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‘Off switch’ for pain discovered: Activating the adenosine A3 receptor subtype is key to powerful pain relief

In research published in the medical journal Brain, Saint Louis University researcher Daniela Salvemini, Ph.D. and colleagues within SLU, the National Institutes of Health (NIH) and other academic institutions have discovered a way to block a pain pathway in animal models of chronic neuropathic pain including pain caused by chemotherapeutic agents and bone cancer pain suggesting a promising new approach to pain relief. The scientific efforts led by Salvemini, who is professor of pharmacological and physiological sciences at SLU, demonstrated that turning on a receptor in the brain and spinal cord counteracts chronic nerve pain in male and female rodents. Activating the A3 receptor — either by its native chemical stimulator, the small molecule adenosine, or by powerful synthetic small molecule drugs invented at the NIH — prevents or reverses pain that develops slowly from nerve damage without causing analgesic tolerance or intrinsic reward (unlike opioids). Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain. The most successful pharmacological approaches for the treatment of chronic pain rely on certain “pathways”: circuits involving opioid, adrenergic, and calcium channels. For the past decade, scientists have tried to take advantage of these known pathways — the series of interactions between molecular-level components that lead to pain. While adenosine had shown potential for pain-killing in humans, researchers had not yet successfully leveraged this particular pain pathway because the targeted receptors engaged many side effects. In this research, Salvemini and colleagues have demonstrated that activation of the A3 adenosine receptor subtype is key in mediating the pain relieving effects of adenosine.

“It has long been appreciated that harnessing the potent pain-killing effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain,” Salvemini said. “Our findings suggest that this goal may be achieved by focusing future work on the A3AR pathway, in particular, as its activation provides robust pain reduction across several types of pain.” Researchers are excited to note that A3AR agonists are already in advanced clinical trials as anti-inflammatory and anticancer agents and show good safety profiles. “These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists such as MRS5698 activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain,” Salvemini said.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2014/11/141126132639.htm Original web page at Science Daily

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How brain ‘reboots’ itself to consciousness after anesthesia

One of the great mysteries of anesthesia is how patients can be temporarily rendered completely unresponsive during surgery and then wake up again, with their memories and skills intact. A new study by Dr. Andrew Hudson, an assistant professor in anesthesiology at the David Geffen School of Medicine at UCLA, and colleagues provides important clues about the processes used by structurally normal brains to navigate from unconsciousness back to consciousness. Their findings are currently available in the early online edition of the Proceedings of the National Academy of Sciences. Previous research has shown that the anesthetized brain is not “silent” under surgical levels of anesthesia but experiences certain patterns of activity, and it spontaneously changes its activity patterns over time, Hudson said. For the current study, the research team recorded the electrical activity from several brain areas associated with arousal and consciousness in a rodent model that had been given the inhaled anesthetic isoflurane. They then slowly decreased the amount of anesthesia, as is done with patients in the operating room, monitoring how the electrical activity in the brain changed and looking for common activity patterns across all the study subjects. The researchers found that the brain activity occurred in discrete clumps, or clusters, and that the brain did not jump between all of the clusters uniformly. A small number of activity patterns consistently occurred in the anesthetized rodents, Hudson noted. The patterns depended on how much anesthesia the subject was receiving, and the brain would jump spontaneously from one activity pattern to another. A few activity patterns served as “hubs” on the way back to consciousness, connecting activity patterns consistent with deeper anesthesia to those observed under lighter anesthesia.

“Recovery from anesthesia is not simply the result of the anesthetic ‘wearing off,’ but also of the brain finding its way back through a maze of possible activity states to those that allow conscious experience,” Hudson said. “Put simply, the brain reboots itself.” The study suggests a new way to think about the human brain under anesthesia, and could encourage physicians to reexamine how they approach monitoring anesthesia in the operating room. Additionally, if the results are applicable to other disorders of consciousness — such as coma or minimally conscious states — doctors may be better able to predict functional recovery from brain injuries by looking at the spontaneously occurring jumps in brain activity. In addition, this work provides some constraints for theories about how the brain leads to consciousness itself, Hudson said. Going forward, the UCLA researchers will test other anesthetic agents to determine if they produce similar characteristic brain activity patterns with “hub” states. They also hope to better characterize how the brain jumps between patterns.

http://www.sciencedaily.com/  Science Daily

July 22, 2014

http://www.sciencedaily.com/releases/2014/06/140618135834.htm  Original web page at Science Daily

 

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To recover consciousness, brain activity passes through newly detected states

“I always found it remarkable that someone can recover from anesthesia, not only that you blink your eyes and can walk around, but you return to being yourself. So if you learned how to do something on Sunday and on Monday, you have surgery, and you wake up and you still know how to do it,” says Alexander Proekt, a visiting fellow in Don Pfaff’s Laboratory of Neurobiology and Behavior at RockefellerUniversity and an anesthesiologist at WeillCornellMedicalCollege. “It seemed like there ought to be some kind of guide or path for the system to follow.” The obvious explanation is that as the anesthetic washes out of the body, electrical activity in the brain gradually returns to its conscious patterns. However, new research by Proekt and colleagues suggests the trip back is not so simple. “Using statistical analysis, our research shows that the recovery from deep anesthesia is not a smooth, linear process. Instead, there are dynamic ‘way stations’ or states of activity the brain must temporarily occupy on the way to full recovery,” Pfaff says. “These results have implications for understanding how someone’s ability to recover consciousness can be disrupted by, for example, brain injury.” Proekt, along with former postdoc Andrew Hudson, now an assistant professor in anesthesiology at the University of California, Los   Angeles, and Diany Paola Calderon, a research associate in the lab, put rats “under” using the common medical and veterinary anesthetic isoflurane. As the rats recovered, the team monitored the electrical potential outside neurons, known as local field potentials (LFPs), in particular parts of the brain known, from previous elecrophysiological and pharmacological studies, to be associated with wakefulness and anesthesia. These recordings gave them a sensitive handle on the activities of whole groups of neurons in particular parts of the thalamus and cortex.

In the awake brain, of both humans and rats, neurons generate electrical voltage that oscillates. Many of these oscillations together form a signal that appears as a squiggly line on a recording of brain activity, such as an LFP. When someone is asleep, under anesthesia, or in a coma, these oscillations occur more slowly, or at a low frequency. When he or she is awake, they speed up. The researchers examined the recordings from the rats’ brains to figure out how the electrical activity in these regions changed as they moved from anesthetized to awake. “Recordings from each animal wound up having particular features that spontaneously appeared, suggesting their brain activity was abruptly transitioning through particular states,” Hudson says. “We analyzed the probability of a brain jumping from one state to another, and we found that certain states act as hubs through which the brain must pass to continue on its way to consciousness.” While the electrical activity in all the rats’ brains passed through these hubs, the precise path back to consciousness was not the same each time, the team reports today in the Proceedings of the National Academy of Sciences. “These results suggest there is indeed an intrinsic way in which the unconscious brain finds its way back to consciousness. The anesthetic is just a tool for severely reducing brain activity in a way in which we can control,” Hudson says. In other scenarios, including coma caused by brain injury or neurological disease, the disruption to brain activity cannot be controlled, making these states much more difficult to study. However, the team’s results may help explain what is going on in these cases. “Maybe a pathway has shut down, or a brain structure that was key for full consciousness is no longer working. We don’t know yet, but our results suggest the possibility that under certain circumstances, someone may be theoretically capable of returning to consciousness but, due to the inability to transition through the hubs we have identified, his or her brain is unable to navigate the way back,” Calderon says.

http://www.sciencedaily.com/  Science Daily

July 8, 2014

http://www.sciencedaily.com/releases/2014/06/140609153429.htm  Original web page at Science Daily

 

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Mice that feel less pain live longer

Scientists have found a way to beat back the hands of time and fight the ravages of old age, at least in mice. A new study finds that mice bred without a specific pain sensor, or receptor, live longer and are less likely to develop diseases such as diabetes in old age. What’s more, exposure to a molecule found in chili peppers and other spicy foods may confer the same benefits as losing this pain receptor—meaning that humans could potentially benefit, too. When you touch something hot or get a nasty paper cut, pain receptors in your skin are activated, causing neurons to relay a message to your brain: “Ouch!” Although pain protects your body from damage, it also causes harm. People who experience chronic pain, for example, are more likely to have shorter lifespans, but the reason for this has remained unclear. To investigate further, researchers from the University of California (UC), Berkeley, bred mice without a pain receptor called TRPV1. Found in the skin, nerves, and joints, it’s known to be activated by the spicy compound found in chili peppers, known as capsaicin. (When you feel like your mouth is burning after eating a jalapeño, that’s TRPV1 at work.) Surprisingly, the mice without TRPV1 lived on average 14% longer than their normal counterparts, the team reports today in Cell. (Meanwhile, calorie restriction—another popular way of lengthening mouse lifespans—can make them live up to 40% longer.) When the TRPV1-less mice got old, they still showed signs of fast, youthful metabolisms. Their bodies continued to quickly clear sugar from the blood—a trait called glucose tolerance that usually declines with age—and they burned more calories during exercise than regular elderly mice. The reason for the mice’s increased longevity may lie in the TRPV1 receptor’s role in regulating insulin, a hormone that removes sugar from the blood, says lead researcher Andrew Dillin, a molecular biologist at UC Berkeley. In the pancreas, TRPV1 neurons stimulate the release of a substance called CGRP, which prevents insulin from entering the bloodstream. With less insulin, it’s harder to control blood sugar. Mice without the TRPV1 gene had low levels of CGRP, which meant that they had more insulin, explaining their enhanced ability to manage glucose levels. Interestingly, the extremely long-lived naked mole rat, which lives more than 30 years, naturally lacks CGRP, suggesting a key role for this chemical in the aging process, according to Dillin.

