New research led by The Hospital for Sick Children (SickKids) and the University of Toronto has identified more genes in attention deficit hyperactivity disorder (ADHD) and shows that there is an overlap between some of these genes and those found in other neuropsychiatric conditions such as autism spectrum disorder (ASD).
The study is published in the August 10 advance online edition of Science Translational Medicine.
The research team was led by Dr. Russell Schachar, Senior Scientist and Psychiatrist at SickKids and Professor of Psychiatry at the University of Toronto, and Dr. Stephen Scherer, Senior Scientist at SickKids, Director of The Centre for Applied Genomics at SickKids and the McLaughlin Centre at the University of Toronto.
The scientists used microarrays (gene-chip technology) to study the DNA of 248 unrelated patients with ADHD. They specifically searched for copy number variants (CNVs), which are insertions or deletions affecting the genes. In three of 173 children for whom the DNA of both parents was available, they found spontaneous CNVs, which occur when the parents are not affected and mutations are new to the child. Rare CNVs that were inherited from affected parents were found in 19 of 248 patients.
Within the group of inherited CNVs, the researchers found some of the genes that had previously been identified in other neuropsychiatric conditions including ASD. To explore this overlap, they tested a different group for CNVs. They found that nine of the 349 children in the study, all of whom had previously been diagnosed with ASD, carried CNVs that are related to ADHD and other disorders.
The findings suggest that some CNVs, which play a causal role in ADHD, demonstrate common susceptibility genes in ADHD, ASD and other neuropsychiatric disorders.
"For the first time, we've tested these genetic alterations in ADHD and have a pretty good handle on a couple of decent ADHD candidate genes," says Scherer, who is also Professor in the Department of Molecular Genetics at the University of Toronto and GlaxoSmithKline Chair in Genome Sciences at SickKids. "This is critical, as it gives us confidence in interpreting our results."
Like ASD, ADHD cases are largely unique, notes Schachar, who is also the TD Chair in Child and Adolescent Psychiatry at SickKids. People carrying the same CNVs can have different symptoms, he says. "It's not always the same risk. As we've seen in autism and other conditions, relatively few of these CNVs repeat in affected individuals."
Most individuals with ADHD also have at least one other condition, such as anxiety, mood, conduct or language disorders. Up to 75 per cent of people with ASD also have attention deficits or hyperactivity. "A lot of these associated problems probably arise from the fact that they are sharing genetic risk for different conditions," says Schachar.
The research results could be reassuring for clinicians who may see characteristics of different neuropsychiatric conditions in their patients -- such as ASD-like social problems in a child with ADHD -- but are concerned that they are over-interpreting these traits. "This research reinforces the notion that their gut observation is correct," Schachar says.
According to Scherer, the historical mindset in research has been to define the specific clinical syndrome and explore it. "Researchers don't tend to look across disorders very often. This method is perhaps one of the most exciting findings in neuropsychiatric genetics and it is really starting to redefine how we think about neuropsychiatric conditions," he says.
"These are probably genetic factors that increase the risk for various kinds of neuropsychiatric disorders and it poses a huge challenge to us to figure out what makes an ADHD case, what makes an ASD case. There are lots of different possibilities to explain why some common risks can manifest into different kinds of disorders," Schachar says, adding that while the new study observed this phenomenon, more research is needed to determine the cause.
ADHD is a common neuropsychiatric disorder that affects four per cent of school-age children worldwide. It is associated with inattention, hyperactivity and impulsiveness that often results in learning difficulties, social problems and underachievement.
ASDs are diagnosed in roughly one in 100 children in North America and cause deficits in communication, social understanding and behaviour.
The study was funded by The Centre for Applied Genomics, Genome Canada, The Ontario Genomics Institute, the Canadian Institutes of Health Research, the Canadian Institute for Advanced Research, the McLaughlin Centre, the Canada Foundation for Innovation, the Ministry of Research and Innovation, NeuroDevNet, Autism Speaks and SickKids Foundation.
Saturday, August 13, 2011
Increased Light May Moderate Fearful Reactions
Psychologist Brian Wiltgen and biologists Ignacio Provencio and Daniel Warthen of U.Va.'s College of Arts & Sciences worked together to combine studies of fear with research on how light affects physiology and behavior.
Using mice as models, they learned that intense light enhances fear or anxiety in mice, which are nocturnal, in much the same way that darkness can intensify fear or anxiety in diurnal humans.
The finding is published in the Aug. 1 issue of the journal Proceedings of the National Academy of Sciences.
"We looked at the effect of light on learned fear, because light is a pervasive feature of the environment that has profound effects on behavior and physiology," said Wiltgen, an assistant professor of psychology and an expert on learning. "Light plays an important role in modulating heart rate, circadian rhythms, sleep/wake cycles, digestion, hormones, mood and other processes of the body. In our study we wanted to see how it affects learned fear."
Fear is a natural mechanism for survival. Some fears -- such as of loud noise, sudden movements and heights -- appear to be innate. Humans and other mammals also learn from their experiences, which include dangerous or bad situations. This "learned fear" can protect us from dangers.
That fear also can become abnormally enhanced in some cases, sometimes leading to debilitating phobias. About 40 million people in the United States suffer from dysregulated fear and heightened states of anxiety.
"Studies show that light influences learning, memory and anxiety," Wiltgen said. "We have now shown that light also can modulate conditioned fear responses."
"In this work we describe the modulation of learned fear by ambient light," said Provencio, an expert on light and photoreception. "The dysregulation of fear is an important component of many disorders, including generalized anxiety disorder, panic disorder, specific phobias and post-traumatic stress disorder. Understanding how light regulates learned fear may inform therapies aimed at treating some of these fear-based disorders."
The researchers used a common method for studying learned fear. They cued their mice with a minute-long tone that was followed two seconds later by a quick, mild electrical shock. The mice learned to associate the tone with the shock and quickly became conditioned to duck down and remain motionless when they heard the tone, in the same way they would if a predator appeared.
The researchers discovered that by intensifying the ambient light, the mice showed a greater fear reaction to the tone than when the light was dimmer. This makes sense Wiltgen said, because mice naturally avoid detection by predators by hunkering down motionless as a defense mechanism. In a natural habitat they likewise would become particularly anxious in the presence of a predator in bright light where they would be more easily detected.
"We showed that light itself does not necessarily enhance fear, but more light enhances learned fear," Wiltgen said. "It may be similar to a person learning to be more fearful in the dark."
The researchers wanted to understand what visual pathways to the brain in mammals may be responsible for this behavior in the presence of more light. The eye has two pathways that begin in the retina and end in the brain: one is image-forming and made up of rods and cones; the other is the non-image-forming retinal ganglion cells where melanopsin, a circadian rhythm-regulating photo-pigment, is located.
Using two types of mutant mice, ones without rods and cones but with the melanopsin retinal ganglion cells, the others without functioning melanopsin ganglion cells but with rods and cones, the researchers were able to determine that the visual pathway affecting light behavior was in the rods and cones -- the image-forming pathway.
"Both pathways have connections to the emotional circuitry of the brain," Wiltgen said. "The two types of mice are a nice tool for figuring out which pathway controls the light effect."
By indexing the two types of fear reactions in the presence of increased light, the researchers learned that the image-forming pathway of the rods and cones had the modulating effect on fear.
"The implications of this in humans is this: that being diurnal, the absence of light can be a source of fear," Wiltgen said. "But increased light can be used to reduce fear and anxiety and to treat depression. If we can come to understand the cellular mechanisms that affect this, then eventually abnormal anxiety and fear might be treated with improved pharmaceuticals to mimic or augment light therapy."
