of them showed excellent healing signs, Kanz said. The fighters, it seems, received excellent medical care if they survived their bouts and received particularly good care (better medical care, diet and massage) if they lasted one year or more. One gladiator had a distinctive double puncture wound to the front of his skull. The spacing of the holes perfectly matched that of a trident – a three-pronged, pitchfork-like weapon – found nearby in the cemetery. Art and literary sources indicate that gladiators normally wore helmets, but it seems that this unfortunate gladiator may have lost his protective headgear. Perhaps there was a certain point in the fight where the organizer ordered them to take off their helmets, or else he just lost his helmet, Kanz said. Other gladiators had sharp, slice-like wounds, which the scientists think were caused by the dagger like gladius.
A gladiator typically took on a distinct persona – and the weapons to go with it. For instance, during the second and third centuries the retiarius-and-secutor gladiator pairing was the most popular. The retiarius was the ?fisherman,’ who fought with a net, a gladius, and a trident [and was] protected with just a small shoulder shield, Kanz said. His opponent, the secutor, was the ?fish,’ protected by a fishlike helmet with very narrow eye holes and a large shield, and fighting with a gladius, Kanz said. Ten of the gladiators had square holes in the sides of their skulls, validating the theory that very badly wounded gladiators were killed by a hammer-wielding executioner who waited in the wings. This matches what we know from literary and other sources. The blow to the side of the head suggests an avoidance of eye-to-eye contact, said Latin professor Kathleen Coleman of Harvard University in Cambridge, Massachusetts. Despite the bloodthirsty fights depicted in the movie Gladiator, for which Coleman was a consultant, it seems that real gladiators didn’t fight to kill. The audience and the organizer of the games decided whether gladiators would live or die, but if two brave gladiators put up a good fight, they often both got out alive, study co-author Kanz said. Ancient fight records show that around 90% of trained gladiators survived their fights. While fighting as an untrained gladiator meant almost certain death, life as a trained gladiator may not have been so terrible – especially considering that the alternative for many gladiators (who were often criminals, slaves, or war prisoners) was a life of indentured servitude or even execution. Providing they survived their one-year of training, gladiators in established troupes were well fed and highly respected. After a few successful years, the fighters were often released from servitude to their troupes. For another yet-to-be-published study, Kanz and Grosschmidt have analyzed the chemical composition of the bones. Their results suggest that gladiators ate a diet rich in barley and beans. Gladiators were nicknamed hordearii, which means ?barley eaters,’ Kanz said.
Despite the harsh discipline, successful gladiators represented a substantial investment for their lanista and were otherwise well cared for. Their high-energy, vegetarian diet combined barley, boiled beans, oatmeal, ash (believed to help fortify the body) and dried fruit. Compared to modern athletes, they were probably overweight, but this may have protected their vital organs from the cutting blows of their opponents. The same research suggests they may have fought barefoot. Regular massage and high quality medical care helped mitigate an otherwise very severe training regimen. Part of Galen’s medical training was at a gladiator school in Pergamum where he saw (and would later criticize) the training, diet, and long term health prospects of the gladiators. For a time, Galen was the chief physician of Roman gladiators. To die well, a gladiator was not supposed to ask for mercy, or to cry out. A good death redeemed a defeated gladiator from the dishonorable weakness and passivity of defeat, and provided a noble example to those who watched. For death, when it stands near us, gives even to inexperienced men the courage not to seek to avoid the inevitable. So the gladiator, no matter how faint-hearted he has been throughout the fight, offers his throat to his opponent and directs the wavering blade to the vital spot. (Seneca. Epistles, 30.8)
Some mosaics show defeated gladiators kneeling in preparation for the moment of death. Seneca’s vital spot seems to have meant the neck Gladiator remains from Ephesus confirm this. The body of a gladiator who had died well was placed on a couch and removed from the arena with dignity. Once in the arena morgue, the corpse would have been stripped of armor, and probably had his throat cut to prove that he was dead. The Christian author Tertullian, commenting on ludi meridiani in Roman Carthage during the peak era of the games, describes a more humiliating method of removal. One arena official, dressed as the brother of Jove, Dis Pater (god of the underworld) strikes the corpse with a mallet. Another, dressed as Mercury, tests for life-signs with a heated wand; once confirmed as dead, the body is dragged from the arena. Whether these victims were gladiators or noxii slaves is unknown. Modern pathological examination confirms the probably fatal use of a mallet on some, but not all the gladiator skulls found in a gladiators’ cemetery. Kyle (1998) proposed that gladiators who disgraced themselves might have been subjected to the same indignities as noxii, denied the relative mercies of a quick death and dragged from the arena as carrion. Whether the corpse of such a gladiator could be redeemed from further ignominy by friends or familia is not known.