TRPV1 is already a popular target for drug companies trying to treat pain, and a therapy that blocks CGRP is now in development for migraines. But Dillin suggests that companies should think beyond pain control. “These drugs might also be useful for treating diabetes and obesity,” he says. Already, diets rich in capsaicin have been linked to lower incidences of diabetes and metabolic problems in humans, he notes. So might spicy foods be a way of extending life? Maybe, Dillin says, but you’d have to eat a lot of them over a long period of time. “Prolonged exposure to capsaicin can actually kill the neuron” that transmits signals from TRPV1, he explains. Knocking out those signals might mimic the effects of being born without TRPV1 in the first place and, therefore, could lead to a longer life. The idea that pain could cause aging is an intriguing one, says molecular biologist David Sinclair of Harvard Medical School in Boston, who was not involved in the study. “It is striking that the mice without TRPV1 were protected from some of the ravages of old age, including declines in metabolism, cognition, and physical activity,” Sinclair says. While there’s no guarantee that pain receptors control aging in humans, he notes, perhaps the next step could be “to see if people with different variations of the CGRP gene are protected from age-related diseases.”

http://news.sciencemag.org/news  ScienceNow

June 24, 2014

http://news.sciencemag.org/biology/2014/05/mice-feel-less-pain-live-longer  Original web page at ScienceNow

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* One molecule blocks both pain and itch, discovered in mouse study

The new antibody works by targeting the voltage-sensitive sodium channels in the cell membrane of neurons. The results appear online on May 22 in Cell. Voltage-sensitive sodium channels control the flow of sodium ions through the neuron’s membrane. These channels open and close by responding to the electric current or action potential of the cells. One particular type of sodium channel, called the Nav1.7 subtype, is responsible for sensing pain. Mutations in the human gene encoding the Nav1.7 sodium channel can lead to either the inability to sense pain or pain hypersensitivity. Interestingly, these mutations do not affect other sensations such as touch or temperature. Hence, the Nav1.7 sodium channel might be a very specific target for treating pain disorders without perturbing the patients’ ability to feel other sensations. “Originally, I was interested in isolating these sodium channels from cells to study their structure,” said Seok-Yong Lee, assistant professor of biochemistry in the Duke University Medical School and principal investigator of the study. He designed antibodies that would capture the sodium channels so that he could study them. “But then I thought, what if I could make an antibody that interferes with the channel function?” The team first tested the antibody in cultured cells engineered to express the Nav1.7 sodium channel. They found that the antibody can bind to the channel and stabilize its closed state. “The channel is off when it is closed,” Lee explained. “Since the antibody stabilizes the closed state, the channel becomes less sensitive to pain.” If this held true in live animals, then the animals would also be less sensitive to pain. To test this idea, Lee sought the help of Ru-Rong Ji, professor of anesthesiology and neurobiology, who is an expert in the study of pain and itch sensation. Using laboratory mouse models of inflammatory and neuropathic pain, they showed that the antibody can target the Nav1.7 channel and reduce the pain sensation in these mice. More importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the antibody.

“Pain and itch are distinct sensations, and pain is often known to suppress itch,” said Ji. The team found that the antibody can also relieve acute and chronic itch in mouse models, making them the first to discover the role of Nav1.7 in transmitting the itch sensation. “Now we have a compound that can potentially treat both pain and itch at the same time,” said Lee. Both of these symptoms are common in allergic contact dermatitis, which affects more than 10 million patients a year in the United States alone. “We hope our discovery will garner interest from pharmaceutical companies that can help us expand our studies into clinical trials,” Lee said. Their goal is to develop a safer treatment for pain and itch as an alternative to opioids, which often cause addiction and other detrimental side effects.

http://www.sciencedaily.com/  Science Daily

June 24, 2014

http://www.sciencedaily.com/releases/2014/05/140522123538.htm  Original web page at Science Daily

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Untreated cancer pain a ‘scandal of global proportions,’ survey shows

A ground-breaking international collaborative survey, published today in Annals of Oncology, shows that more than half of the world’s population live in countries where regulations that aim to stem drug misuse leave cancer patients without access to opioid medicines for managing cancer pain. The results from the Global Opioid Policy Initiative (GOPI) project show that more than 4 billion people live in countries where regulations leave cancer patients suffering excruciating pain. National governments must take urgent action to improve access to these medicines, says the European Society for Medical Oncology, leader of a group of 22 partners that have launched the first global survey to evaluate the availability and accessibility of opioids for cancer pain management. “The GOPI study has uncovered a pandemic of over-regulation in much of the developing world that is making it catastrophically difficult to provide basic medication to relieve strong cancer pain,” says Nathan Cherny, Chair of the ESMO Palliative Care Working Group and lead author of the report, from Shaare Zedek Medical Center, Jerusalem, Israel. “Most of the world’s population lacks the necessary access to opioids for cancer pain management and palliative care, as well as acute, post-operative, obstetric and chronic pain.” “When one considers that effective treatments are cheap and available, untreated cancer pain and its horrendous consequences for patients and their families is a scandal of global proportions,” Cherny says.

The study conducted in Africa, Asia, Latin America & the Caribbean and the Middle East assessed the availability of the seven opioid medications considered to be essential for the relief of cancer pain by the WHO Model List of Essential Medicines and the International Association for Hospice and Palliative Care . Those essential medications include codeine, oral oxycodone, transdermal fentanyl, immediate and slow release oral morphine, as well as injectable morphine, and oral methadone. While there are problems with the supply of these medicines in many countries, the main problem is over-regulation that makes it difficult for healthcare professionals to prescribe and administer them for legitimate medical use, the authors say. “This is a tragedy born out of good intentions,” says Cherny. “When opioids are over-regulated, the precautionary measures to prevent abuse and diversion are excessive and impair the ability of healthcare systems to relieve real suffering. The GOPI study has uncovered over-regulation in much of the developing world.” “The next step is for international and local organizations working alongside governments and regulators to thoughtfully address the problems,” adds study co-author James Cleary, Director of the Pain and Policy Studies Group and Founding Director of the Palliative Medicine at the UW Carbone Cancer Center, Madison, Wisconsin, USA.

“Regulatory reform must be partnered with education of healthcare providers in the safe and responsible use of opioid medication, education of the public to destigmatize opioid analgesics and improved infrastructure for supply and distribution,” he says. There are already concrete examples of countries reforming their policies to improve access to opioid medicines, the study authors say, among them the Ukraine, which previously had a limited opioid formulary. “Concerted efforts supported by the Open Society Institute, reports from Human Rights Watch, together with the investment in local clinical champions through programs such as the Pain and Policy Studies Group’s (PPSG) International Pain Policy Fellowship (IPPF) Program, have led to the government approving the manufacture and distribution of immediate release oral morphine in the Ukraine with concurrent changes in policy,” Cleary says. “The ongoing initiatives to reform regulations, improve accessibility and promote the education of clinicians and consumers in the effective use of opioid medications for the relief of cancer pain will require vision, determination and the same spirit of cooperation between organizations that made this study successful. The challenges are great, but no greater than our resolution to the task of making pain relief for cancer patients a reality irrespective of geography. Governments should look at the GOPI survey data for their country and take concrete actions to reduce the barriers,” Cherny concludes. The “Global Opioid Policy Initiative project to evaluate the availability and accessibility of opioids for cancer pain management” is published as a Supplement of Annals of Oncology; free access available here: http://annonc.oxfordjournals.org/content/24/suppl_11.toc.

Science Daily
Jan 7, 2014

Original web page at Science Daily

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Epigenetics a key to controlling acute and chronic pain

Epigenetics, the study of changes in gene expression through mechanisms outside of the DNA structure, has been found to control a key pain receptor related to surgical incision pain, according to a study in the November issue of Anesthesiology. This study reveals new information about pain regulation in the spinal cord. “Postoperative pain is an incompletely understood and only partially controllable condition that can result in suffering, medical complications, unplanned hospital admissions and disappointing surgery outcomes,” said David J. Clark, M.D., Ph.D., Professor of Anesthesia at Stanford University and Director of Pain Management at the VA Palo Alto Health Care System. “We know that histone acetylation and deacetylation modifies many cellular processes and produces distinct outcomes. In this study we found that histones can epigenetically activate or silence gene expression to either increase or decrease incision pain.” Human DNA is wrapped around proteins called histones, much like thread is wrapped around a spool. When a histone undergoes deacetylation, the DNA wraps more tightly around the spool, effectively silencing genes. Conversely, when it undergoes acetylation, the DNA is loosened, allowing for transcription or modifications of genes to occur.

In this study, groups of mice had small surgical incisions made in their hind paws after being anesthetized. These mice were then regularly injected with suberoylanilide hydroxamic acid (SAHA), which prevents deacetylation (thus promoting gene transcription), or anacardic acid, which prevents acetylation (thus reducing gene transcription). The authors tested the animals daily for the degree of pain sensitivity in their hind paws. The study found that regulation of histone acetylation can control pain sensitization after an incision. Specifically, maintaining histone in a relatively deacetylated state reduced hypersensitivity after incision. This is due, in part, to the epigenetic regulation of a specific gene known as CXCR2 and one of its chemokine ligands (KC). The authors also found that these epigenetic changes far outlasted the recovery of animals from their incisions, a property that might help explain why some patients suffer from chronic postoperative pain. Study authors suggest that looking into the roles of these epigenetic mechanisms may help scientists find new ways to treat or prevent acute and chronic postoperative pain in the future. “Epigenetics is a relatively underappreciated area of science, but the discoveries yet to be made in this field will be many,” said Dr. Clark. “While fascinating information has been found by studying specific genes, we need to bridge the gap in science and focus on groups or systems of many genes simultaneously, which could be give us clues to greater breakthroughs in pain control and other areas of medicine.”

Science Daily
November 12, 2013

Original web page at Science Daily

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Scientists confirm functionality of emergency ventilation system for horses

Respiratory or cardiovascular arrest in outdoor animals poses a huge challenge to veterinarians. Ventilation equipment is generally hard to operate and requires electricity and compressed air. Anaesthesiologists at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna) have developed an inexpensive device for the ventilation of large animals. It is easy to transport and can save animal lives in emergencies. In a recent publication in the Journal of Equine Veterinary Education the scientists confirm that their emergency ventilator works in horses. The medical treatment of horses requires not only specialized knowledge but also specialized equipment. Horses’ lungs are large and when they breathe horses take in a correspondingly large volume of air. It is not easy to supply this in an emergency. Suitable respirators are available in hospitals but are not always there when they are needed, for example in the barn, in the pasture, in the woods, during transport or at other places where emergencies can and do occur.

Yves Moens is Head of the Vetmeduni’s Clinical Unit of Anaesthesiology and Perioperative Intensive Care Medicine. He and his colleagues have long been concerned by the number of horses that die avoidable deaths because of the lack of a suitable ventilation device. The scientists have designed a ventilation pump for large animals with which veterinarians can simply and quickly resuscitate animals in the field. The device is similar to the bellows used to inflate air mattresses and is easy to carry and to use. In the event of an emergency, the vet can intubate the animal on site by inserting a breathing tube into its trachea. The ventilator pump is connected to the bellows and operated by foot. Exhalation is effected via a second valve that is manually controlled. An adult horse needs about five to six litres of air in its lungs to be able to obtain enough oxygen. A correspondingly large bellows would be too large to be operated by one man and could not be transported in a conventional car. Although the Vetmeduni’s emergency ventilator can only provide 2.5 litres of air, the researchers believed that it would be sufficient for the respiration of horses if the bellows are activated several times in quick succession. They tested this idea on five anaesthetized Haflinger horses during castration surgery in a pasture. The vets were able to show that gradual ventilation with the 2.5 litre pump is sufficient to keep the animals alive.

In recent decades, anaesthetic medicine for humans and animals has developed highly sophisticated equipment and narcotics. Researchers at the Vetmeduni are developing improved anaesthetic techniques and ventilation equipment to reduce the risks during surgery. The respiratory pump is one of the outcomes. “It improves the safety of large animals in the field, both during routine anaesthesia and in emergencies. It will also help veterinarians to provide emergency first aid in these circumstancesand respect the guidelines for good practice ,” says Moens. The respiratory pump is inexpensive and easy to use and will help veterinarians treat their patients in the field.