New Agent Prevents Stroke in Patients With Atrial Fibrillation, Study Suggests
In the primary result from the largest double-blind study ever completed to assess a drug's effect in the prevention of stroke in patients with atrial fibrillation, a common heart rhythm abnormality, rivaroxaban, an anti-clotting drug, was shown to be an attractive alternative to warfarin, the current standard for treatment of atrial fibrillation.
The full intention-to-treat analysis, which includes patients who discontinued study drug, showed that rivaroxaban was noninferior to warfarin for the prevention of stroke or blood clots. Importantly, rivaroxaban use led to less intra-cranial and fatal bleeding.
The findings, co-authored by a research team from the Duke Clinical Research Institute, were published online August 10 in the New England Journal of Medicine.
"Warfarin has been a standard treatment for decades, but requires a rigorous monitoring schedule to ensure therapeutic dosing levels, and is subject to the potential of food and drug interactions that present treatment obstacles for patients and doctors alike," said the study's lead author, Manesh R. Patel, MD assistant professor of medicine at Duke University School of Medicine.
"The results of this large global trial have convincingly shown rivaroxaban to be an alternative to warfarin in treating patients with atrial fibrillation and, importantly, with no increase in bleeding."
Atrial fibrillation is the most common abnormal heart rhythm disorder in the U.S. and is characterized by an unusual and dangerously fast heart beat. It can cause blood to pool in the heart resulting in the formation of clots that may become lodged in the artery to the brain resulting in a stroke, or in formation of non-central nervous system blood clots.
Approximately 2.2 million Americans suffer from atrial fibrillation, which increases a person's stroke risk by four to six times on average.
Warfarin has been documented over the years to reduce the rate of stroke for those who have atrial fibrillation by approximately one-half to two-thirds, at the cost of increased bleeding.
"In addition to addressing an important therapeutic need for patients with atrial fibrillation, ROCKET AF provides a model for how clinical trials of investigational therapies should be conducted to assess safety and efficacy prior to FDA submission," said Robert M. Califf, MD, the study's co-chair, who is vice chancellor for clinical research at Duke University School of Medicine, and director of the Duke Translational Medicine Institute.
"The sponsors of the study should be congratulated for taking this approach in which an international committee of leaders in the field designed the trial and provided independent oversight, including an independent analysis of the trial results," Califf added.
The ROCKET AF (Rivaroxaban once daily oral direct factor xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) study included 14,264 patients with atrial fibrillation who had a history of stroke or additional independent risk factors for future stroke and were randomized to receive either rivaroxaban or warfarin. The trial included more than 1,100 centers in 45 countries.
In the analysis of the intent to treat population -- patients followed from the time of entry and throughout the full study duration, even if they discontinued study medication -- rivaroxaban was not inferior to warfarin (p< 0.001) and showed a nonsignificant trend toward benefit compared to warfarin (event rates = 2.12 vs. 2.42).
Rates of bleeding and adverse events were similar between treatment groups. Compared to warfarin, rivaroxaban showed similar rates for the principal safety measure of major and non-major clinically relevant bleeding events (event rates = 14.9 vs. 14.5, p=0.442). Rates of major bleeding were also comparable between rivaroxaban and warfarin (event rates = 3.6 vs. 3.4, p=0.576).
Patients treated with rivaroxaban had significantly fewer intracranial hemorrhages (event rates = 0.4 vs. 0.7), critical organ bleeds (event rates = 0.8 vs. 1.2) and bleeding-related deaths (event rates = 0.2 vs. 0.5) compared with warfarin, respectively. However, patients treated with rivaroxaban did show increased rates of hemoglobin/hematocrit drop (event rates = 2.8 vs. 2.3) and transfusions (event rates = 1.7 vs. 1.3), compared to warfarin.
"Atrial fibrillation is becoming increasingly prevalent and can be life-threatening if not properly managed. Stroke prevention is a key treatment goal in atrial fibrillation management," said Keith A. A. Fox, MB ChB, professor of cardiology at the University and Royal Infirmary of Edinburgh, Centre for Cardiovascular Science, in Edinburgh, UK, and one of the study's co-leaders "Rivaroxaban appears to be an attractive and well-tolerated clinical alternative to warfarin for patients with atrial fibrillation."
The trial was coordinated by the Duke Clinical Research Institute and led by an international Executive Committee: Chair Robert M. Califf, Co-Chair Keith AA Fox MB ChB; members: Guenter Breithardt, MD; Jonathan Halperin, MD; Graeme Hankey, MD; Kenneth Mahaffey, MD; Manesh Patel, MD; Daniel Singer, MD; Richard Becker, MD; Scott Berkowitz, MD; Werner Hacke, MD; Christopher Nessel, MD; and John Paolini, MD.
The study was sponsored by Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare.
The full intention-to-treat analysis, which includes patients who discontinued study drug, showed that rivaroxaban was noninferior to warfarin for the prevention of stroke or blood clots. Importantly, rivaroxaban use led to less intra-cranial and fatal bleeding.
The findings, co-authored by a research team from the Duke Clinical Research Institute, were published online August 10 in the New England Journal of Medicine.
"Warfarin has been a standard treatment for decades, but requires a rigorous monitoring schedule to ensure therapeutic dosing levels, and is subject to the potential of food and drug interactions that present treatment obstacles for patients and doctors alike," said the study's lead author, Manesh R. Patel, MD assistant professor of medicine at Duke University School of Medicine.
"The results of this large global trial have convincingly shown rivaroxaban to be an alternative to warfarin in treating patients with atrial fibrillation and, importantly, with no increase in bleeding."
Atrial fibrillation is the most common abnormal heart rhythm disorder in the U.S. and is characterized by an unusual and dangerously fast heart beat. It can cause blood to pool in the heart resulting in the formation of clots that may become lodged in the artery to the brain resulting in a stroke, or in formation of non-central nervous system blood clots.
Approximately 2.2 million Americans suffer from atrial fibrillation, which increases a person's stroke risk by four to six times on average.
Warfarin has been documented over the years to reduce the rate of stroke for those who have atrial fibrillation by approximately one-half to two-thirds, at the cost of increased bleeding.
"In addition to addressing an important therapeutic need for patients with atrial fibrillation, ROCKET AF provides a model for how clinical trials of investigational therapies should be conducted to assess safety and efficacy prior to FDA submission," said Robert M. Califf, MD, the study's co-chair, who is vice chancellor for clinical research at Duke University School of Medicine, and director of the Duke Translational Medicine Institute.
"The sponsors of the study should be congratulated for taking this approach in which an international committee of leaders in the field designed the trial and provided independent oversight, including an independent analysis of the trial results," Califf added.
The ROCKET AF (Rivaroxaban once daily oral direct factor xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) study included 14,264 patients with atrial fibrillation who had a history of stroke or additional independent risk factors for future stroke and were randomized to receive either rivaroxaban or warfarin. The trial included more than 1,100 centers in 45 countries.
In the analysis of the intent to treat population -- patients followed from the time of entry and throughout the full study duration, even if they discontinued study medication -- rivaroxaban was not inferior to warfarin (p< 0.001) and showed a nonsignificant trend toward benefit compared to warfarin (event rates = 2.12 vs. 2.42).
Rates of bleeding and adverse events were similar between treatment groups. Compared to warfarin, rivaroxaban showed similar rates for the principal safety measure of major and non-major clinically relevant bleeding events (event rates = 14.9 vs. 14.5, p=0.442). Rates of major bleeding were also comparable between rivaroxaban and warfarin (event rates = 3.6 vs. 3.4, p=0.576).
Patients treated with rivaroxaban had significantly fewer intracranial hemorrhages (event rates = 0.4 vs. 0.7), critical organ bleeds (event rates = 0.8 vs. 1.2) and bleeding-related deaths (event rates = 0.2 vs. 0.5) compared with warfarin, respectively. However, patients treated with rivaroxaban did show increased rates of hemoglobin/hematocrit drop (event rates = 2.8 vs. 2.3) and transfusions (event rates = 1.7 vs. 1.3), compared to warfarin.