The average gladiator lifespan was short; few survived more than 10 matches or lived past the age of 30. One (Felix) is known to have lived to 45 and one retired gladiator lived to 90. George Ville calculated an average age at death at 27 for gladiators (based on headstone evidence), with mortality among all who entered the arena around the 1st century CE at 19/100. A rise in the risk of death for losers, from 1/5 to 1/4 between the early and later Imperial periods, seems to suggest that mercy was granted less often. Historian, Marcus Junkelmann disputes Ville’s calculation for average age at death; the majority would have received no headstone, and would have died early in their careers, at 18-25 years of age. Historians Keith Hopkins and Mary Beard tentatively estimate a total of 400 arenas throughout the Roman Empire at its greatest extent, with a combined total of 8,000 gladiator deaths, per annum from all causes, including execution, combat and accident.
Link Between Powerful Gene Regulatory Elements and Autoimmune Diseases
Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases, for example, the joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families.
Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.
Investigators with the NIH have discovered the genomic switches regulating the human immune system. The findings, published in Nature (16 February 2015), open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis. The research team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of Dr. Francis Collins and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction.
The investigators began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease. Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response. But the most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs. Additional experiments provided further evidence for a central role for SEs in rheumatoid arthritis. When human T cells were exposed to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs to alter the activities of important T cell genes.
Eylea Outperforms Lucentis and Avastin for Diabetic Macular Edema with Moderate or Worse Vision but Results are Equivalent When Vision Loss is Mild
Diabetic macular edema (DME) can occur in people with diabetic retinopathy, a type of diabetic eye disease that can cause the growth of abnormal blood vessels in the retina. The macula is the area of the retina used when looking straight ahead, for tasks such as reading, driving, and watching television. Macular edema, or swelling, occurs when fluid leaks from retinal blood vessels and accumulates in the macula, distorting vision. Macular edema can arise during any stage of diabetic retinopathy and is the most common cause of diabetes-related vision loss. About 7.7 million Americans have diabetic retinopathy. Of these, about 750,000 have DME.
An NIH-supported clinical trial compared three drugs for DME, Eylea (aflibercept; Regeneron), Avastin (bevacizumab; Genentech) or Lucentis (ranibizumab; Genentech). All three drugs target a substance called vascular endothelial growth factor (VEGF), which can cause leakage from blood vessels and the growth of new, abnormal blood vessels. Anti-VEGF drugs work for DME by reducing vascular leakage.
For the study, DRCR.net investigators enrolled 660 people with macular edema at 88 clinical trial sites across the United States. The DRCR.net is dedicated to facilitating multicenter clinical research of diabetic eye disease. The network formed in 2002 and comprises more than 350 physicians practicing at more than 140 clinical sites across the country. When the study began, participants were 61 years old on average, and had had type 1 or type 2 diabetes 17 years on average. Only people with a visual acuity of 20/32 or worse were eligible to participate. (To see clearly, a person with 20/32 vision would have to be 20 feet away from an object that a person with normal vision could see clearly at 32 feet.) At enrollment, about half the participants had 20/32 or 20/40 vision, and the other half had 20/50 or worse vision. In many states, a corrected visual acuity of 20/40 or better in at least one eye is required for a driver’s license that allows both day- and nighttime driving.
Each participant was randomly assigned to receive Eylea (2.0 milligrams/0.05 milliliter), Avastin (1.25 mg/0.05 mL), or Lucentis (0.3 mg/0.05 mL). Participants were evaluated monthly and received the assigned study drug by injection directly into the eye until the DME resolved or stabilized. Additionally, laser treatment was given if DME persisted without continual improvement after six months of injections. Laser treatment alone was the standard treatment for DME until widespread adoption of these drugs a few years ago.
Results showed that one year after starting treatment, vision had improved substantially for the majority of trial participants. When visual acuity was 20/32 or 20/40 at the start of the trial, vision improved on average almost two lines on an eye chart in all three treatment groups. In contrast, for participants whose visual acuity was 20/50 or worse at the start of the trial, Eylea improved vision on average almost four lines, Avastin improved vision on average almost 2.5 lines, and Lucentis improved vision on average almost three lines.