Science Daily
October 15, 2013

Original web page at Science Daily

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Best way to kill lab animals sought

Researchers debate most humane methods of dispatch. Killing research animals is one of the most unpleasant tasks in science, and it is imperative to do it as humanely as possible. But researchers who study animal welfare and euthanasia are growing increasingly concerned that widely used techniques are not the least painful and least stressful available. This week, experts from across the world will gather in Newcastle upon Tyne, UK, to debate the evidence and try to reach a consensus. “There are lots of assumptions made about the humaneness of various techniques for euthanizing animals,” says Penny Hawkins, deputy head of the research animals department at the Royal Society for the Prevention of Cruelty to Animals, a charity based in Southwater, UK. “Sometimes an animal might not appear to be suffering, but might be conscious and suffering.” Much of the debate centres on rodents, which make up the vast majority of research animals. Current techniques for killing them include inhalation methods — such as chambers that fill with carbon dioxide or anaesthetic gases — and injecting barbiturates. Physical methods include cervical dislocation (breaking of the neck), or decapitation with specialist rodent guillotines. Some methods recommended by the American Veterinary Medical Association.

Barbiturate injection: Fast-acting, but injection may cause pain. Inhaled anaesthetic (halothane, isoflurane, sevoflurane or desflurane): Useful when restraint of animal is difficult. Carbon dioxide: Acceptable, but chamber must be filled over several minutes and not pre-filled. Death to be verified afterwards or ensured by physical method. Cervical dislocation: Causes rapid death, but skill must be learned. Decapitation: Useful when tissues must be free of euthanasia chemicals. Unacceptable: Nitrous oxide alone; nitrogen or argon asphyxiation (unless animals already anaesthetized); opioids. MoreExperts hotly debate which method is preferable. The most-discussed question at the meeting is likely to be about the use of CO2. “People do still worry about CO2 and it’s still almost certainly the most widely used method for killing rodents,” says Huw Golledge, who studies the anaesthesia of lab animals at Newcastle University, UK. Golledge organized the meeting, which is backed by the London-based National Centre for the Replacement, Refinement and Reduction of Animals in Research. Its aim is to update a 2006 consensus document produced by international experts to give guidance to researchers working with animals. CO2 is used to make rodents unconscious. They are then killed by either asphyxiating them with the gas, or by another method. But increasingly, studies suggest rodents find CO2 stressful.

Evidence for this comes mainly from ‘aversion studies’. A key study by animal welfare researcher Daniel Weary’s group at the University of British Columbia in Vancouver, Canada, shows that albino rats will move away from a dark compartment filling with CO2 into a brightly lit box, despite disliking bright lights. The study found that they were less likely to move away from isoflurane, also used in euthanasia (D. Wong et al. Biol. Lett. http://doi.org/ncv; 2012). Other evidence is contradictory (H. Valentine et al. J. Am. Assoc. Lab. Anim. Sci. 51, 50–57; 2012), but Weary is firm in his beliefs. “Our own results indicate CO2 is highly aversive,” he says. There are also question marks over physical methods. Performed perfectly with animals accustomed to being handled, cervical dislocation may be the best method, but it may not be practical for killing large numbers of rodents. The issues are even more uncertain for the new animal models that scientists are pursuing. For example, a huge increase in the use of zebrafish has put them on the meeting’s agenda. Although much progress has been made with lab rodents, says Weary, “there’s been much less work on fish welfare in general”.

Widely used guidelines on animal euthanasia from the American Veterinary Medical Association (AVMA) in Schaumburg, Illinois, were updated earlier this year, in part to adapt to changes in the animals used in labs, with zebrafish guidance one of the additions. The association says it expects the lab animals section of these guidelines to continue to expand. Some of this guidance comes with regulatory teeth. Later this year, the US National Institutes of Health, which funds biomedical research, says that it expects “full implementation” of the AVMA guidelines, with previously approved projects reviewed using them. Regulation is also driving more unusual animals onto the agenda. New legislation on the treatment of laboratory animals is currently being incorporated into the laws of European Union member states and will cover cephalopods, in some nations for the first time.

Nature
August 20, 2013

Original web page at Nature

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Concerns about anesthesia’s impact on the brain

As pediatric specialists become increasingly aware that surgical anesthesia may have lasting effects on the developing brains of young children, new research suggests the threat may also apply to adult brains. Researchers from Cincinnati Children’s Hospital Medical Center report June 5 the Annals of Neurology that testing in laboratory mice shows anesthesia’s neurotoxic effects depend on the age of brain neurons — not the age of the animal undergoing anesthesia, as once thought. Although more research is needed to confirm the study’s relevance to humans, the study suggests possible health implications for millions of children and adults who undergo surgical anesthesia annually, according to Andreas Loepke, MD, PhD, a physician and researcher in the Department of Anesthesiology. “We demonstrate that anesthesia-induced cell death in neurons is not limited to the immature brain, as previously believed,” said Loepke. “Instead, vulnerability seems to target neurons of a certain age and maturational stage. This finding brings us a step closer to understanding the phenomenon’s underlying mechanism” New neurons are generated abundantly in most regions of the very young brain, explaining why previous research has focused on that developmental stage. In a mature brain, neuron formation slows considerably, but extends into later life in dentate gyrus and olfactory bulb.

The dentate gyrus, which helps control learning and memory, is the region Loepke and his research colleagues paid particular attention to in their study. Also collaborating were researchers from the University of Cincinnati College of Medicine and the Children’s Hospital of Fudan University, Shanghai, China. Researchers exposed newborn, juvenile and young adult mice to a widely used anesthetic called isoflurane in doses approximating those used in surgical practice. Newborn mice exhibited widespread neuronal loss in forebrain structures — confirming previous research — with no significant impact on the dentate gyrus. However, the effect in juvenile mice was reversed, with minimal neuronal impact in the forebrain regions and significant cell death in the dentate gyrus. The team then performed extensive studies to discover that age and maturational stage of the affected neurons were the defining characteristics for vulnerability to anesthesia-induced neuronal cell death. The researchers observed similar results in young adult mice as well. Research over the past 10 years has made it increasingly clear that commonly used anesthetics increase brain cell death in developing animals, raising concerns from the Food and Drug Administration, clinicians, neuroscientists and the public. As well, several follow-up studies in children and adults who have undergone surgical anesthesia show a link to learning and memory impairment.

Cautioning against immediate application of the current study’s findings to children and adults undergoing anesthesia, Loepke said his research team is trying to learn enough about anesthesia’s impact on brain chemistry to develop protective therapeutic strategies, in case they are needed. To this end, their next step is to identify specific molecular processes triggered by anesthesia that lead to brain cell death. “Surgery is often vital to save lives or maintain quality of life and usually cannot be performed without general anesthesia,” Loepke said. “Physicians should carefully discuss with patients, parents and caretakers the risks and benefits of procedures requiring anesthetics, as well as the known risks of not treating certain conditions.” Loepke is also collaborating with researchers from the Pediatric Neuroimaging Research Consortium at Cincinnati Children’s Hospital Medical Center to examine anesthesia’s impact on children’s brain using non-invasive magnetic resonance imaging (MRI) technology.

Science Daily
June 25, 2013

Original web page at Science Daily

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Are patients under anesthesia really unconscious?

EEG can be used to make sure you’re really under. The prospect of undergoing surgery while not fully “under” may sound like the stuff of horror movies. But one patient in a thousand remembers moments of awareness while under general anesthesia, physicians estimate. The memories are sometimes neutral images or sounds of the operating room, but occasionally patients report being fully aware of pain, terror, and immobility. Though surgeons scrupulously monitor vital signs such as pulse and blood pressure, anesthesiologists have no clear signal of whether the patient is conscious. But a new study finds that the brain may produce an early-warning signal that consciousness is returning—one that’s detectable by electroencephalography (EEG), the recording of neural activity via electrodes on the skull. “We’ve known since the 1930s that brain activity changes dramatically with increasing doses of anesthetic,” says the study’s corresponding author, anesthesiologist Patrick Purdon of Massachusetts General Hospital in Boston. “But monitoring a patient’s brain with EEG has never become routine practice.”

Beginning in the 1990s, some anesthesiologists began using an approach called the bispectral (BIS) index, in which readings from a single electrode are connected to a device that calculates, and displays, a single number indicating where the patient’s brain activity falls on a scale of 100 (fully conscious) to zero (a “flatline” EEG). Anything between 40 and 60 is considered the target range for unconsciousness. But this index and other similar ones are only indirect measurements, Purdon explains. In 2011, a team led by anesthesiologist Michael Avidan at the Washington University School of Medicine in St. Louis, Missouri, found that monitoring with the BIS index was slightly less successful at preventing awareness during surgery than the nonbrain-based method of measuring exhaled anesthesia in the patient’s breath. Of the 2861 patients monitored with the BIS index, seven had memories of the surgery, whereas only two of 2852 patients whose breath was analyzed remembered anything.

Despite that, Purdon and his co-workers were hopeful that an “unconsciousness signature” in the brain could be found. Last year, the team worked with three epilepsy patients who’d had electrodes implanted in their brains in preparation for surgery to reduce their seizures. Recording from single neurons in the cortex, where awareness is thought to reside, the researchers gave the patients an injection of the anesthetic propofol. They asked the volunteers to press a button whenever they heard a tone, recording the activity of the neurons. Loss of consciousness, defined as the point when the patients stopped pressing the button, was immediate—40 seconds after injection. Just as immediately, groups of neurons began to emit a characteristic slow oscillation, a kind of ripple in the cells’ electrical field. The neurons weren’t entirely inactive, but bursts of activity occurred only at specific points in this oscillation, resulting in inconsistent brain cell activity. The next step was to see if the same signature could be detected externally, with an EEG. Purdon and his team recruited 10 healthy volunteers to “go under” extremely slowly with propofol: The anesthetic was delivered so gradually that the dropping-off process took not 40 seconds, but almost an hour. Every 4 seconds, the volunteers pressed a button in response to clicks or to words including their names, until they reached unconsciousness. At that point, the researchers report today in the Proceedings of the National Academy of Sciences, EEG readings showed activity analogous to that seen in the study of epilepsy patients. Alpha waves, associated with relaxation and drowsiness, increased with loss of consciousness, as did the even slower, “low-frequency waves.” Both patterns of activity began to decrease with returning consciousness.

The researchers also found a pattern unique to the transition period. During the transition in and out of unconsciousness, the waves almost cancel each other out: The high point or “peak” of the alpha waves occurred at the “trough” of the low-frequency waves. This conjunction, called the “trough-max” pattern, can be read on an EEG and may be the early warning signal that the patient is returning to consciousness. When the patient is deeply unconscious, the “peak-max” pattern, in which the high points of the two wave types occur together, may prove to be a reliable sign that the patient is out. “It’s a rigorous, elegant study,” Avidan says. “The trough-max pattern may well prove to be an early warning signal.” He cautions, however, that the volunteers were healthy and not undergoing any actual surgery, so further research in surgical patients is needed to confirm the findings.