"Atrial fibrillation is becoming increasingly prevalent and can be life-threatening if not properly managed. Stroke prevention is a key treatment goal in atrial fibrillation management," said Keith A. A. Fox, MB ChB, professor of cardiology at the University and Royal Infirmary of Edinburgh, Centre for Cardiovascular Science, in Edinburgh, UK, and one of the study's co-leaders "Rivaroxaban appears to be an attractive and well-tolerated clinical alternative to warfarin for patients with atrial fibrillation."
The trial was coordinated by the Duke Clinical Research Institute and led by an international Executive Committee: Chair Robert M. Califf, Co-Chair Keith AA Fox MB ChB; members: Guenter Breithardt, MD; Jonathan Halperin, MD; Graeme Hankey, MD; Kenneth Mahaffey, MD; Manesh Patel, MD; Daniel Singer, MD; Richard Becker, MD; Scott Berkowitz, MD; Werner Hacke, MD; Christopher Nessel, MD; and John Paolini, MD.
The study was sponsored by Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare.
Friday, August 12, 2011
Increased Light May Moderate Fearful Reactions
Psychologist Brian Wiltgen and biologists Ignacio Provencio and Daniel Warthen of U.Va.'s College of Arts & Sciences worked together to combine studies of fear with research on how light affects physiology and behavior.
Using mice as models, they learned that intense light enhances fear or anxiety in mice, which are nocturnal, in much the same way that darkness can intensify fear or anxiety in diurnal humans.
The finding is published in the Aug. 1 issue of the journal Proceedings of the National Academy of Sciences.
"We looked at the effect of light on learned fear, because light is a pervasive feature of the environment that has profound effects on behavior and physiology," said Wiltgen, an assistant professor of psychology and an expert on learning. "Light plays an important role in modulating heart rate, circadian rhythms, sleep/wake cycles, digestion, hormones, mood and other processes of the body. In our study we wanted to see how it affects learned fear."
Fear is a natural mechanism for survival. Some fears -- such as of loud noise, sudden movements and heights -- appear to be innate. Humans and other mammals also learn from their experiences, which include dangerous or bad situations. This "learned fear" can protect us from dangers.
That fear also can become abnormally enhanced in some cases, sometimes leading to debilitating phobias. About 40 million people in the United States suffer from dysregulated fear and heightened states of anxiety.
"Studies show that light influences learning, memory and anxiety," Wiltgen said. "We have now shown that light also can modulate conditioned fear responses."
"In this work we describe the modulation of learned fear by ambient light," said Provencio, an expert on light and photoreception. "The dysregulation of fear is an important component of many disorders, including generalized anxiety disorder, panic disorder, specific phobias and post-traumatic stress disorder. Understanding how light regulates learned fear may inform therapies aimed at treating some of these fear-based disorders."
The researchers used a common method for studying learned fear. They cued their mice with a minute-long tone that was followed two seconds later by a quick, mild electrical shock. The mice learned to associate the tone with the shock and quickly became conditioned to duck down and remain motionless when they heard the tone, in the same way they would if a predator appeared.
The researchers discovered that by intensifying the ambient light, the mice showed a greater fear reaction to the tone than when the light was dimmer. This makes sense Wiltgen said, because mice naturally avoid detection by predators by hunkering down motionless as a defense mechanism. In a natural habitat they likewise would become particularly anxious in the presence of a predator in bright light where they would be more easily detected.
"We showed that light itself does not necessarily enhance fear, but more light enhances learned fear," Wiltgen said. "It may be similar to a person learning to be more fearful in the dark."
The researchers wanted to understand what visual pathways to the brain in mammals may be responsible for this behavior in the presence of more light. The eye has two pathways that begin in the retina and end in the brain: one is image-forming and made up of rods and cones; the other is the non-image-forming retinal ganglion cells where melanopsin, a circadian rhythm-regulating photo-pigment, is located.
Using two types of mutant mice, ones without rods and cones but with the melanopsin retinal ganglion cells, the others without functioning melanopsin ganglion cells but with rods and cones, the researchers were able to determine that the visual pathway affecting light behavior was in the rods and cones -- the image-forming pathway.
"Both pathways have connections to the emotional circuitry of the brain," Wiltgen said. "The two types of mice are a nice tool for figuring out which pathway controls the light effect."
By indexing the two types of fear reactions in the presence of increased light, the researchers learned that the image-forming pathway of the rods and cones had the modulating effect on fear.
"The implications of this in humans is this: that being diurnal, the absence of light can be a source of fear," Wiltgen said. "But increased light can be used to reduce fear and anxiety and to treat depression. If we can come to understand the cellular mechanisms that affect this, then eventually abnormal anxiety and fear might be treated with improved pharmaceuticals to mimic or augment light therapy."
No Proof Fibrate Drugs Reduce Heart Risk in Diabetes Patients On Statins, Experts Say
Type 2 diabetes patients, who face higher risk of cardiovascular disease, often take a combination of medications designed to lower their LDL or "bad" cholesterol and triglyceride levels while raising their HDL or "good" cholesterol because doctors long have thought that taken together, the drugs offer protection from heart attacks and improve survival.
But in a commentary in the current New England Journal of Medicine, a trio of doctors who served on a recent Food and Drug Administration panel that evaluated the drugs' effectiveness says the commonly prescribed medications have not been proven successful at preventing heart attacks in Type 2 diabetes patients with elevated cholesterol.
The drugs, called fibrates, seek to lower blood triglyceride levels and raise the amount of HDL cholesterol. They often are prescribed to diabetes patients as an add-on to statins, drugs that lower LDL cholesterol. Annual sales in the U.S. for the three fibrates now approved by the FDA -- gemfibrozil (Lopid), fenofibrate (Tricor) and fenofibric acid (Trilipix) -- amount to billions of dollars.
"There have been few studies regarding the clinical outcome efficacy of fibrates," said Sanjay Kaul, MD, a commentary author and director of the Cardiology Fellowship Training Program at the Cedars-Sinai Heart Institute. "Thousands and thousands of Americans take fibrates every day but so far, there are no long-term studies showing that fibrates lower cardiovascular risk or improve survival among diabetes patients who are also on statins."
The commentary calls for more studies. Meantime, the authors suggest that doctors prescribe the statin-fibrate combination only to diabetic patients at high risk for a heart attack and only after optimal control of LDL cholesterol has been achieved with statin treatment.
But in a commentary in the current New England Journal of Medicine, a trio of doctors who served on a recent Food and Drug Administration panel that evaluated the drugs' effectiveness says the commonly prescribed medications have not been proven successful at preventing heart attacks in Type 2 diabetes patients with elevated cholesterol.
The drugs, called fibrates, seek to lower blood triglyceride levels and raise the amount of HDL cholesterol. They often are prescribed to diabetes patients as an add-on to statins, drugs that lower LDL cholesterol. Annual sales in the U.S. for the three fibrates now approved by the FDA -- gemfibrozil (Lopid), fenofibrate (Tricor) and fenofibric acid (Trilipix) -- amount to billions of dollars.
"There have been few studies regarding the clinical outcome efficacy of fibrates," said Sanjay Kaul, MD, a commentary author and director of the Cardiology Fellowship Training Program at the Cedars-Sinai Heart Institute. "Thousands and thousands of Americans take fibrates every day but so far, there are no long-term studies showing that fibrates lower cardiovascular risk or improve survival among diabetes patients who are also on statins."