While all three drugs reduced swelling of the macula, Eylea and Lucentis reduced the swelling more than Avastin. Also, during the study, a smaller percentage of participants on Eylea (36%) underwent laser treatment for persistent edema that did not resolve with anti-VEGF treatment alone, compared with those on Avastin (56%) or Lucentis (46%).
Based on Medicare allowable charges, the per-injection costs of each drug at the doses used in this study were about $1,960 for Eylea, about $70 for Avastin, and about $1200 for Lucentis. During the year-long study, participants on Avastin and Lucentis received, on average, 10 injections, versus nine for those on Eylea.
Draft Documents Related to Compounding of Human Drugs are Issued
The FDA has issued five draft documents related to drug compounding and repackaging that will help entities comply with important public health provisions. The draft documents are applicable to pharmacies, federal facilities, outsourcing facilities and physicians. The new category of outsourcing facilities was created under the Drug Quality and Security Act (DQSA), enacted by Congress in November 2013 in response to a deadly fungal meningitis outbreak that was linked to contaminated sterile compounded drug products. Drugs compounded in an outsourcing facility that meet certain conditions may be entitled to exemptions from certain provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act), including the new drug approval requirements and the requirement to label drug products with adequate directions for use. Outsourcing facilities are subject to current good manufacturing practice requirements and inspections by the FDA according to a risk-based schedule.
Drugs produced by compounders that are not registered as outsourcing facilities must meet certain other conditions described in the FD&C Act, or they will be subject to all of the requirements applicable to drugs produced by conventional drug manufacturers.
The documents are:
- Draft Guidance: For Entities Considering Whether to Register As Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act
The draft guidance provides an entity considering whether to register with the FDA as an outsourcing facility under the law with information about the regulatory impact of registering. For example, it explains that a facility engaged in only certain activities, including repackaging human drugs and compounding non-sterile drugs, should not register as an outsourcing facility because its drug products will not qualify for the exemptions provided in section 503B, including the exemption from the new drug approval requirements.
- Draft Guidance for Industry: Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
The draft guidance describes the conditions under which the FDA does not intend to take action for certain violations of the law when state-licensed pharmacies, federal facilities or outsourcing facilities repackage certain drug products. Repackaging generally involves taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container. Repackaged drug products are generally not exempt from any of the provisions of the FD&C Act related to the production of drugs, and the compounding provisions of the FD&C Act do not address repackaging. Therefore, the FDA is issuing guidance to describe how it intends to address repackaging when done in a state-licensed pharmacy, federal facility, or outsourcing facility.
- Draft Guidance for Industry: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application (BLA)
The draft guidance describes the conditions under which the FDA does not intend to take action for violations of certain sections of the Public Health Service Act (PHS Act) and the FD&C Act when state-licensed pharmacies, federal facilities or outsourcing facilities mix, dilute or repackage specific biological products without an approved BLA, or when such facilities or physicians prepare prescription sets of allergenic extracts (used to treat allergies) without an approved BLA. The draft guidance notes that a biological product that is mixed, diluted or repackaged outside the scope of an approved BLA is an unlicensed biological product under section 351 of the PHS Act and may not be legally marketed without an approved BLA. Additionally, the compounding provisions of the FD&C Act do not address biological products subject to licensure under section 351 of the PHS Act. Therefore, the FDA is issuing guidance to describe how it intends to address these practices.
- Draft Guidance for Industry: Adverse Event Reporting for Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act
Entities registered as outsourcing facilities are required to report adverse events to the FDA. The draft guidance explains adverse event reporting for outsourcing facilities.
- Draft Memorandum of Understanding Between A State and the U.S. Food and Drug Administration Addressing Certain Distributions of Compounded Human Drug Products
The draft MOU under section 503A of the FD&C Act describes the responsibilities of a state that chooses to sign the MOU in investigating and responding to complaints related to compounded human drug products distributed outside the state, and in addressing the interstate distribution of inordinate amounts of compounded human drug products.
These documents are the latest in a series of policy documents related to FDA oversight of drugs produced by state-licensed pharmacies, federal facilities and outsourcing facilities. The draft guidance documents are available for public comment for 90 days. The public has 120 days to comment on the draft MOU between the states and the FDA.