ScienceNow
March 19, 2013

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Longer cardiopulmonary resuscitation improves survival in both children and adults

Experts from The Children’s Hospital of Philadelphia were among the leaders of two large national U.S. studies showing that extending cardiopulmonary resuscitation (CPR) longer than previously thought useful saves lives in both children and adults. The research teams analyzed impact of duration of cardiopulmonary resuscitation in patients who suffered cardiac arrest while hospitalized. “These findings about the duration of CPR are game-changing, and we hope these results will rapidly affect hospital practice,” said Robert A. Berg, M.D., chief of Critical Care Medicine at The Children’s Hospital of Philadelphia. Berg is the chair of the Scientific Advisory Board of the American Heart Association’s Get With Guidelines-Resuscitation program (GWTG-R). That quality improvement program is the only national registry that tracks and analyzes resuscitation of patients after in-hospital cardiac arrests. The investigators reported data from the GWTG-Resuscitation registry of CPR outcomes in thousands of North American hospital patients in two landmark studies — one in children, published January 2013, the other in adults, published in October 2012. Berg was a co-author of the pediatric study, appearing online January 21 in Circulation, which analyzed hospital records of 3,419 children in the U.S. and Canada from 2000 through 2009. This study, whose first author was Renee I. Matos, M.D., M.P.H., a mentored young investigator, found that among children who suffered in-hospital cardiac arrest, more children than expected survived after prolonged CPR — defined as CPR lasting longer than 35 minutes. Of those children who survived prolonged CPR, over 60 percent had good neurologic outcomes.

The conventional thinking has been that CPR is futile after 20 minutes, but Berg said these results challenge that assumption. In addition to Berg, two other co-authors are critical care and resuscitation science specialists at The Children’s Hospital of Philadelphia: Vinay M. Nadkarni, M.D., and Peter A. Meaney, M.D., M.P.H. Nadkarni noted that illness categories affected outcomes, with children hospitalized for cardiac surgery having better survival and neurological outcomes than children in all other patient groups. The overall pediatric results paralleled those found in the adult study of 64,000 patients with in-hospital cardiac arrests between 2000 and 2008. Berg also was a co-author of that GWTG-R study, published in The Lancet on Oct. 27, and led by Brahmajee K. Nallamothu, M.P.H., M.D., of the University of Michigan. Patients at hospitals in the top quartile of median CPR duration (25 minutes), had a 12 percent higher chance of surviving cardiac arrest, compared to patients at hospitals in the bottom quartile of median CPR duration (16 minutes). Survivors of prolonged CPR had similar neurological outcomes to those who survived after shorter CPR efforts.

Science Daily
February 5, 2013

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Scientists home in on cause of osteoarthritis pain

Researchers at Rush University Medical Center, in collaboration with researchers at Northwestern University, have identified a molecular mechanism central to the development of osteoarthritis (OA) pain, a finding that could have major implications for future treatment of this often-debilitating condition. “Clinically, scientists have focused on trying to understand how cartilage and joints degenerate in osteoarthritis. But no one knows why it hurts,” said Dr. Anne-Marie Malfait, associate professor of biochemistry and of internal medicine at Rush, who led the study. An article describing the research was published in the Dec. 11 print version of the Proceedings of the National Academy of Sciences. Joint pain associated with OA has unique clinical features that provide insight into the mechanisms that cause it. First, joint pain has a strong mechanical component: It is typically triggered by specific activities (for example, climbing stairs elicits knee pain) and is relieved by rest. As structural joint disease advances, pain may also occur in rest. Heightened sensitivity to pain, including mechanical allodynia (pain caused by a stimulus that does not normally evoke pain, such as lightly brushing the skin with a cotton swab), and reduced pain-pressure thresholds are features of OA.

Malfait and her colleagues took a novel approach to unraveling molecular pathways of OA pain in a surgical mouse model exhibiting the slow, chronically progressive development of the disease. The study was conducted longitudinally, that is, the researchers were able to monitor development of both pain behaviors and molecular events in the sensory neurons of the knee and correlate the data from repeated observations over an extended period. “This method essentially provides us with a longitudinal ‘read-out’ of the development of OA pain and pain-related behaviors, in a mouse model” Malfait said. The researchers assessed development of pain-related behaviors and concomitant changes in dorsal root ganglia (DRG), nerves that carry signals from sensory organs toward the brain. They found that a chemokine known as monocyte chemoattractant protein (MCP)-1 (CCL2) and its receptor, chemokine receptor 2 (CCR2), are central to the development of pain associated with knee OA. Monocyte chemoattractant protein-1 regulates migration and infiltration of monocytes into tissues where they replenish infection-fighting macrophages. Previous research has shown that MCP-1/CCR2 are central in pain development following nerve injury.

In the study, following surgery the laboratory mice developed mechanical allodynia that lasted 16 weeks. Levels of MCP-1, CCR2 mRNA and protein were temporarily elevated, and neuronal signaling activity increased in the DRG at eight weeks after surgery. This result correlated with the presentation of movement-provoked pain behaviors (for instance, mice with OA travelled less distance, when monitored overnight, and climbed less often on the lid of their cage — suggesting that they avoid movement that triggers pain) which were maintained up to 16 weeks. Mice that lack Ccr2 (knockout mice) also developed mechanical allodynia, but this began to resolve from eight weeks onward. Despite having severe allodynia and structural knee joint damage equal to that in normal mice, Ccr2-knockout mice did not develop movement-provoked pain behaviors at eight weeks. To confirm the key role of CCR2 signaling in development of the observed movement-provoked pain behavior after surgery, the researchers administered a CCR2 receptor-blocker to normal mice at nine weeks after surgery and found that this reversed the decrease in distance traveled, that is, movement-provoked pain behavior.

Interestingly, levels of MCP-1 and CCR2 returned to baseline or lower by 16 weeks in mice exhibiting movement-provoked pain behaviors. This finding may suggest that the MCP-1/CCR2 pathway is involved only in the initiation of changes in the DRG, but once macrophages are present, the process is no longer dependent on increased MCP-1/CCR2. “Increased expression of both MCP-1 and its receptor CCR2 may mediate increased pain signaling through direct excitation of DRG neurons, as well as through attracting macrophages to the DRG,” the researchers said. “This is an important contribution to the field of osteoarthritis research. Rather than looking at the cartilage breakdown pathway in osteoarthritis, Dr. Malfait and her colleagues are looking at the pain pathway, and this can take OA research in to a novel direction that can lead to new pain remedies in the future,” said Dr. Joshua Jacobs, professor and chairman of orthopedic surgery at Rush University Medical Center. Osteoarthritis (OA) is one of the oldest and most common forms of arthritis and is a chronic condition characterized by the breakdown of the joint’s cartilage. Cartilage is the part of the joint that cushions the ends of the bones and allows easy movement of joints. The breakdown of cartilage causes the bones to rub against each other, causing stiffness, pain and loss of movement in the joint.

Science Daily
January 22, 2013

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Rodent euthanasia methods under scrutiny

Study shows anaesthetics may be a more humane way to kill rats and mice than carbon dioxide, but reveals a surprising twist. Albino laboratory rats find carbon dioxide — a gas commonly used for euthanising them — even more unpleasant than bright light. One particularly fraught challenge for animal research is finding humane ways to kill the vast numbers of rodents that are used in experiments every year. Now, a Vancouver-based team of researchers seems to have solid evidence that using anaesthetic gas is preferable to established methods that use carbon dioxide. But the results come with a twist that may further complicate things for experimentalists. Animal-welfare researchers have become increasingly concerned in recent years that killing rats and mice with CO2 may cause distress to the animals. For mice, some researchers advocate physical methods such as cervical dislocation — a skilled breaking of the neck — but this is difficult to achieve with conscious rats because of their size. The main alternative is to use an anaesthetic gas, such as isoflurane, to render the rodents unconscious, and then to kill them using CO2 or another method. Studies attempting to tease out which method is superior have proved contentious.

Daniel Weary, a researcher at the Animal Welfare Program at the University of British Columbia in Vancouver, and his colleagues set up an experiment in which albino rats had a choice of remaining in a dark compartment that was filling with either isoflurane or CO2, or of escaping to a brightly lit compartment filled with normal air. Albino rats generally prefer to stay in the dark, so the researchers wanted to determine which bothered the animals the most — bright light or a noxious atmosphere. With isoflurane, 9 out of 16 rats remained in the dark until they appeared unconscious. But none of the rats remained in the dark chamber when it contained CO2: all preferred the light chamber. The team’s conclusion, published in Biology Letters, is that sedation with isoflurane is “a refinement” over using CO2 alone because rats clearly dislike CO2 more. “I think our results are so clear and consistent,” says Weary. “I’m convinced that some type of halogenated anaesthetic, such as isoflurane, is an advantage over rendering the animal unconscious with CO2.” The results do show that rats prefer even an uncomfortably bright environment rather than one in which they breathe CO2, says Huw Golledge, who works on anaesthesia and analgesia of laboratory animals at Newcastle University, UK. To avoid carbon dioxide, he says, “these animals are choosing to go somewhere they would prefer not to be”.

Golledge points out that previous studies on aversion involved animals choosing either to leave an environment that contained CO2 or to stay and get a reward. In that case, he says, one could have made an argument that the rodents were just being cautious. The surprise in Weary’s work came when he and his team ran the same experiment with rats that had already been exposed to isoflurane. They found that many more animals fled to the light chamber, with just one rat out of 16 remaining in the dark isoflurane chamber. This suggests that re-exposure to isoflurane might be unpleasant for the animals — perhaps because they experience nausea after recovering from the anaesthetic, and remember this the next time around. The implications go beyond euthanasia, says Weary. Researchers may need to reconsider experiments that involve repeatedly exposing animals to isoflurane, during surgery for example. The euthanasia issue is still not settled. “We’re still pretty unclear about what we should be doing with rats,” Golledge says. “I suspect we shouldn’t be using carbon dioxide, but we don’t know what’s substantially better.”

Nature
January 8, 2013

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By improving pain treatment and therapy in dogs, research offers medical insight for humans

A Kansas State University professor’s research improving post-surgery pain treatment and osteoarthritis therapy in dogs may help develop better ways to treat humans for various medical conditions. From the use of hot and cold packs to new forms of narcotics, James Roush, professor of clinical sciences, is studying ways to lessen pain after surgery and improve care for small animals, particularly dogs. He is working with the clinical patients who come to the College of Veterinary Medicine’s Veterinary Health Center. Because humans and dogs experience some diseases in similar ways, his research may improve how doctors and physicians understand human health, too. “Several of our projects have human applications, particularly one involving intra-articular prolotherapy,” Roush said.