The commentary calls for more studies. Meantime, the authors suggest that doctors prescribe the statin-fibrate combination only to diabetic patients at high risk for a heart attack and only after optimal control of LDL cholesterol has been achieved with statin treatment.
Understanding the Effects of Underwater Pressure On Divers
Reaching a new threshold in underwater medical studies, the Office of Naval Research (ONR) has announced a novel capability for examining how cells work at pressures far below the sea surface.
Researchers at the Navy Experimental Diving Unit (NEDU) have designed, built and validated a novel hyperbaric environment to study cellular behavior at greater depths. The joint ONR-NEDU effort is designed to explore advances to protect Navy divers working at depths of up to 1,000 feet.
"This is a huge leap forward in our ability to understand cellular function at pressurized depths," said Cmdr. Matthew Swiergosz, ONR's undersea medicine program officer. "This capability will bridge a gap in our understanding of identifying potential applications for diving operations."
Using a laboratory technique called patch clamping, in which electrodes are attached to a cell membrane and clamped, scientists can now monitor, stimulate and record the cell's electrical activity in a pressurized environment.
Few studies have been performed to address the underlying molecular mechanisms of diving disorders such as decompression sickness.
In addition to providing future payoff for the Navy, the patch clamping method could also bring benefit to those in the commercial diving community, who are vulnerable to the same hazardous conditions associated with difficult underwater work.
In 2008, ONR began sponsoring the work of principal investigator Lt. Denis Colomb Jr., NEDU, and partners including the University of South Florida, Université Laval, Arehart Model Makers LLC and other NEDU personnel.
The ONR Undersea Medicine Program is a National Naval Responsibility, a science and technology research area the Department of the Navy has deemed critically important to maintaining naval superiority.
Researchers at the Navy Experimental Diving Unit (NEDU) have designed, built and validated a novel hyperbaric environment to study cellular behavior at greater depths. The joint ONR-NEDU effort is designed to explore advances to protect Navy divers working at depths of up to 1,000 feet.
"This is a huge leap forward in our ability to understand cellular function at pressurized depths," said Cmdr. Matthew Swiergosz, ONR's undersea medicine program officer. "This capability will bridge a gap in our understanding of identifying potential applications for diving operations."
Using a laboratory technique called patch clamping, in which electrodes are attached to a cell membrane and clamped, scientists can now monitor, stimulate and record the cell's electrical activity in a pressurized environment.
Few studies have been performed to address the underlying molecular mechanisms of diving disorders such as decompression sickness.
In addition to providing future payoff for the Navy, the patch clamping method could also bring benefit to those in the commercial diving community, who are vulnerable to the same hazardous conditions associated with difficult underwater work.
In 2008, ONR began sponsoring the work of principal investigator Lt. Denis Colomb Jr., NEDU, and partners including the University of South Florida, Université Laval, Arehart Model Makers LLC and other NEDU personnel.
The ONR Undersea Medicine Program is a National Naval Responsibility, a science and technology research area the Department of the Navy has deemed critically important to maintaining naval superiority.
Blocking Receptor in Key Hormone Fires Up Enzyme to Kill Pancreatic Cancer Cells
Pancreatic cancer researchers at Thomas Jefferson University have shown, for the first time, that blocking a receptor of a key hormone in the renin-angiotensin system (RAS) reduces cancer cell growth by activating the enzyme AMPK to inhibit fatty acid synthase, the ingredients to support cell division.
With that, a new chemopreventive agent that inhibits the angiotensin II type 2 receptor -- never before thought to play a role in tumor growth -- could be developed to help treat one of the fastest-moving cancers that has a 5-year survival rate of only 5 percent.
Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University and the co-director of the Jefferson Pancreatic, Biliary and Related Cancers Center, and her fellow researchers, including the chair of the Department of Surgery at Jefferson, Charles J. Yeo, M.D., FACS, present their findings in the August issue of Surgery.
Angiotensin II (AngII) is the principal hormone in the RAS that regulates our blood pressure and water balance; it has two receptors: type 1 and type 2. AngII is also generated actively in the pancreas and has been shown to be involved in tumor angiogenesis.
Previous studies have pointed to the hormone's type 1 receptor as the culprit in cancer cell proliferation and tumor inflammation; however, the idea that type 2 had any effect was never entertained.
By looking at pancreatic ductal adenocarcinoma (PDA) cells in vitro, Jefferson researchers discovered that the type 2 receptor, not just type 1, mediates the production of fatty acid synthase (FAS), which has been shown to supply the cell wall ingredients necessary for cancer cells to multiply.
FAS was previously identified as a possible oncogene in the 1980s. It is up-regulated in breast cancers and is indicator of poor prognosis, and thus believed to be a worthwhile chemopreventive target.
"AngII is not just involved in cell inflammation and angiogenesis; it's involved in tumor metabolism as well," said Dr. Arafat, a member of the Kimmel Cancer Center at Jefferson. "It promotes FAS with both receptors, which makes the tumor grow."
"Blocking the type 2 receptor reduces PDA cell growth with the activation of AMPK, revealing a new mechanism by which chemoprevention can exploit," she added. "In fact, maybe combined blocking of the two receptors would be more efficient than just blocking one receptor."
AMPK, or adenosine monophosphate-activated protein kinase, is the focus of several agents today, including ones for diabetes and related metabolic diseases. It is a master metabolic regulator for cells that is activated in times of reduced energy availability, like starvation. Activation of AMPK has been shown to improve energy homeostasis, lipid profile and blood pressure. The enzyme also activates a well-known tumor suppressor, p53.
"The main thing is activation of AMPK in tumor cells," said Dr. Arafat. "AMPK is the perfect candidate as it regulates multiple targets that both halt tumor cell division and activate programmed cell death. Although it is yet to be determined how the type 2 receptor imposes deregulation of AMPK activity, identification of the type 2 receptor as a novel target for therapy is very exciting"
Next, Dr. Arafat and fellow researchers are proposing to take this research into animal studies. They hope to target the receptors early on in the disease to better understand its prevention capabilities and also study its treatment potential. Considering pancreatic cancer is typically detected in later stages, finding better ways to treat cases that have progressed further along would be of great benefit to patients.
With that, a new chemopreventive agent that inhibits the angiotensin II type 2 receptor -- never before thought to play a role in tumor growth -- could be developed to help treat one of the fastest-moving cancers that has a 5-year survival rate of only 5 percent.
Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University and the co-director of the Jefferson Pancreatic, Biliary and Related Cancers Center, and her fellow researchers, including the chair of the Department of Surgery at Jefferson, Charles J. Yeo, M.D., FACS, present their findings in the August issue of Surgery.
Angiotensin II (AngII) is the principal hormone in the RAS that regulates our blood pressure and water balance; it has two receptors: type 1 and type 2. AngII is also generated actively in the pancreas and has been shown to be involved in tumor angiogenesis.
Previous studies have pointed to the hormone's type 1 receptor as the culprit in cancer cell proliferation and tumor inflammation; however, the idea that type 2 had any effect was never entertained.
By looking at pancreatic ductal adenocarcinoma (PDA) cells in vitro, Jefferson researchers discovered that the type 2 receptor, not just type 1, mediates the production of fatty acid synthase (FAS), which has been shown to supply the cell wall ingredients necessary for cancer cells to multiply.
FAS was previously identified as a possible oncogene in the 1980s. It is up-regulated in breast cancers and is indicator of poor prognosis, and thus believed to be a worthwhile chemopreventive target.
"AngII is not just involved in cell inflammation and angiogenesis; it's involved in tumor metabolism as well," said Dr. Arafat, a member of the Kimmel Cancer Center at Jefferson. "It promotes FAS with both receptors, which makes the tumor grow."
"Blocking the type 2 receptor reduces PDA cell growth with the activation of AMPK, revealing a new mechanism by which chemoprevention can exploit," she added. "In fact, maybe combined blocking of the two receptors would be more efficient than just blocking one receptor."
