Breakthrough toward developing blood test for pain

Researchers are developing an objective test for patient pain.

A breakthrough test developed by Indiana University School of Medicine researchers to measure pain in patients could help stem the tide of the opioid crisis in Indiana, and throughout the rest of the nation.

A study led by psychiatry professor Alexander Niculescu, MD, PhD and published this week in the Nature journal Molecular Psychiatrytracked hundreds of participants at the Richard L. Roudebush VA Medical Center in Indianapolis to identify biomarkers in the blood that can help objectively determine how severe a patient's pain is. The blood test, the first of its kind, would allow physicians far more accuracy in treating pain -- as well as a better long-term look at the patient's medical future.

"We have developed a prototype for a blood test that can objectively tell doctors if the patient is in pain, and how severe that pain is. It's very important to have an objective measure of pain, as pain is a subjective sensation. Until now we have had to rely on patients self-reporting or the clinical impression the doctor has," said Niculescu, who worked with other Department of Psychiatry researchers on the study. "When we started this work it was a farfetched idea. But the idea was to find a way to treat and prescribe things more appropriately to people who are in pain."

During the study, researchers looked at biomarkers found in the blood -- in this case molecules that reflect disease severity. Much like as glucose serves as a biomarker to diabetes, these biomarkers allow doctors to assess the severity of the pain the patient is experiencing, and provide treatment in an objective, quantifiable manner. With an opioid epidemic raging throughout the state and beyond, Niculescu said never has there been a more important time to administer drugs to patients responsibly.

"The opioid epidemic occurred because addictive medications were overprescribed due to the fact that there was no objective measure whether someone was in pain, or how severe their pain was," Niculescu said. "Before, doctors weren't being taught good alternatives. The thought was that this person says they are in pain, let's prescribe it. Now people are seeing that this created a huge problem. We need alternatives to opioids, and we need to treat people in a precise fashion. This test we've developed allows for that."

In addition to providing an objective measure of pain, Niculescu's blood test helps physicians match the biomarkers in the patient's blood with potential treatment options. Like a scene out of CSI, researchers utilize a prescription database -- similar to fingerprint databases employed by the FBI -- to match the pain biomarkers with profiles of drugs and natural compounds cataloged in the database.

"The biomarker is like a fingerprint, and we match it against this database and see which compound would normalize the signature," said Niculescu, adding that often the best treatment identified is a non-opioid drug or compound. "We found some compounds that have been used for decades to treat other things pair the best with the biomarkers. We have been able to match biomarkers with existing medications, or natural compounds, which would reduce or eliminate the need to use the opioids."

In keeping with the IU Grand Challenge Precision Health Initiative launched in June 2016, this study opens the door to precision medicine for pain. By treating and prescribing medicine more appropriately to the individual person, this prototype may help alleviate the dilemmas that have contributed to the current opioid epidemic.

"In any field, the goal is to match the patient to the right drug, which hopefully does a lot of good and very little harm," Niculescu said. "But through precision health, by having lots of options geared toward the needs of specific patients, you prevent larger problems, like the opioid epidemic, from occurring."

Additionally, study experts discovered biomarkers that not only match with non-addictive drugs that can treat pain, but can also help predict when someone might experience pain in the future -- helping to determine if a patient is exhibiting chronic, long-term pain which might result in future emergency room visits.

"Through precision medicine you're giving the patient treatment that is tailored directly to them and their needs," Niculescu said. "We wanted first to find some markers for pain that are universal, and we were able to. We know, however, based on our data that there are some markers that work better for men, some that work better for women. It could be that there are some markers that work better for headaches, some markers that work better for fibromyalgia and so on. That is where we hope to go with future larger studies."

The study was supported by an NIH Director's New Innovator Award and a VA Merit Award. Moving forward, Niculescu's group looks to secure more funding through grants or outside philanthropy to continue and accelerate these studies -- with the hopes of personalizing the approach even more and moving toward a clinical application. A self-described longshot at the start, Niculescu said that the work his group has done could have a major impact on how doctors around the world treat pain in the future.

"It's been a goal of many researchers and a dream to find biomarkers for pain," Niculescu said. "We have come out of left field with an approach that had worked well in psychiatry for suicide and depression in previous studies. We applied it to pain, and we were successful. I give a lot of credit for that to my team at IU School of Medicine and the Indianapolis VA, as well as the excellent environment and support we have."