Roush’s current projects: A recent project with Ralph Millard, former Veterinary Health Center resident, focuses on ways that hot packing and cold packing affect tissue temperature in beagles and beagle-sized dogs after surgery. After surgery in both humans and dogs it is common to put a cold pack or hot pack on tissue to prevent and reduce swelling. How long the pack is used and what type of cold or hot pack is used depends on the type of injury and surgery. Roush said that no studies have looked at how deep in the tissue the packs affect temperature and how long the packs must be applied so that the tissue reaches a desired temperature. The researchers studied the temperature and tissue depth that hot and cold packing affected and the time it took to reach that temperature. “We found that you don’t really need to cold pack anything longer than 10 minutes because there is not a great change in temperature after that,” Roush said. When tissue is cold packed, it will stay cold for a while after the ice pack is removed. But when tissue is hot packed and the pack is removed, the tissue temperature will return to normal much more quickly. Leaving the hot or cold pack on the tissue longer than 10 minutes will extend the time that the tissue stays at the same hot or cold temperature, Roush said. There just will not be a great change in temperature after 10 minutes. The same technique of hot and cold packing after surgery is also used in humans. Although more research in humans is needed, Roush said there is a strong possibility that a similar 10-minute time frame for hot and cold packing may apply to humans as well. The research appears in two upcoming publications in the Journal of Veterinary Research.

For another project, Roush and Matt Sherwood, Veterinary Health Center resident, are using a mat system to study lameness and osteoarthritis in dogs. When dogs step on the mat, it measures the pressure in their step. The mat system is a useful clinical tool for evaluating and developing treatment of lameness, Roush said. Roush and Sherwood are using the mat for measuring lameness and determining in which leg the lameness is worse. “We’ve designed the study to help improve osteoarthritis treatment,” Roush said. “We will also use it to measure clinical patients when they come in for regular checkups. We can measure their recovery and a variety of other aspects: how they respond to nonsteroidal anti-inflammatories, how they respond to narcotics or how they respond to a surgical procedure that is designed to take that pressure off the joint.” Roush also is working with Marian Benitez, Veterinary Health Center resident, on an analgesic pharmacology study. Rose McMurphy, professor of clinical sciences, and Butch KuKanich, associate professor of anatomy and physiology, are also involved. The researchers are studying the effectiveness of a painkiller used to treat dogs and researching potential alternatives to the drug. The same drug also is commonly used to treat pain in humans. “To achieve the drug’s effect, the dosage in dogs is much higher than in people,” Roush said. “It also may not be a very good analgesic in dogs. We want to see if there is an alternative that requires smaller doses and does not have not as much of a discrepancy for patients.”

Science Daily
October 16, 2012

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Popular pain-relieving medicines linked to hearing loss in women

Analgesics are the most frequently used medications in the United States and are commonly used to treat a variety of medical conditions. But although popping a pill may make the pain go away, it may do some damage to your ears. According to a study by researchers at Brigham and Women’s Hospital (BWH), women who took ibuprofen or acetaminophen two or more days per week had an increased risk of hearing loss. The more often a woman took either of these medications, the higher her risk for hearing loss. Also, the link between these medicines and hearing loss tended to be greater in women younger than 50 years old, especially for those who took ibuprofen six or more days per week. There was no association between aspirin use and hearing loss. The study will be published in the September 15, 2012 issue of the American Journal of Epidemiology. The researchers prospectively examined the relationship between frequency of aspirin, ibuprofen and acetaminophen use and risk of hearing loss among women in the Nurses’ Health Study II.

Data from 62,261 women ages 31 to 48 years at baseline was studied. The women were followed for 14 years, from 1995 to 2009. Ten thousand and twelve women self-reported hearing loss. Compared with women who used ibuprofen less than once per week, those who used ibuprofen 2 to 3 days per week had a 13 percent increased risk for hearing loss, while women who used the medication 4 to 5 days per week had a 21 percent increased risk. For those who used ibuprofen six or more days per week, the increased risk was 24 percent. Compared with women who used acetaminophen less than once per week, women who used acetaminophen 2 to 3 days per week had an 11 percent increased risk for hearing loss, while women taking the medicine 4 to 5 days per week had a 21 percent increased risk. “Possible mechanisms might be that NSAIDs may reduce blood flow to the cochlea—the hearing organ—and impair its function,” said first study author Sharon G. Curhan, MD, BWH Channing Division of Network Medicine. “Acetaminophen may deplete factors that protect the cochlea from damage.” Curhan notes that although analgesics are widely available without a prescription, they are still medicines that carry potential side effects. “If individuals find a need to take these types of medications regularly, they should consult with their health care professional to discuss the risks and benefits and to explore other possible alternatives,” said Curhan. Over 50 percent of American adults suffer from high-frequency hearing loss by the time they reach 60 years old. One-third of women in their 50s and nearly two-thirds in their 60s have experienced hearing loss. According to the World Health Organization, adult-onset hearing loss is the sixth most common disease burden in high-income countries.

EurekAlert! Medicine
October 2, 2012

Original web page at EurekAlert! Medicine

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Discovery of essential genes for drug-resistant bacteria reveals new, high-value drug targets

Biomedical scientists collaborating on translational research at two Buffalo institutions are reporting the discovery of a novel, and heretofore unrecognized, set of genes essential for the growth of potentially lethal, drug-resistant bacteria. The study not only reveals multiple, new drug targets for this human infection, it also suggests that the typical methods of studying bacteria in rich laboratory media may not be the best way to identify much-needed antimicrobial drug targets. The paper focuses on a Gram-negative bacteria called A. baumannii. It is published in the current issue of mBio, as an ‘editor’s choice’ paper. The findings may be relevant to other Gram-negative bacteria as well. A. baumannii is responsible for a growing number of hospital-acquired infections around the world. It can be fatal to patients with serious illnesses, the elderly and those who have had surgeries. Infections also have been seen in soldiers returning from Iraq and Afghanistan with battlefield injuries.

“Generally, healthy people don’t get infected,” explains lead author Timothy C. Umland, PhD, research scientist at Hauptman-Woodward Medical Research Institute (HWI) and professor of structural biology in the University at Buffalo School of Medicine and Biomedical Sciences. “But what’s challenging about A. baumannii is that it can survive in the hospital environment and is very hard to eradicate with common disinfectants, leading to healthcare-associated infections.” Typically, the way that essential genes for microbial pathogens are found is by growing the bacteria under optimal conditions, says co-author Thomas A. Russo, MD, professor in the UB departments of medicine and microbiology and immunology. Genes found to be essential for growth are then entered into the Database of Essential Genes (DEG), which contains genes considered essential for the sustenance of each organism. The researchers at HWI and UB decided to try to better understand what A. baumannii needs in order to grow when infecting patients. “Laboratory conditions create a different type of environment from what happens in patients,” Umland says, “where certain nutrients the bacteria need will be present in very low amounts and where the bacteria encounter immune and inflammatory responses. We were purposely trying to test for genes that are important for growth in these more realistic environments.”

The team performed a genetic screen designed to identify bacterial genes absolutely required for the growth and survival of A. baumannii in human ascites, a peritoneal fluid that accumulates under a variety of pathologic conditions. “We found that nearly all of these 18 genes had not been identified as essential in the DEG because they weren’t necessary for growth in an ideal laboratory environment,” explains Russo. “This is a large set of genes that has been flying under the radar.” He adds: “The biggest concern is that quite a few strains of A. baumannii are resistant to nearly all anti-microbial drugs and some strains are resistant to all of them. To make things worse, there are no new agents being tested for human use in the drug pipeline that are active against A. baumannii. This is a huge problem.” Not only do the new genes suggest brand new, high-value drug targets for A. baumannii infections, but the genes that have been identified may be relevant to other Gram-negative infections. “So far, our computational models show that these genes seem to be conserved across Gram-negative infections, meaning that they may lead to new drugs that would be effective for other drug-resistant infections as well,” says Umland.

Science Daily
October 2, 2012

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The big sleep: How do you anesthetize a hippopotamus?

It may rank fairly low in most lists of pressing problems to be solved but an increasing number of zoos and wildlife collections as well as gamekeepers nevertheless need to come up with an answer: How do you anesthetize a hippopotamus? Difficulties are posed not only by the undesirability of approaching waking animals but also by hippos’ unique skin morphology and by the animals’ sensitivity to standard anesthetic methods. A new procedure is now described by the group of Chris Walzer at the Research Institute of Wildlife Ecology of the University of Veterinary Medicine, Vienna and published in the current issue of the Journal of the American Veterinary Medical Association. All zoo animals — and sometimes also wild animals — occasionally need veterinary treatment and anesthesia is clearly required in many cases. For most animals the procedures are well established but for a variety of reasons it has proven difficult to anaesthetize hippopotamuses. The thick skin and the dense subcutaneous tissue make it difficult to introduce sufficient amounts of anesthetics and opioid-based anesthetics often cause breathing irregularities and occasionally even death. In addition, the level of anesthesia is only rarely sufficient to enable surgery to be undertaken: few vets wish to be around when a drugged hippopotamus starts to wake up.

Together with Thierry Petit from the Zoo de la Palmyre, France, and collaborators in Germany and Israel, Gabrielle Stalder and Chris Walzer from the Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna (Vetmeduni Vienna) have now developed a new anesthetic protocol based on the use of two non-opiate drugs, medetomidine and ketamine. The procedure has been tested on a total of ten captive hippopotamuses, all of which were successfully anesthetized to an extent that enabled surgery — although due to the difficulty to estimate their exact weight some animals needed additional doses of anesthetic before they could be safely handled. Crucially, all animals recovered rapidly and completely from the procedure and showed no lasting after-effects.

Diving during anesthesia? This does not mean that the anesthesia always passed without incident: five of the ten animals stopped breathing for periods of up to nearly ten minutes. But in each case the hippopotamus spontaneously recommenced breathing without the need for any intervention. The VetMed scientists interpret the temporary suspension of breathing as a dive response: their aquatic lifestyle means that hippopotamuses are able to hold their breath for relatively long periods, so it is likely that the animals also “dived” during the period of unconsciousness. The researchers thus had a unique opportunity to learn what happens when hippopotamuses stop breathing. The level of oxygen in the blood naturally decreases but this is not associated with an increase in heart rate nor, surprisingly, with increased levels of lactate. As Walzer says, “all diving mammals have evolved a strategy to cope with the shortage of oxygen while they are underwater. The reaction of hippopotamuses to anesthesia suggests that they do not switch to anaerobic metabolism when they dive but possibly have other mechanisms to help them use the oxygen in their blood more efficiently. The hooded seal is known to have very high levels of myoglobin in its muscles: maybe the hippopotamus has a similar trick to help it survive?”