AMPK, or adenosine monophosphate-activated protein kinase, is the focus of several agents today, including ones for diabetes and related metabolic diseases. It is a master metabolic regulator for cells that is activated in times of reduced energy availability, like starvation. Activation of AMPK has been shown to improve energy homeostasis, lipid profile and blood pressure. The enzyme also activates a well-known tumor suppressor, p53.
"The main thing is activation of AMPK in tumor cells," said Dr. Arafat. "AMPK is the perfect candidate as it regulates multiple targets that both halt tumor cell division and activate programmed cell death. Although it is yet to be determined how the type 2 receptor imposes deregulation of AMPK activity, identification of the type 2 receptor as a novel target for therapy is very exciting"
Next, Dr. Arafat and fellow researchers are proposing to take this research into animal studies. They hope to target the receptors early on in the disease to better understand its prevention capabilities and also study its treatment potential. Considering pancreatic cancer is typically detected in later stages, finding better ways to treat cases that have progressed further along would be of great benefit to patients.
Frequent Tanning Bed Users Exhibit Brain Changes and Behavior Similar to Addicts, Study Finds
People who frequently use tanning beds may be spurred by an addictive neurological reward-and-reinforcement trigger, researchers at UT Southwestern Medical Center have found in a pilot study.
This could explain why some people continue to use tanning beds despite the increased risk of developing melanoma, the most lethal form of skin cancer. The brain activity and corresponding blood flow tracked by UT Southwestern scientists involved in the study is similar to that seen in people addicted to drugs and alcohol.
"Using tanning beds has rewarding effects in the brain so people may feel compelled to persist in the behavior even though it's bad for them," said Dr. Bryon Adinoff, professor of psychiatry and senior author of the study available online and in a future print edition of Addiction Biology. "The implication is, 'If it's rewarding, then could it also be addictive?' It's an important question in the field."
About 120,000 new cases of melanoma are diagnosed in the U.S. each year, according to the Skin Cancer Foundation. People younger than 30 who use a tanning bed 10 times a year have eight times the risk of developing malignant melanoma. While public knowledge of these dangers has grown, so has the regular use of tanning beds.
In this study, participants used tanning beds on two separate occasions: one time they were exposed to ultraviolet radiation and another time special filters blocked exposure to ultraviolet radiation. Participants did not know on which session they received the real or the filtered ultraviolet exposure. At each visit, participants were asked before and after each session how much they felt like tanning. Participants were also administered a compound that allowed scientists to measure brain blood flow while they were tanning.
Dr. Adinoff, who also is a staff physician at the Veterans Affairs North Texas Health Care System, said the next step is to create technology to further study brain changes among frequent tanners.
Other UT Southwestern researchers involved in the study were Dr. Heidi Jacobe, assistant professor of dermatology; Dr. Michael Devous, professor of radiology; and Thomas Harris, senior research scientist. Former dermatology resident Dr. Cynthia Harrington served as lead author.
The study was funded by the Department of Dermatology at UT Southwestern. Dr. Steven Feldman of Wake Forest University donated the ultraviolet radiation filters used in the tanning bed, and GE Healthcare donated the radioligand, the compound that traced the brain changes.
This could explain why some people continue to use tanning beds despite the increased risk of developing melanoma, the most lethal form of skin cancer. The brain activity and corresponding blood flow tracked by UT Southwestern scientists involved in the study is similar to that seen in people addicted to drugs and alcohol.
"Using tanning beds has rewarding effects in the brain so people may feel compelled to persist in the behavior even though it's bad for them," said Dr. Bryon Adinoff, professor of psychiatry and senior author of the study available online and in a future print edition of Addiction Biology. "The implication is, 'If it's rewarding, then could it also be addictive?' It's an important question in the field."
About 120,000 new cases of melanoma are diagnosed in the U.S. each year, according to the Skin Cancer Foundation. People younger than 30 who use a tanning bed 10 times a year have eight times the risk of developing malignant melanoma. While public knowledge of these dangers has grown, so has the regular use of tanning beds.
In this study, participants used tanning beds on two separate occasions: one time they were exposed to ultraviolet radiation and another time special filters blocked exposure to ultraviolet radiation. Participants did not know on which session they received the real or the filtered ultraviolet exposure. At each visit, participants were asked before and after each session how much they felt like tanning. Participants were also administered a compound that allowed scientists to measure brain blood flow while they were tanning.
Dr. Adinoff, who also is a staff physician at the Veterans Affairs North Texas Health Care System, said the next step is to create technology to further study brain changes among frequent tanners.
Other UT Southwestern researchers involved in the study were Dr. Heidi Jacobe, assistant professor of dermatology; Dr. Michael Devous, professor of radiology; and Thomas Harris, senior research scientist. Former dermatology resident Dr. Cynthia Harrington served as lead author.
The study was funded by the Department of Dermatology at UT Southwestern. Dr. Steven Feldman of Wake Forest University donated the ultraviolet radiation filters used in the tanning bed, and GE Healthcare donated the radioligand, the compound that traced the brain changes.
Thursday, August 11, 2011
Popular Muscle-Boosting Supplement Does Not Increase Blood Flow, Study Suggests
In recent years, various nutritional supplements have been developed containing arginine-alpha-ketoglutarate (AAKG), which is alleged to increase nitric oxide production thereby resulting in "vasodilation," the widening of blood vessels and increased blood flow to the muscles. The AAKG supplement-enhanced blood flow to working muscles during resistance exercise is alleged to provide increased muscle strength than just exercise alone.
The Baylor researchers studied the effects in 24 men of seven days of AAKG supplementation using the nutritional supplement on arterial blood flow in the arms after a single bout of resistance exercise. The results showed that seven days of AAKG supplementation had no significant impact on blood movement or increased brachial artery blood flow in response to a single bout of resistance exercise.
"We did see a slight increase in blood flow but those effects can only be attributed to the resistance exercise and not to the supplement," said study author Dr. Darryn Willoughby, associate professor of exercise, nutritional biochemistry and molecular physiology at Baylor. "The data appear to refute the alleged supposition and manufacturer's claims that 'vasodilating supplements' are effective at causing vasodilation, thereby resulting in increased blood flow to active skeletal muscle during resistance exercise. Furthermore, we specifically demonstrated that a single bout of resistance exercise increases vasodilation, arterial blood flow and circulating nitric oxide levels, but that the AAKG supplement provided no additive, preferential response compared to a placebo."
Pharmacist-Directed Anticoagulation Service Improves Care Coordination
The study, published online August 10 in the July/August issue of the Journal of Hospital Medicine, found that the transition of care directed by the anticoagulation service was seamless in more than 70 percent of patients treated and risk of bleeding and thrombosis declined by nearly 5 percent compared to patients not treated by the anticoagulation service.
"Our pharmacist-directed anticoagulation service has shown to improve the quality of care for patients taking warfarin in the hospital and transitioning to an outpatient setting," says James Kalus, PharmD, senior clinical pharmacy manager at Henry Ford and senior author of the study.
"The advantage of this service is that it improved the patient transition, enhanced communication between inpatient and outpatient clinicians and ensured that patients made it to their outpatient follow-up appointment after being discharged from the hospital."
Warfarin, used to prevent clots from forming or growing larger in the blood or blood vessels, is prescribed for certain heart-related conditions. It is linked to an estimated 30 percent of anticoagulant-related medication errors.
Henry Ford sought to evaluate the impact of the anticoagulation service for managing the care and safety of patients receiving warfarin during hospitalization and after discharge to an outpatient anticoagulation clinic. Researchers followed 500 patients hospitalized in two Internal Medicine units and two cardiology units.