Why getting enough sleep reduces cardiovascular disease risk

Images of plaque from the artery of a mouse model of atherosclerosis that experienced a normal sleeping pattern (left) and an image of arterial plaque from a mouse model that underwent sleep fragmentation (right). The amount of arterial plaque in the sleep-fragmented mouse is significantly larger.

Getting enough sleep is key to good health, and studies have shown that insufficient sleep increases the risk of serious problems, including cardiovascular disease. Now Massachusetts General Hospital (MGH) investigators have discovered one way that sleep protects against the buildup of arterial plaques called atherosclerosis. In their paper receiving advance online publication in Nature, they describe the mechanism by which insufficient sleep increases production of inflammatory white blood cells known to be major contributors to atherosclerosis.

"We have discovered that sleep helps to regulate the production in the bone marrow of inflammatory cells and the health of blood vessels and that, conversely, sleep disruption breaks down control of inflammatory cell production, leading to more inflammation and more heart disease," says Filip Swirski, PhD, of the MGH Center for Systems Biology, senior author of the Nature paper. "We also have identified how a hormone in the brain known to control wakefulness controls processes in the bone marrow and protects against cardiovascular disease."

To investigate how insufficient sleep increases atherosclerosis, Swirski's team subjected mice genetically programmed to develop atheroslcerosis to repeated interruptions of their sleep, similar to the experience of someone constantly waking up because of noise or discomfort. While there were no changes in weight, cholesterol levels or glucose tolerance in the sleep-deprived mice, compared to animals from the same strain allowed to sleep normally, those subjected to sleep fragmentation developed larger arterial plaques and had higher levels of monocytes and neutrophils -- inflammatory cells that contribute to atherosclerosis -- in their blood vessels.

Further experiments revealed that the sleep-deprived mice had a nearly two-fold increase in the production in their bone marrow of stem cells that give rise to white blood cells. A hormone called hypocretin, produced in the brain structure called the hypothalamus and known to have a role in the regulation of sleep, was found to play an unexpected role in controlling white blood cell production. While normally produced at high levels when animals -- including humans -- are awake, hypocretin levels were significantly reduced in the sleep-deprived mice.

The MGH team found that hypocretin regulates production of white blood cells through interaction with neutrophil progenitors in the bone marrow. Neutrophils, they discovered, induce monocyte production through release of a factor called CSF-1, and experiments with mice lacking the gene for hypocretin revealed that the hormone controls CSF-1 expression, monocyte production and the development of arterial plaques. In sleep-deprived animals, the drop in hypocretin led to increased CSF-1 production by neutrophils, elevated monocyte production and accelerated atherosclerosis.

"This is a direct demonstration that hypocretin is also an important inflammatory mediator," says Swirski, an associate professor of Radiology at Harvard Medical School. "We now need to study this pathway in humans, explore additional mechanisms by which proper sleep maintains vascular health and further explore this newly identified neuro-immune axis."

Giant 'megalodon' shark extinct earlier than previously thought

Megalodon extinction graphical abstract.

Megalodon -- a giant predatory shark that has inspired numerous documentaries, books and blockbuster movies -- likely went extinct at least one million years earlier than previously thought, according to new research published Feb. 13 in PeerJ -- the Journal of Life and Environmental Sciences.

Earlier research, which used a worldwide sample of fossils, suggested that the 50-foot-long, giant shark Otodus megalodonwent extinct 2.6 million years ago. Another recent study attempted to link this extinction (and that of other marine species) with a supernova known to have occurred at about this time.

However, a team of researchers led by vertebrate paleontologist Robert Boessenecker with the College of Charleston, Charleston, South Carolina, noted that in many places there were problems with the data regarding individual fossils in the study estimating the extinction date.

In the new study, the researchers reported every fossil occurrence of O. megalodon from the densely sampled rock record of California and Baja California (Mexico) in order to estimate the extinction.

Besides Boessenecker, the research team included Dana Ehret, of New Jersey State Museum; Douglas Long, of the California Academy of Sciences; Morgan Churchill, of the University of Wisconsin Oshkosh; Evan Martin, of the San Diego Natural History Museum; and Sarah Boessenecker, of the University of Leicester, United Kingdom.