Science Daily
July 24, 2012

Original web page at Science Daily

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Regional anesthesia reduces complications and death for hip fracture patients

In a study of more than 18,000 patients having surgery for hip fracture, researchers at the Perelman School of Medicine at the University of Pennsylvania found that the use of regional anesthesia versus general anesthesia, was associated with a significant reduction in major pulmonary complications and death. The new study will be published in the July issue of the journal Anesthesiology. “Hip fracture is a common and costly event among older adults,” said lead study author Mark D. Neuman, MD, assistant professor of Anesthesiology and Critical Care and senior fellow at the Leonard Davis Institute for Health Economics. “One out of five hip fracture patients dies within a year of their injury. There is an urgent need for better information to guide patients and clinicians make decisions about anesthesia for hip fracture surgery, but so far very few large observational studies in the general population have examined this issue.” Hip fractures are a global public health problem, occurring 1.6 million times worldwide, and their incidence is anticipated to grow rapidly during the next three decades because of the aging of the population. Most hip fractures occur in people older than 65, with the mortality and morbidity compilations increasing rapidly after age 80. A hip fracture almost always requires surgical repair or replacement, followed by weeks to months of physical therapy.

Dr. Neuman and his co-authors examined a retrospective cohort of patients undergoing surgery for hip fracture in 126 hospitals in New York in 2007 and 2008, which included a total of 18,158 patients. They tested the association of regional (epidural, spinal or nerve block) versus general anesthesia with inpatient mortality, major inpatient pulmonary complications, and major inpatient cardiovascular complications. Among patients undergoing hip fracture surgery, the researchers found a 29 percent lower adjusted odds of mortality among patients receiving regional versus general anesthesia. They also found a 24 percent decrease in the adjusted odds of any inpatient pulmonary complication with regional anesthesia. “These findings have important implications for practice, policy, and research related to the treatment of older adults with hip fracture,” said Lee A. Fleisher, MD, chair and Robert Dunning Dripps Professor of Anesthesiology and Critical Care and the senior author of the study. “Given the high rate of mortality associated with hip fracture and the large and growing worldwide public health burden attributed to complications of hip fracture care, our findings highlight an important potential opportunity to improve outcomes among a growing population of vulnerable surgical patients.”

Science Daily
July 10, 2012

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Share local anesthetic stops pain at the source after hip replacement surgery

In patients undergoing hip replacement surgery, using a special wound catheter to infuse local anesthetic directly into the hip joint provides significant and lasting improvements in postoperative pain control, reports a study in the February issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS). By stopping pain at the source, continuous wound infusion with local anesthetic produces lower pain scores, reduced morphine use, and less nausea and vomiting, according to the new research. “Moreover, a positive effect on superficial and deep wound pain was still present three months later,” write Dr Jose Aguirre and colleagues of Balgrist University Hospital Zurich, Switzerland. The study included 76 patients undergoing minimally invasive hip arthroplasty surgery. In all patients, a specially designed wound catheter was placed into the hip joint during the operation. In one group, the catheter was used to infuse ropivacaine, a local anesthetic drug, into the joint at the end of the procedure and for 48 hours afterward. The other group received continuous wound infusion with an inactive placebo solution.

Both groups had patient-controlled morphine available for pain relief. The two groups were compared in terms of pain scores and amount of morphine used. Patients receiving continuous wound infusion with ropivacaine had better pain control during the first 48 hours after surgery, with lower scores for pain at rest and pain with motion. This was reflected by a significant reduction in morphine use, especially on the day after surgery. Overall, patients in the ropivacaine group used 36 percent less morphine than those in the placebo group. The ropivacaine group also had less postoperative nausea and vomiting — a common side effect of morphine — and were more satisfied with their pain management. None of the patients had toxic levels of ropivacaine in their bloodstream. Continuous wound infusion with ropivacaine reduced pain not only in the days after the operation, but also in subsequent weeks and months. Three months after surgery, patients in the ropivacaine group had lower scores for wound pain, including both superficial and deep pain.

Pain is a significant problem for patients undergoing hip replacement surgery. Instilling local anesthetic directly into the wound is increasingly recognized as an effective part of “multimodal” (combination) approaches to pain control after various types of surgery. The new study is the first to specifically evaluate the effects of continuous wound infusion with modern minimally invasive hip arthroplasty techniques. The results suggest that continuous wound infusion with ropivacaine significantly improves pain control after hip replacement surgery. What’s more, better pain control in the days after surgery may reduce problems with wound pain in the weeks and months after the operation. Dr Aguirre and colleagues suggest further studies to evaluate continuous wound infusion with different kinds of drugs known to affect “central sensitization” to pain. “Wound catheters are very inexpensive and highly effective,” comments Dr. Steven L. Shafer of Columbia University, Editor-in-Chief of Anesthesia & Analgesia. “This is an important advance in providing high quality pain relief with minimal cost.”

Science Daily
February 21, 2012

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High-dose opiates could crack chronic pain

Powerful analgesics can restore normal nerve function. Has a cheap and effective treatment for chronic pain been lying under clinicians’ noses for decades? Researchers have found that a very high dose of an opiate drug that uses the same painkilling pathways as morphine can reset the nerve signals associated with continuous pain — at least in rats. If confirmed in humans, the procedure could reduce or eliminate the months or years that millions of patients spend on pain-managing prescription drugs. The results of the study are described in Science. Higher than normal doses of opiates may be able to cure chronic pain. “We have discovered a new effect of opiates when they are given, not constantly at a low dose, but at a very high dose,” says Jürgen Sandkühler, a neurophysiologist at the Center for Brain Research of the Medical University of Vienna, and a co-author of the paper. Chronic pain is a nerve condition that lingers long after the immediate, or acute, pain-causing stimulus has receded. It can follow surgery or injury, and is also associated with conditions such as rheumatoid arthritis and cancer.

Sandkühler says that the original stimulus changes how the central nervous system deals with pain over time. In a model known as long-term potentiation, nerves carrying pain signals fire repeatedly, turning on a cellular pain amplifier that causes anything from exaggerated pain to outright agony on a long-term basis. Opiates such as morphine and heroin remain the ‘gold standard’ in pain relief, but they work only temporarily for those with chronic pain. Sandkühler and his colleagues decided to push the boundaries of the opiates’ action and measure whether the drugs could have any effect on the underlying problem. The team induced long-term potentiation in 25 rats by exposing nerve fibres known to carry pain signals to low-frequency electrical stimulation. They subjected some of the rats to high-frequency electrical stimulation, or gave them injections of capsaicin, the pain-causing ingredient in chill peppers, as alternative stimuli. After the pain stimulus ceased, the researchers gave the rats a very high intravenous dose of the opiate remifentanil. As expected, the pain signals slumped at once — remifentanil is an extremely fast-acting painkiller, and was chosen because its effects tend to wear off in rats after just 10 minutes. When the drug’s effects did wear off, the chronic pain was significantly reduced in the rats treated with low-frequency stimulation. A second infusion of the drug an hour later abolished the long-term potentiation and restored these rats’ pain levels to normal. A high dose of remifentanil was also effective in reducing the pain of the rats treated with capsaicin or high-frequency stimulation.

Treating the rats with half the dose of remifentanil did not produce the same effect. Sandkühler suggests that a threshold level of the drug is needed to disrupt the movement of calcium signalling ions between nerves and neutralize the long-term potentiation. “The dose of drugs we use is very high, probably 2–4 times higher than used for normal pain control,” says Sandkühler. “The animals almost stop breathing, which is probably one reason why this was not discovered before.” But he adds that the equivalent amount of the opiate for a human is well below a fatal dose. He and his colleagues have conducted pre-clinical experiments that have shown that people can tolerate it. Michael Serpell, a consultant anaesthetist and pain doctor at the University of Glasgow School of Medicine, UK, is impressed with the paper’s methodology. He says the idea has always been that if you hit acute pain hard enough, then you can reduce the chance of it becoming chronic. “It would be appropriate to try this. It could be rolled out into the clinical arena in high-risk patients first,” he says.

Nature
January 24, 2012

Original web page at Nature

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Does that hurt? Objective way to measure pain being developed

Researchers from the Stanford University School of Medicine have taken a first step toward developing a diagnostic tool that could eliminate a major hurdle in pain medicine — the dependency on self-reporting to measure the presence or absence of pain. The new tool would use patterns of brain activity to give an objective physiologic assessment of whether someone is in pain. The scientists used functional magnetic resonance imaging scans of the brain combined with advanced computer algorithms to accurately predict thermal pain 81 percent of the time in healthy subjects, according to a study that will is published Sept. 13 in the online journal PLoS ONE. “People have been looking for a pain detector for a very long time,” said Sean Mackey, MD, PhD, chief of the Division of Pain Management and associate professor of anesthesiology. “We’re hopeful we can eventually use this technology for better detection and better treatment of chronic pain.” Researchers stressed that future studies are needed to determine whether these methods will work to measure various kinds of pain, such as chronic pain, and whether they can distinguish accurately between pain and other emotionally arousing states, such as anxiety or depression.

“A key thing to remember is that this approach objectively measured thermal pain in a controlled lab setting,” Mackey said. “We should take care not to extrapolate these findings to say we can measure and detect pain in all circumstances.” The need for a better way to objectively measure pain instead of relying on the current method of self-reporting has long been acknowledged. But the highly subjective nature of pain has made this an elusive goal. Advances in neuroimaging techniques have re-invigorated the debate over whether it might be possible to measure pain physiologically, and, in fact, led to this current study. A study released by the Institute of Medicine in June reported that more than 100 million Americans suffer chronic pain, costing around $600 billion each year in medical expenses and lost productivity. Mackey was a member of the committee that produced the report. What’s more, it found that cultural bias against chronic pain sufferers as being weak or even worse — they are often perceived as lying about their pain — complicates the delivery of appropriate treatment. Similar biases crop up in the legal field, with hundreds of thousands of cases each year that hinge on the existence of pain, said Stanford law professor Hank Greely, an expert on the legal, ethical and social issues surrounding the biosciences.

Researchers took eight subjects, and put them in the brain-scanning machine. A heat probe was then applied to their forearms, causing moderate pain. The brain patterns both with and without pain were then recorded and interpreted by advanced computer algorithms to create a model of what pain looks like. The process was repeated with a second group of eight subjects. The idea was to train a linear support vector machine — a computer algorithm invented in 1995 — on one set of individuals, and then use that computer model to accurately classify pain in a completely new set of individuals. The computer was then asked to consider the brain scans of eight new subjects and determine whether they had thermal pain. “We asked the computer to come up with what it thinks pain looks like,” Chatterjee said. “Then we could measure how well the computer did.” And it did amazingly well. The computer was successful 81 percent of the time.

Science Daily
October 4, 2011

Original web page at Science Daily

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Compound offers pain relief without the complications

The synthesis of a natural pain reliever could lead to an analgesic without serious side effects. The pinwheel flower (Tabernaemontana divaricata) contains miniscule amounts of the pain-relieving compound conolidine. Chemists have succeeded in synthesising a natural compound that shows promise as a painkiller — and might not cause the side effects that bedevil analgesics currently used to treat acute and chronic conditions. Conolidine is found in the bark of the tropical flowering shrub Tabernaemontana divaricata, commonly called the pinwheel flower. The plant is native to southeast Asia, where it has long been used in traditional Chinese, Ayurvedic and Thai medicines to treat fever and pain. But the shrubs contain so little of the compound that pharmacologists have been unable to study its medicinal applications. Now, a team at the Scripps Research Institute in Jupiter, Florida, has made conolidine in the lab from simple starting materials, and found that it has analgesic effects. The researchers describe their findings in a paper published today in Nature Chemistry.