Researchers applied four key compliance metrics to measure how well care was coordinated as patients transitioned from the hospital to the outpatient anticoagulant clinic:
Number of patients enrolled in an outpatient anticoagulation clinic.
Documented communication between the inpatient and outpatient anticoagulation clinics to reflect how the care was being coordinated.
Documented communication between the inpatient anticoagulation service and physician responsible for managing the patient at the outpatient anticoagulation clinic.
Number of patients who actually kept their initial appointment with the outpatient anticoagulation clinic within five days of being discharged from the hospital.
To determine the safety and efficacy of the anticoagulation service, researchers evaluated any episodes of major bleeding or new thrombosis patients experienced.
"The pharmacist-directed anticoagulation service is a viable approach to standardizing care and improving anticoagulant safety," Dr. Kalus says. "Based on our findings, it may be possible this model can be applied to other complicated medication regimens or chronic diseases."
The study was funded by Henry Ford Hospital.
Possible Therapeutic Target for Depression and Addiction Identified
A research team from St. Louis and Seattle reports in the Aug. 11 issue of the journal Neuron that in mice exposed to stress, a protein called p38α mitogen-activated protein kinase (MAPK) influences the animal's behavior, contributing to depression-like symptoms and risk for addiction.
The first author is Michael R. Bruchas, PhD, assistant professor of anesthesiology and of anatomy and neurobiology at Washington University School of Medicine in St. Louis, and the senior investigator is Charles Chavkin, PhD, professor of pharmacology at the University of Washington in Seattle.
The researchers demonstrate that p38α MAPK protein is activated by kappa-opioid receptors on neurons to regulate serotonin, a key neurotransmitter that helps regulate mood. When exposed to stress, the brain releases hormones that specifically interact with kappa-opioid receptors on neurons. Those receptors, in turn, activate p38α MAPK, which then interacts with the serotonin transporter in the cells to reduce the amount of available serotonin.
In this study, funded by the National Institute on Drug Abuse, the researchers looked at a brain region, called the dorsal raphe nucleus, where many stress-related factors and serotonin converge. They found that after stress exposure, mouse brains activate p38α MAPK, lowering serotonin levels and triggering depression-like behaviors as well as drug-seeking behavior in the mice.
Stressed animals withdrew and did not interact with other mice. In animals that had been given cocaine injections while in specific places in their cages, stress made them more likely to physically seek out those locations where they had received the drug.
"We call these responses 'depression-like' and 'addiction-like' behaviors because, we can't ask mice if they're addicted or sad," Bruchas says. "But just as depressed people often withdraw from social interactions, stressed mice do the same thing. We also observed that stressed mice return more often to the place where they received cocaine."
Next, investigators used a relatively novel genetic technology to disable the p38α MAPK protein only in cells of the brain's serotonin system. Without the p38α protein, the stress-exposed mice no longer withdrew from social interactions, displayed depression-like behavior or sought drugs.
While working in Chavkin's laboratory at the University of Washington, Bruchas and his colleagues studied mice exposed to what they call social defeat stress.
"We put a mouse into an enclosure with an 'aggressor' mouse," Bruchas says. "Some mice, like some humans, are more dominant and aggressive. When a non-aggressive mouse is put into a cage with an aggressive animal, that aggression causes stress similar to what we might see in an adult human working for a difficult boss or a teenager who has to deal with a bully at school."
Just as interacting with a "bully" mouse is similar to dealing with stressful environments, Bruchas and Chavkin say the cascade of events in the brain that contributes to serotonin reduction appears to be similar in both mice and humans.
"When people take antidepressant drugs called selective serotonin reuptake inhibitors, or SSRIs, to relieve depression, the drugs act on a cellular pump called the serotonin transporter, and this results in more serotonin in the brain," Bruchas says. "We think that the involvement of the p38α protein and kappa-opioid receptors represents an important finding in figuring out how it is that cells regulate depressive and addictive behaviors."
In his new laboratory at Washington University, Bruchas says he plans to test whether the same p38α MAPK protein is involved when the drug is nicotine or amphetamine.
"It will be important to determine whether this pathway is conserved for drugs of abuse other than cocaine," he says. "If so it will further highlight the importance of working with chemists to target this pathway for potential therapies."
Bruchas also plans to look at other brain areas to learn whether similar responses are occurring in response to stress.
Meanwhile, in Seattle, Chavkin's group continues to examine stress effects on addiction, long-term addiction models and whether humans regulate stress through the same kappa-opioid/p38α pathway.
"Our data demonstrate that p38α is required for local regulatory control of serotonin transport, which ultimately controls behavioral responses, including social avoidance and relapse of drug-seeking," Chavkin says. "These results are important because they highlight novel therapeutic targets to promote stress resilience."
This work was supported by grants from the National Institute on Drug Abuse of the National Institutes of Health (NIH) and the Hope for Depression Research Foundation.
Red Meat Linked to Increased Risk of Type 2 Diabetes
The study, led by An Pan, research fellow in the HSPH Department of Nutrition, will be published online in the American Journal of Clinical Nutrition on August 10, 2011 and will appear in the October print edition.
Pan, senior author Frank Hu, professor of nutrition and epidemiology at HSPH, and colleagues analyzed questionnaire responses from 37,083 men followed for 20 years in the Health Professionals Follow-Up Study; 79,570 women followed for 28 years in the Nurses' Health Study I; and 87,504 women followed for 14 years in the Nurses' Health Study II. They also conducted an updated meta-analysis, combining data from their new study with data from existing studies that included a total of 442,101 participants, 28,228 of whom developed type 2 diabetes during the study. After adjusting for age, body mass index (BMI), and other lifestyle and dietary risk factors, the researchers found that a daily 100-gram serving of unprocessed red meat (about the size of a deck of cards) was associated with a 19% increased risk of type 2 diabetes. They also found that one daily serving of half that quantity of processed meat -- 50 grams (for example, one hot dog or sausage or two slices of bacon) -- was associated with a 51% increased risk.
"Clearly, the results from this study have huge public health implications given the rising type 2 diabetes epidemic and increasing consumption of red meats worldwide," said Hu. "The good news is that such troubling risk factors can be offset by swapping red meat for a healthier protein."
The researchers found that, for an individual who eats one daily serving of red meat, substituting one serving of nuts per day was associated with a 21% lower risk of type 2 diabetes; substituting low-fat dairy, a 17% lower risk; and substituting whole grains, a 23% lower risk.
Based on these results, the researchers advise that consumption of processed red meat -- like hot dogs, bacon, sausage, and deli meats, which generally have high levels of sodium and nitrites -- should be minimized and unprocessed red meat should be reduced. If possible, they add, red meat should be replaced with healthier choices, such as nuts, whole grains, low-fat dairy products, fish, or beans.
Worldwide, diabetes has reached epidemic levels, affecting nearly 350 million adults. In the U.S. alone, more than 11% of adults over age 20 -- 25.6 million people -- have the disease, according to the Centers for Disease Control and Prevention. Most have type 2 diabetes, which is primarily linked to obesity, physical inactivity, and an unhealthy diet.
Previous studies have indicated that eating processed red meats increases the risk of developing type 2 diabetes. Risks from unprocessed meats have been less clear. For instance, in 2010, HSPH researchers found no clear evidence of an association between eating unprocessed meats and increased risk for either coronary heart disease or type 2 diabetes, but that study was based on smaller samples than the current study, and the researchers recommended further study of unprocessed meats. Another HSPH study in 2010 linked eating red meat with an increased risk of heart disease -- which is strongly linked to diabetes -- but did not distinguish between processed and unprocessed red meats.