They found that genuine fossil occurrences were present until the end of the early Pliocene epoch, 3.6 million years ago. All later fossils either had poor data provenance and likely came from other fossil sites or showed evidence of being eroded from older deposits. Until 3.6 million years ago, O. megalodon had a continuous fossil record on the West Coast.

"We used the same worldwide dataset as earlier researchers but thoroughly vetted every fossil occurrence, and found that most of the dates had several problems-fossils with dates too young or imprecise, fossils that have been misidentified, or old dates that have since been refined by improvements in geology; and we now know the specimens are much younger," Boessenecker said.

"After making extensive adjustments to this worldwide sample and statistically re-analyzing the data, we found that the extinction of O. megalodon must have happened at least one million years earlier than previously determined."

This is a substantial adjustment as it means that O. megalodonlikely went extinct long before a suite of strange seals, walruses, sea cows, porpoises, dolphins and whales all disappeared sometime about 1-2.5 million years ago.

"The extinction of O. megalodon was previously thought to be related to this marine mass extinction-but in reality, we now know the two are not immediately related," Boessenecker said.

It also is further unclear if this proposed mass extinction is actually an extinction, as marine mammal fossils between 1 and 2 million years old are extraordinarily rare-giving a two-million- year-long period of "wiggle room."

"Rather, it is possible that there was a period of faunal turnover (many species becoming extinct and many new species appearing) rather than a true immediate and catastrophic extinction caused by an astronomical cataclysm like a supernova," Boessenecker said.

The researchers speculate that competition with the newly evolved modern great white shark (Carcharodon carcharias) is a more likely reason for megalodon's extinction.

Great whites first show up with serrated teeth about 6 million years ago and only in the Pacific; by 4 million years ago, they are finally found worldwide.

"We propose that this short overlap (3.6-4 million years ago) was sufficient time for great white sharks to spread worldwide and outcompete O. megalodon throughout its range, driving it to extinction-rather than radiation from outer space," Boessenecker said.

Ecosystem changes following loss of great white sharks

Great white shark.

A new study has documented unexpected consequences following the decline of great white sharks from an area off South Africa. The study found that the disappearance of great whites has led to the emergence of sevengill sharks, a top predator from a different habitat. A living fossil, sevengill sharks closely resemble relatives from the Jurassic period, unique for having seven gills instead of the typical five in most other sharks.

These findings are part of a long-term collaborative study between shark researcher Neil Hammerschlag from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, and wildlife naturalist Chris Fallows from Apex Shark Expeditions.

The research focused on the waters surrounding Seal Island in False Bay, South Africa, a site well known for its "flying" great white sharks that breach out of the water when attacking Cape fur seals. Since the year 2000, the research team has spent over 8,000 hours observing great whites from boats, during which they recorded 6,333 shark sightings, and 8,076 attacks on seals. These data revealed that for more than a decade, great white numbers were relatively stable, but in 2015 sightings began to drop off steeply.

"In 2017 and 2018, their numbers reached an all-time low, with great whites completely disappearing from our surveys for weeks and months at a time," said study lead author Neil Hammerschlag, a research associate professor at the UM Rosenstiel School and Abess Center for Ecosystem Science & Policy. "While the reasons for their decline and disappearance remains unknown, it provided a truly unique opportunity for us to see what happens to an ocean ecosystem following the loss of an apex predator."

"In 18+ years of working at Seal Island, we had never seen sevengill sharks in our surveys," said co-author Chris Fallows. "Following the disappearance of white sharks in 2017, sevengill began to show up for the first time and have been increasing in number ever since."

During periods of great white absence in 2017 and 2018, the researchers documented 120 sevengill shark sightings and even witnessed an individual attacking a live seal. In South African waters, sevengill sharks have no equal in the food web with the exception of the great white and orca whale. Historically, the only well-known aggregation site for sevengills in False Bay was located 18 km away from Seal Island within inshore kelp beds. The study suggested that the appearance of sevengill sharks at Seal Island was due to the disappearance of great whites, thereby allowing sevengills to exploit the area without risk of predation from great white sharks or competition with them for shared prey.

This 18-year study provided new insights into the diverse ways that a marine ecosystem can be altered following the loss of an apex predator.

Antarctic ice shelves buckle under weight of meltwater lakes

Meltwater lakes in Antarctica.

The filling and draining of meltwater lakes has been found to cause a floating Antarctic ice shelf to flex, potentially threatening its stability.