T. divaricata contains a range of ‘alkaloid’ compounds, the molecules of which have carbon-based frameworks in which the atoms are linked into several rings. Some of these have already been studied as candidate drugs, but they are opioids, belonging to the same class of compounds as morphine and hydrocone. Opioids cause serious side effects, including addiction, nausea and breathing problems. Conolidine is not an opioid, so it might offer pain relief without these complications. However, Glenn Micalizio, a chemist at Scripps, and his colleagues did not become interested in the compound because of its pharmaceutical potential. Rather, they realized that its complex carbon skeleton was an ideal target for testing a type of reaction that they had recently devised. Although putting together the complex frameworks of natural molecules is a well developed art, each molecule poses its own unique challenges. “This ring system is particularly challenging,” says Micalizio. The team worked out how to make an intermediate molecule in which the shape of the carbon skeleton led to easy forging of the final link in the network of rings — in other words, a structure with loose ends dangling close to one another in more or less the right configuration.

The conolidine molecule has two mirror-image versions, both of which the authors made starting with the same commercially available molecule. They first converted this reagent into two mirror-image forms, which they separated using an enzyme capable of telling them apart. A further eight steps brought them to their target. Each step in a synthesis inevitably produces some side products, so not all of the starting material ends up as conolidine. But 18% of it does — a respectable proportion for a complicated synthesis. It was only after working out how to make the molecule that Micalizio’s team decided to approach Laura Bohn, a pharmacologist at Scripps, to investigate its biological effects. Although researchers had been aware of the analgesic effects of similar compounds, it hadn’t previously been possible to investigate conolidine, because there wasn’t enough of the compound available from the natural source for testing. It makes up just 0.00014% of the bark of T. divaricata. In trials with mice, Bohn and her colleagues established that the synthetic conolidine reduces inflammatory pain. What’s more, there is evidence that it does so using a different biological pathway to opioids.

Morphine and other opioids increase the activity of the locomotor centres in the brain , which control the mice’s movements, by raising levels of the neurotransmitter dopamine. This seems to be related to their addictive properties. But “conolidine does not affect locomotor activity, suggesting that it does not induce dopamine elevations”, says Bohn. One of the goals now, she adds, is to identify just how conolidine does suppress pain. Even if conolidine proves a success in clinical trials, it remains to be seen whether Micalizio’s synthesis will be the way to make it on a large scale. But, he says, “we believe that this is certainly a good start”. He also suspects that this won’t be the only potential drug to come from the family of compounds produced by this plant.

Nature
June 15, 2011

Original web page at Nature

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Introducing the world’s first intubation robot

Researchers have introduced the first intubation robot operated by remote control. The robotic system — named The Kepler Intubation System (KIS), and developed by Dr. Thomas M. Hemmerling, McGill University Health Centre (MUHC) specialist and McGill University Professor of Anesthesia and his team — may facilitate the intubation procedure and reduce some complications associated with airway management. The world’s first robotic intubation in a patient was performed at the Montreal General Hospital earlier this month by Dr. Hemmerling. “The KIS allows us to operate a robotically mounted video-laryngoscope using a joystick from a remote workstation,” says Dr. Hemmerling who is also a neuroscience researcher at the Research Institute of the MUHC. “This robotic system enables the anaesthesiologist to insert an endotracheal tube safely into the patient’s trachea with precision.”

The insertion of an endotracheal tube allows artificial ventilation, which is used in almost all cases of general anesthesia. Correct insertion of this tube into patients’ airways is a complex manoeuvre that requires considerable experience and practice to master. “Difficulties arise because of patient characteristics but there is no doubt that there are also differences in individual airway management skills that can influence the performance of safe airway management,” says Dr. Hemmerling. “These influences may be greatly reduced when the KIS is used.” After successfully performing extensive tests in the airways of medical simulation mannequins, which closely resemble intubation conditions in humans, clinical testing in patients has now begun. “High tech equipment has revolutionized the way surgery is done, allowing the surgeon to perform with higher precision and with almost no physical effort — I believe that the KIS can do for anesthesia what these systems have done for surgery,” says Dr. Armen Aprikian, Director of MUHC’s Department of Urology who performed surgery on the first patient treated using the KIS.

“We think that The Kepler Intubation System can assist the anesthesiologist’s arms and hands to perform manual tasks with less force, higher precision and safety. One day, it might actually be the standard practice of airway management,” concludes Dr. Hemmerling, whose laboratory developed the world’s first anesthesia robot, nicknamed McSleepyTM, in 2008, which provides automated anesthesia delivery.

Science Daily
May 3, 2011

Original web page at Science Daily

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Pain therapy for piglets

Torunn Krangnes Fosse’s doctoral thesis shows that piglets of different age groups have a unique ability to break down and excrete painkillers. She also demonstrates that the painkilling and anti-inflammatory effect of the medicines studied work to varying degrees on piglets. The results of her research will be important for the choice of medicine and dosage used in the treatment of pain in piglets. Every year, 98 million male pigs are castrated in Europe and this surgery is usually carried out before the pigs are 14 days old. Castration is proven to be painful for these animals, not just during the course of the surgery itself, but also for several hours or days afterwards. It is the treatment of this post-operative pain that Fosse has focused on in her thesis. In addition, piglets often experience pain in connection with conditions such as inflamed joints or traumatic injuries. Fosse has studied the pharmacology of the two painkillers meloxicam and ketoprofen in piglets. She found that the piglets had a better ability to excrete ketoprofen when they were six days old than when they were three weeks old. This may mean that different dosages should be used, according to the age of the pigs being treated.

By means of an inflammatory model, Fosse showed that piglets treated with ketoprofen experienced significantly less pain when pressure was applied to the inflamed area than pigs receiving no treatment. The painkilling effect was evident for up to 24 hours after the treatment had been given. Meloxicam achieved only a low degree of painkilling effect in this model. Using another model, this medicine was also shown to have a low ability to prevent the production of inflammatory mediators in tissue. The results of this doctorate can make a big difference to the choice of medicine and dosage to be used in the pain therapy of piglets up to a month old.

Science Daily
January 24, 2011

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Uncovering the neurobiological basis of general anesthesia

The use of general anesthesia is a routine part of surgical operations at hospitals and medical facilities around the world, but the precise biological mechanisms that underlie anesthetic drugs’ effects on the brain and the body are only beginning to be understood. A review article in the December 30 New England Journal of Medicine brings together for the first time information from a range of disciplines, including neuroscience and sleep medicine, to lay the groundwork for more comprehensive investigations of processes underlying general anesthesia. “A key point of this article is to lay out a conceptual framework for understanding general anesthesia by discussing its relation to sleep and coma, something that has not been done in this way before,” says Emery Brown, MD, PhD, of the Massachusetts General Hospital (MGH) Department of Anesthesia, Critical Care and Pain Medicine, lead author of the NEJM paper. “We started by stating the specific physiological states that comprise general anesthesia – unconsciousness, amnesia, lack of pain perception and lack of movement while stable cardiovascular, respiratory and thermoregulatory systems are maintained – another thing that has never been agreed upon in the literature; and then we looked at how it is similar to and different from the states that are most similar – sleep and coma.”

After laying out their definition, Brown and his co-authors – Ralph Lydic, PhD, a sleep expert from the University of Michigan, and Nicholas Schiff, MD, an expert in coma from Weill Cornell Medical College – compare the physical signs and electroencephalogram (EEG) patterns of general anesthesia to those of sleep. While it is common to describe general anesthesia as going to sleep, there actually are significant differences between the states, with only the deepest stages of sleep being similar to the lightest phases of anesthesia induced by some types of agents. While natural sleep normally cycles through a predictable series of phases, general anesthesia involves the patient being taken to and maintained at the phase most appropriate for the procedure, and the phases of general anesthesia at which surgery is performed are most similar to states of coma. “People have hesitated to compare general anesthesia to coma because the term sounds so harsh, but it really has to be that profound or how could you operate on someone?” Brown explains. “The key difference is this is a coma that is controlled by the anesthesiologist and from which patients will quickly and safely recover.”

In detailing how different anesthetic agents act on different brain circuits, the authors point out some apparently contradictory information – some drugs like ketamine actually activate rather than suppress neural activity, an action that can cause hallucinations at lower doses. Ketamine blocks receptors for the excitatory transmitter glutamate, but since it has a preference for receptors on certain inhibitory neurons, it actually stimulates activity when it blocks those inhibitors. This excess brain activity generates unconsciousness through a process similar to what happens when disorganized data travels through an electronic communication line and blocks any coherent signal. A similar mechanism underlies seizure-induced unconsciousness. Brown also notes that recent reports suggest an unexpected use for ketamine – to treat depression. Very low doses of the drug have rapidly reduced symptoms in chronically depressed patients who had not responded to traditional antidepressants. Ketamine is currently being studied to help bridge the first days after a patient begins a new antidepressant – a time when many may be at risk of suicide – and the drug’s activating effects may be akin to those of electroconvulsive therapy.

Another unusual situation the authors describe is the case of a brain-injured patient in a minimally conscious state who actually recovered some functions through administration of the sleep-inducing drug zolpidem (Ambien). That patient’s case, analyzed previously by Schiff, mirrors a common occurrence called paradoxical excitation, in which patients in the first stage of general anesthesia may move around or vocalize. The authors describe how zolpidem’s suppression of the activity of a brain structure called the globus pallidus – which usually inhibits the thalamus – stimulates activity in the thalamus, which is a key neural control center. They hypothesize that a similar mechanism may underlie paradoxical excitation. “Anesthesiologists know how to safely maintain their patients in the states of general anesthesia, but most are not familiar with the neural circuit mechanisms that allow them to carry out their life-sustaining work,” Brown says. “The information we are presenting in this article – which includes new diagrams and tables that don’t appear in any anesthesiology textbook – is essential to our ability to further understanding of general anesthesia, and this is the first of several major reports that we anticipate publishing in the coming year.” Schiff adds, “We think this is, conceptually, a very fresh look at phenomena we and others have noticed and studied in sleep, coma and use of general anesthesia. By reframing these phenomena in the context of common circuit mechanisms, we can make each of these states understandable and predictable.”