This new study -- the largest of its kind in terms of sample size and follow-up years -- finds that both unprocessed and processed meats pose a type 2 diabetes risk, thus helping to clarify the issue. In addition, this study is among the first to estimate the risk reduction associated with substituting healthier protein choices for red meat.
"Our study clearly shows that eating both unprocessed and processed red meat -- particularly processed -- is associated with an increased risk of type 2 diabetes," said Pan. He noted that the 2010 U.S. dietary guidelines continue to lump red meat together with fish, poultry, eggs, nuts, seeds, beans, and soy products in the "protein foods" group. But since red meat appears to have significant negative health effects -- increased risk of diabetes, cardiovascular disease, and even total mortality, as suggested by several recent studies -- Pan suggested the guidelines should distinguish red meat from healthier protein sources and promote the latter instead.
Support for the study was provided by the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute.
New Genetic Links to MS Also Play Roles in Other Autoimmune Diseases
The study, conducted by an international consortium of researchers from the Yale School of Medicine and 129 other institutions, appears in the Aug. 11 issue of the journal Nature. Common genetic links between multiple autoimmune diseases were also confirmed in a second study by Yale and Harvard University researchers in a second study published contemporaneously in the journal PLoS Genetics.
"We have known for some time that many devastating diseases of the immune system must have common genetic causes," said Chris Cotsapas, assistant professor of neurology and genetics at Yale and lead author of the PLoS paper. "Now we have the outline of a map that tells us where we can look for common treatments."
In the Nature study, researchers studied the DNA from 9,772 individuals with multiple sclerosis and 17,376 unrelated healthy controls. They were able to confirm 23 previously known genetic associations and identified a further 29 new genetic variants as well as five strongly suspected of conferring susceptibility to the disease.
A large number of the genes implicated by these findings play pivotal roles in the workings of the immune system, specifically in the function of T-cells, which mount an immune response against foreign substances in the body, and interleukins, chemicals that facilitate interactions between different types of immune cells. One-third of the genes identified in this research have previously been implicated in playing a role in other autoimmune diseases such as Crohn's disease and Type 1 diabetes.
The PLoS research paper found that nearly half of the 107 genetic variants previously linked to an autoimmune disease are also found in at least one other autoimmune disease, such as MS, Crohn's disease, psoriasis, rheumatoid arthritis, lupus, celiac disease and Type 1 diabetes.
"These findings will help focus future research to find new ways to intervene in the course of MS and other diseases," said Yale's David Hafler, the Gilbert H. Glaser Professor of Neurology and professor of immunobiology, chair of the department of neurology and an author on both papers.
Authors of the Nature paper are the International Multiple Sclerosis Genetics Consortium along with the Wellcome Trust Case Control Consortium 2, which brought together hundreds of scientists from 130 institutions to help conduct this ground-breaking genome-wide analysis of patients with MS. The IMSGC was founded by Hafler while he was at the Harvard Medical School and the Broad Institute, along with Alastair Compston of the University of Cambridge and Stephen Hauser from the University of San Francisco.
"Our research settles a longstanding debate on what happens first in the complex sequence of events that leads to disability in multiple sclerosis, and has important implications for future treatment strategies," said Compston, a senior author of the work.
While it is clear that these common genetic variations are one critical component underlying the multiple sclerosis, environmental factors also play a role in the onset of the disease. For instance, previous research has shown vitamin D deficiency may lead to increased risk of MS.
"It is not that there are bad genes or necessarily a bad environment, but instead a disconnection between the interaction of genes with the environment," Hafler said.
The National Institutes of Neurologic Disorders and Stroke of the National Institutes of Health and the National Multiple Sclerosis Society also provided key funding for both studies.
Wednesday, August 10, 2011
Think Fast: The Neural Circuitry of Reaction Time
We often prepare movements in anticipation of events, such as pressing the accelerator in the car when a traffic light turns green, but our reaction time can be frustratingly variable. Sometimes we are too slow to react, while other times we perform the movement before we are fully ready. "What is the cause of this imprecision?" asks senior study author, Dr. Krishna V. Shenoy from Stanford University. "Presumably, it is related to the neural operation of planning and executing movements." Based on earlier observation that neural activity follows a movement-dependent trajectory during preparation, Dr. Shenoy's group in collaboration with co-senior author Dr. Maneesh Sahani from University College London developed a hypothesis called the "initial condition hypothesis." It states that during movement preparation, the network firing activity in the motor system is brought to a suitable initial condition from which the sequence of neural commands that underlies a movement may be efficiently generated.
To test their new hypothesis, the researchers simultaneously recorded from tens to hundreds of neurons in the monkey premotor cortex, a part of the brain associated with the control of movement, while the animals were performing delayed-reach movements. The monkeys had extensive training in the movement and exhibited stereotypical neural activity trajectories, making it possible for the researchers to compare subtle differences in activity.
"We found that the degree to which the neural activity had advanced, and the speed with which it had been advancing, along this trajectory at the time of the 'go' cue contributed substantially to determining reaction time," explains Dr Shenoy. "To our knowledge, the initial condition hypothesis leads to the best known trial-by-trial predictor of fluctuations in reaction time. Future studies are needed to determine whether reaction time can be predicted with similar accuracy under less-stereotypical conditions with untrained subjects."
How an antibiotic-producing organism controls resistance to its own antibiotic
The natural production of antibiotics by certain microorganisms is a complex and highly regulated process, not least because the organism making these compounds must protect itself from their toxic effects. Researchers at the John Innes Centre, which is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), have been studying the production of simocyclinone, produced by Streptomyces antibioticus, and in particular how the production of this potent antibiotic triggers an efficient pumping mechanism that exports the antibiotic from the cell.
Much of the work elucidating this protection mechanism has been carried out by Tung Le, a Vietnamese PhD student enrolled in the JIC's four-year rotation PhD programme. Tung, working under the supervision of Mark Buttner and David Lawson, showed that SimR, the protein Streptomyces antibioticus uses to regulate antibiotic export, can bind either to DNA or to the antibiotic itself, but crucially cannot bind to both. This means that when the antibiotic is around, SimR releases the DNA, which allows the expression of a gene that encodes a pump responsible for removing simocyclinone from the cell.
"This provides a mechanism that couples the potentially lethal biosynthesis of the antibiotic to its export, which has wider implications for resistance to clinically important antibiotics," commented Prof. Buttner. "However, we needed to know more detail about the interaction between SimR and DNA."
In this latest research, published in the journal Nucleic Acids Research, they show that the SimR protein has a novel 'arm' and that cutting off this arm unexpectedly weakened SimR binding to DNA. To determine the function of this arm, the researchers needed to work out the crystal structure of the protein bound to DNA, something which hadn't been achieved in Norwich before.
To overcome this skills gap, Tung won both a Korner Travelling Fellowship and an EMBO Short-Term Travel Fellowship to visit the University of Texas M.D. Anderson Cancer Center, home to one of the leading laboratories specialising in this technique. Tung spent three months working in the labs of Richard Brennan and Maria Schumacher, learning how to solve the structures of protein-DNA complexes. He was then able to apply this to his own project.
"I learned a lot and it was a great experience," said Tung. "The knowledge I brought back was not only useful for my project but will also be beneficial for others, and I feel very proud about that."
Usually, the SimR arm is unstructured, but in the presence of DNA they saw that it becomes ordered and binds into the minor groove of the DNA molecule. The crystal structure also shows how other parts of the SimR protein form sequence-specific interactions with a binding site in front of the export pump gene.
SimR is a member of a large family of regulatory proteins found in bacteria, and is the fifth one to have its structure solved when bound to DNA. The way these proteins recognise their target DNA sequences differs. This new example has wider implications, as a bioinformatic search of this family of regulators showed that many of them also have arms similar to the one characterised in this study.