A team of British and American researchers, co-led by the University of Cambridge, has measured how much the McMurdo ice shelf in Antarctica flexes in response to the filling and draining of meltwater lakes on its surface. This type of flexing had been hypothesised before and simulated by computer models, but this is the first time the phenomenon has been measured in the field. The results are reported in the journal Nature Communications.

The results demonstrate a link between surface melting and the weakening of Antarctic ice shelves and support the idea that recent ice shelf breakup around the Antarctic Peninsula may have been triggered, at least in part, by large amounts of surface meltwater produced in response to atmospheric warming.

As the climate continues to warm, more and more ice shelves may become susceptible to flex, fracture and break up over the coming century.

Most of the Antarctic continent is covered by the Antarctic Ice Sheet, which is up to four kilometres thick and contains enough ice to raise global sea levels by about 58 metres. Over most of the continent and for most of the year, air temperatures are well below zero and the ice surface remains frozen. But around 75% of the ice sheet is fringed by floating ice shelves, which are up to a kilometre thick, mostly below sea level, but with tens of metres of their total height protruding above the water. In the summer months, when air temperatures rise above freezing, the surfaces of these ice shelves are susceptible to melting.

"Surface water on ice shelves has been known about for a long time," said co-author Dr Ian Willis from Cambridge's Scott Polar Research Institute. "Over 100 years ago, members of both Shackleton's Nimrod team and the Northern Party team of Scott's British Antarctic Expedition mapped and recorded water on the Nansen Ice Shelf, around 300 kilometres from where we did our study on the McMurdo Ice Shelf. For the last few decades, it has also been possible to see widespread surface meltwater forming on many ice shelves each summer from satellite imagery."

What is not fully known is the extent to which surface water might destabilise an ice shelf, especially in warmer summers when more meltwater is produced. If the slope of the ice shelf is sufficiently steep, the water may flow off the ice shelf to the ocean in large surface rivers, mitigating against any potential instability.

The danger comes if water pools up in surface depressions on the ice shelf to form large lakes. The extra weight of the water will push down on the floating ice, causing it to sink a bit further into the sea. Around the edge of the lake, the ice will flex upwards to compensate. "If the lake then drains, the ice shelf will now flex back, rising up where the lake used to be, sinking down around the edge," said lead author Dr Alison Banwell, also from SPRI. "It is this filling and draining of lakes that causes the ice shelf to flex, and if the stresses are large enough, fractures might also develop."

Banwell and co-author Professor Doug MacAyeal from the University of Chicago had previously suggested that the filling and draining of hundreds of lakes might have led to the catastrophic breakup of the Larsen B Ice Shelf 2002 when 3,250 square kilometres of ice was lost in just a few days.

"We had been able to model the rapid disintegration of that ice shelf via our meltwater loading-induced fracture mechanism," said Banwell. "However, the problem was that no one had actually measured ice shelf flex and fracture in the field, and so we were unable to fully constrain the parameters in our model. That's partly why we set out to try to measure the process on the McMurdo ice shelf."

Using helicopters, snow machines and their own two feet, the researchers set up a series of pressure sensors to monitor the rise and fall of water levels in depressions which filled to become lakes, and GPS receivers to measure small vertical movements of the ice shelf.

"It was a lot of work to obtain the data, but they reveal a fascinating story," said MacAyeal. "Most of the GPS signal is due to the ocean tides, which move the floating ice shelf up and down by several metres twice a day. But when we removed this tidal signal we found some GPS receivers moved down, then up by around one metre over a few weeks whereas others, just a few hundred metres away, hardly moved at all. The ones that moved down then up the most were situated where lakes were filling and draining, and there was relatively little movement away from the lakes. It is this differential vertical motion that shows the ice shelf is flexing. We'd anticipated this result, but it was very nice when we found it."

The team hope that their work will inspire others to look for evidence of flex and fracture on other ice shelves around Antarctica. Their work will also help in developing ice sheet scale models that could be used to predict the stability of ice shelves in the future and to understand the controls on ice shelf size since they act as buffers against fast-moving ice from the continent. As ice shelves shrink, glaciers and ice streams behind them flow more rapidly to the ocean, contributing to global sea level rise.

The work was funded by the US National Science Foundation, the Leverhulme Trust, NASA, and CIRES, University of Colorado, Boulder.