PhysOrg.com
January 11, 2011

Original web page at PhysOrg.com

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Anesthetic gases heats climate as much as one million cars

When doctors want their patients asleep during surgery, they gently turn the gas tap. But anesthetic gasses have a global warming potential as high as a refrigerant that is on its way to be banned in the European Union. Yet there is no obligation to report anesthetic gasses along with other greenhouse gasses such as carbon dioxide, refrigerants and laughing gas. One kilogram of anesthetic gas affects the climate as much as 1,620 kilos of CO2. That has been shown by a recent study carried out by chemists from University of Copenhagen and NASA in collaboration with anesthesiologists from the University of Michigan Medical School. The amount of gas needed for a single surgical procedure is not high, but in the US alone surgery related anesthetics affected the climate as much as would one million cars. Analyses of the anesthetics were carried out by Ole John Nielsen. He is a professor of atmospheric chemistry at the University of Copenhagen, and he’s got an important message for doctors. “We studied three different gasses in regular use for anesthesia, and they’re not equally harmful,” explains Nielsen. All three are worse than CO2, but where the mildest ones — isoflurane and sevoflurane — have global warming potentials of 210 and 510 respectively, desflurane the most harmful will cause 1,620 times as much global warming as an equal amount of CO2, explains the professor.

“This ought to make anesthesiologists sit up and take notice. If all three compounds have equal therapeutic worth, there is every reason to choose the one with the lowest global warming potential,” says professor Ole John Nielsen. The three anesthetic gasses — isofluran, desflurane and sevoflurane — were studied at the Ford atmospheric laboratories in Michigan. Research scientist Mads Andersen of NASA’s Jet Propulsion Laboratory collaborated on the analyses with Nielsen, his former PhD supervisor. Andersen relates how he got the idea for the study while his wife was giving birth. “The anesthesiologist told me that the gas used is what we chemist know as a halogenated compound. That’s the same family of compound as the freon that was famously eating the ozone layer back in the eighties,” says Andersen. Freon is a compound that Andersen knows well. It got his supervisor Nielsen on the scientific map. With a global warming potential of a whopping 11,000, the refrigerant freon has been banned all over the world since 1992. When the search was on for an alternative to the harmful substance, Nielsen analysed just how much heat was retained by new compounds, and how long they would stay in the atmosphere. His methods went to prove that the refrigerant HFC-134a had a global warming potential of 1,300 and left the atmosphere in just 14 years to freon’s 50 to 100 years. HFC-134a has spared the atmosphere a considerable climate effect. But it, too, is being prohibited all across the European Union. And unless therapeutic arguments speak for using all three, sevoflurane should be the only legal anesthetic gas as shown by the study done by NASA, Ford and the Department of Chemistry at the University of Copenhagen (British Journal of Anaestecia).

Science Daily
December 21, 2010

Original web page at Science Daily

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Propofol poses low risk in pediatric imaging studies, but risk increases with anesthesia duration, study finds

A new study finds that propofol, a well-known anesthesia medication, has a low occurrence of adverse events for children undergoing research-driven imaging studies. The study, led by a pediatric anesthesiologist now at Children’s National Medical Center, showed a low incidence of adverse events and no long term complications when propofol was used to sedate children for imaging studies that require them to be still for long periods of time. Lead author Zena Quezado, MD, director of the Pain Neurobiology Laboratory at the Sheikh Zayed Institute for Pediatric Surgical Innovation, also found, however, that propofol, a commonly used anesthetic, does show an increased risk for respiratory, cardiovascular, and other side effects if anesthesia is administered over a long period of time or if the child has other complicating factors, including some systemic disease or an airway abnormality. It is also the first imaging study to show an increase in risk to the child with each 30 minute increment a child was under anesthesia.

The findings will help Institutional Review Boards and parents, who are dealing with the ethics debate around research involving children, evaluate the risk-benefit ratio of proposed studies, particularly those involving prolonged imaging studies. “Getting a child to remain still in an uncomfortable environment during a medical imaging procedure, such an MRI or CT scan, where bodily movement undermines the procedure’s quality, is a near impossible task, which is why anesthesia is commonly used,” Dr. Quezado said. “We know that propofol can be safely administered in pediatric research studies by well-trained anesthesiologists who are prepared to anticipate and respond to all events, which minimizes the risk of adverse issues. We are applying the findings of this research immediately in our own work, and will help others ensure that every study involving children is safe, ethical and effective.” The study reviews 1,480 propofol anesthetics in 607 children over an eight year period at the NIH’s Clinical Research Center and appeared in the June 7 issue of Archives of Pediatric and Adolescent Medicine. A total of 98 notable events were observed in 63 patients. Only one event led to an escalation of planned therapy. No events led to prolonged hospitalization. The increased risk related to severity of systemic disease is in concert with clinical studies that show increasingly severe systemic disease is associated with an increased risk for anesthesia related complications, while patients with airway abnormalities are predisposed to airway obstruction.

Science Daily
July 6, 2010

Original web page at Science Daily

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Mice may make morphine

Mice can synthesize morphine from various intermediate chemicals. Meinhart Zenk of the Donald Danforth Plant Science Center in St Louis, Missouri, and colleagues detected traces of morphine in the urine of mice after injecting chemical precursors of the drug. They report their findings today in the Proceedings of the National Academy of Sciences. Like other opioids, morphine is a potent, potentially addictive pain reliever. Scientists have speculated for decades that animals naturally synthesize morphine because specialized receptors in the brain respond to the drug. Trace amounts of morphine had been found in human urine and cells. But studies using living animals yielded inconclusive results because of possible contamination from external sources of morphine in their food or in the environment. “This paper seems to be one of the most definitive I’ve seen,” says Chris Evans, a neurobiologist and expert on opioid drugs at the University of California, Los Angeles. “They’ve convincingly shown that there’s a pathway there which could possibly produce morphine.”

Alkaloids are ring-shaped chemical compounds that contain nitrogen. The presence of an alkaloid called tetrahydropapaveroline (THP) in brain tissue and urine has led to speculation that it may be a precursor to morphine made naturally inside the body. The mouse pathway for making morphine is likely to have evolved independently from that of the opium poppy. The research team injected mice daily with THP and other potential morphine precursors for four days and evaluated the metabolites of these compounds in the urine. By labelling the precursors with deuterium (heavy hydrogen) to replace hydrogen atoms, they were able to distinguish the injected compounds from other sources of morphine, and thus eliminate the possibility of contamination. After isolating alkaloids from the urine samples the team analyzed their chemical make-up using highly sensitive mass spectrometry. Zenk and his colleagues identified several intermediate biochemical steps between THP and morphine. After injecting THP, they found a four-ringed metabolite of THP called salutaridine in the urine. Salutaridine is an intermediate on the morphine-synthesis pathway in the opium poppy. Injecting salutaridine yielded a five-ringed opiate called thebaine, and injecting thebaine generated three similarly structured opiates: codeine, oripavine and morphine.

Although the latter stages of morphine production are conserved between plants and mammals, the early stages differ: the first alkaloid intermediate in mammals, preceding salutaridine, has an extra hydroxyl (OH) group compared to that in plants. “It may seem trivial to you, but in biochemistry, hydroxylation more or less determines whether a baby is male or female,” Zenk says. These differences suggest that the morphine pathways in mammals and plants evolved independently, he says. The researchers did not find any traces of morphine in blood or tissue. As a result, this study does not prove that mammals make morphine naturally, or that the compound would serve any specific purpose, such as pain relief or addiction, Evans says. “The question is whether there are significant quantities to have any effect on the endogenous receptors, which I think is unlikely.”

Aside from detecting morphine in relevant organs, such as the brain and spinal cord, future studies should identify enzymes that are involved in transforming THP to morphine. Then scientists could interfere with the genes coding for the enzymes to determine their functional roles, Evans says. “To show that endogenous morphine naturally exists and has functional significance in mammals, I think there’s still a lot to be done.” Zenk’s team plans on using more sensitive techniques to look for traces of morphine in tissues. He’d also like to identify enzymes in the pathway and analyze how the formation of morphine fluctuates in humans depending on their pain levels. “Because it’s a fact that morphine is found, we have to consider that there must be a function for it,” Zenk says.

Nature
May 25, 2010

Original web page at Nature

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Brain responses during anesthesia mimic those during natural deep sleep

The brains of people under anesthesia respond to stimuli as they do in the deepest part of sleep — lending credence to a developing theory of consciousness and suggesting a new method to assess loss of consciousness in conditions such as coma. Scientists at the University of Wisconsin School of Medicine and Public Health, led by brain researcher Fabio Ferrarelli, reported their findings in this week’s edition of the Proceedings of the National Academy of Science. The group gave the anesthetic midazolam, commonly used at lower doses in “conscious sedation” procedures such as colonoscopies, to volunteers. Then they used transcranial magnetic stimulation (TMS), a noninvasive technique to stimulate the brain cortical neurons from the scalp, in combination with electroencephalography (EEG), which recorded the TMS-evoked brain responses. What they found is a pattern that looks much as it does when the brain is in deep, non-rapid eye movement (non-REM) sleep, another condition when consciousness fades.

Co-author and consciousness expert Giulio Tononi says that when the brain is unconscious it appears to lose the connectivity that underlies the coordinated, yet differentiated responses to electrical stimuli observed when the brain is awake or in REM sleep. The group’s earlier studies demonstrated the differences between the sleeping and awake brain. “Based on a theory about how consciousness is generated, we expect to see a response that is both integrated and differentiated when the brain is conscious,” says Tononi, professor of psychiatry. “When there is a loss of consciousness, either due to sleep or anesthesia, the response is radically different. We see a stereotyped burst of activity that remains localized and fades quickly.” The team believes that the response patterns observed in the awake brain, characterized by long-lasting activations moving over time to different cortical areas, reflect the connectivity of the cortical areas activated by TMS. This could be because when we are awake, the cortex is involved in many activities which require a constant communication between different cortical areas. But in the unconscious brain, this connectivity is temporarily lost, and therefore the TMS-evoked brain responses remain localized.

Ferrarelli says the results lend weight to the idea that a breakdown of cortical connectivity is a key aspect of loss of consciousness, and are consistent with the “integrated information theory of consciousness.” Co-author Dr. Robert Pearce, chair and professor of anesthesiology at UW SMPH, said it is interesting that the cortical responses under anesthesia were so similar to changes seen during natural sleep. “The idea that some anesthetics “hijack” the natural sleep-promoting centers was proposed recently by others,” says Pearce. “While our present findings do not directly confirm this hypothesis, they are consistent with a set of shared mechanisms. That is, that the loss of functional connectivity between brain regions is a characteristic that sleep and anesthesia share, and that we think might be causal in the loss of consciousness in both cases.” Tononi says that a similar test of cortical connectivity could be used to provide a non-invasive way to test an unresponsive patient for consciousness during anesthesia or in medical conditions such as coma. “One practical application would be a test to help assess how conscious a patient is,” Tononi says. Current tests rely partly on clinical observations, and may be altered by drugs or medical conditions that render an otherwise conscious patient unable to respond. “We want to know whether a person is really there, and to us, it is important that the method is grounded on a theoretical model of what is required for consciousness,” Tononi says.

Science Daily
February 23, 2010

Original web page at Science Daily