Tung submitted his PhD thesis in early August, and his research has already produced four first-author papers. He is due to take up a post-doctoral position at the Massachusetts Institute of Technology in January.
"It can be very difficult for non-EU students to find the funding to study for a PhD in the UK, and so I was delighted to be offered a place on the JIC rotation programme. I am keen to encourage and help build relations between JIC and Vietnam. I was very happy to see the JIC is involved in joint work with Vietnam to sequence the genomes of different varieties of rice" said Tung, who left Vietnam at the age of seventeen for a bioscience career in the UK.
The researchers have also recently received a grant from the BBSRC to continue investigating the complexities of the regulation of antibiotic biosynthetic pathways, focussing on SimR and two other antibiotic-responsive transcription factors encoded in the simocyclinone biosynthetic cluster. This will establish the roles that the antibiotic plays in regulating self-resistance and its own biosynthesis. With the ever-growing problem of resistance, this kind of fundamental research is vital.
Fading Ability to Taste Iron Raises Health Concerns for People Over Age 50
The study appears in the American Chemical Society's journal Environmental Science & Technology on Aug. 10.
Andrea Dietrich, professor of civil and environmental engineering at Virginia Tech, and her colleagues, Susan Mirlohi, of Christiansburg, Va., a Ph.D. student in environmental engineering, and Susan Duncan, professor of food science and technology, point out that the perception of a metallic flavor in water can help people limit exposure to metals such as iron, which occurs naturally in water or from corrosion of iron water-supply pipes. People need less iron after age 50.
"Metallic flavor, caused by the dissolved iron and copper commonly found in groundwater or which may be introduced to tap water by the nation's corroding infrastructure, has been an issue for drinking water consumers and utilities," Dietrich said.
More than two million miles of the nation's infrastructure of water and wastewater pipes is nearing the end of its useful life, but the mostly underground facilities often do not attract much attention because of this "invisibility," said Sunil Sinha, Virginia Tech associate professor of civil and environmental engineering and a colleague of Dietrich's. Sinha is directing two new research projects to develop a National Pipeline Infrastructure Database.
Studies also suggest that older people who consume too much iron -- especially in dietary supplements and iron-rich foods -- may be at increased risk for Alzheimer's disease and other age-related conditions. Scientists long have known that taste perception fades with age. Dietrich's group set out to fill in gaps in knowledge about how aging affects perception of a metallic flavor in water.
Their results with 69 volunteers, aged 19 to 84 years, identified a distinctive age-related decline in their ability to taste iron. People over age 50 tended to miss the metallic taste of iron in water, even at levels above the thresholds set by the U. S. Environmental Protection Agency and the World Health Association.
"Our findings are . . . unique in that drinking water is the source of the environmental sensory contaminant and evidence is provided for wide variation in the human population," the report states. "Whereas our research focused on iron, there are implications for other metals of health concern, most notably copper from copper pipes as our previous research has demonstrated that copper is less flavorful than iron and it is known that copper is also more toxic than iron."
The scientists acknowledge funding from the Institute for Critical Technology and Applied Science at Virginia Tech.
Antioxidant Spices, Like Turmeric and Cinnamon, Reduce Negative Effects of High-Fat Meal
"Normally, when you eat a high-fat meal, you end up with high levels of triglycerides, a type of fat, in your blood," said Sheila West, associate professor of biobehavioral health, Penn State, who led the study. "If this happens too frequently, or if triglyceride levels are raised too much, your risk of heart disease is increased. We found that adding spices to a high-fat meal reduced triglyceride response by about 30 percent, compared to a similar meal with no spices added."
West and her colleagues prepared meals on two separate days for six men between the ages of 30 and 65 who were overweight, but otherwise healthy. The researchers added two tablespoons of culinary spices to each serving of the test meal, which consisted of chicken curry, Italian herb bread, and a cinnamon biscuit. The control meal was identical, except that spices were not included. The team drew blood from the participants every 30 minutes for three hours. They reported their findings in the current issue of the Journal of Nutrition.
"In the spiced meal, we used rosemary, oregano, cinnamon, turmeric, black pepper, cloves, garlic powder and paprika," said Ann Skulas-Ray, postdoctoral fellow. "We selected these spices because they had potent antioxidant activity previously under controlled conditions in the lab."
When the meal contained a blend of antioxidant spices, antioxidant activity in the blood was increased by 13 percent and insulin response decreased by about 20 percent.
According to West, many scientists think that oxidative stress contributes to heart disease, arthritis and diabetes. "Antioxidants, like spices, may be important in reducing oxidative stress and thus reducing the risk of chronic disease," she said, adding that the spice dose they used provided the equivalent amount of antioxidants contained in 5 ounces of red wine or 1.4 ounces of dark chocolate.
Skulas-Ray noted that adding two tablespoons of spices to meals did not cause stomach upset in the participants. "They enjoyed the food and had no gastrointestinal problems," she said. But, she added, "The participants were notified ahead of time that they would be eating highly spiced foods and they were willing to do so."
In the future, West plans to investigate whether she can get the same results by adding smaller doses of spices to meals.
Other Penn State researchers on the paper include Ann Skulas-Ray, graduate student; Penny Kris-Etherton, Distinguished Professor of Nutrition; Danette Teeter, former research assistant; and John Vanden Heuvel, professor of veterinary science. Chung-Yen (Oliver) Chen, scientist, Tufts University, also was involved in the study.
The McCormick Science Institute and National Institutes of Health supported this work.
Use of CT Scans in Emergency Rooms Increased 330 Percent in 12 Years
The study also showed that the use of CT scans was less common early in the study period, but rose significantly over time. Just 3.2 percent of emergency patients received CT scans in 1996, while 13.9 percent of emergency patients seen in 2007 received them.
"This means that by 2007, 1 in 7 ED patients got a CT scan," says first author Keith Kocher, M.D., M.P.H., a clinical lecturer in U-M Department of Emergency Medicine. "It also means that about 25 percent of all the CT scans done in the United States are performed in the ED."
Using data from the National Hospital Ambulatory Medical Care Survey, compiled by the Centers for Disease Control, the researchers reviewed 1.29 billion weighted records of emergency visits between 1996 and 2007, 97.1 million of which included patients who received a CT scan. Their findings were published online ahead of print publication in the Annals of Emergency Medicine and highlighted as a featured article.
The study doesn't provide the reasons why CT use increased over time -- but "it does make one wonder," Kocher notes.
"There are risks to overuse of CT scans, because each scan involves radiation -- so if they're done for marginal reasons you have to question why," Kocher says. "For example, patients who complained of flank pain (pain in the side) had an almost 1 in 2 chance of getting a CT scan by the end of the study period. Usually most physicians are doing that to look for a kidney stone, but it's not clear if it's necessary to use a CT scan for that purpose."
He adds, "Also, during the study period, ED visits increased by about 30 percent, while CT use increased 330 percent, meaning the rate of CT use grew 11 times faster than the rate of ED visits."
Patients who received a CT scan in the beginning of the study had a 25 percent chance of being admitted to the hospital directly from the ED, while by 2007, this rate had been cut in half.
For all of the 20 most common reasons patients came to the ER for treatment, the study found that CT use increased during the study period. However, CT use was particularly high for the following complaints, with at least 25 percent of all patients receiving a scan by 2007:
- impairments of nerve, spinal cord or brain function
- flank pain
- convulsions
- vertigo, dizziness or light-headedness
- headache
- abdominal pain
- general weakness
"I think a lot of the increase is related to changes in how doctors practice medicine and the availability of CT scanners," Kocher says. "They provide lots of information quickly and so doctors and patients see CTs as a means of arriving at diagnoses efficiently and conveniently. Couple that with the fact that CT scanners are commonly housed in or near the ED itself, and the barriers to getting the test done are lower than in the past."
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