Posts tagged medicine
Articles and news from the latest research reports.
![Researchers identify how zinc regulates a key enzyme involved in cell death
Findings may help develop targeted drug interventions and fight cancer and neurodegenerative diseases
The molecular details of how zinc, an essential trace element of human metabolism, interacts with the enzyme caspase-3, which is central to apoptosis or cell death, have been elucidated in a new study led by researchers at Virginia Commonwealth University. The study is featured on the cover of the April issue of the journal Angewandte Chemie’s International Edition.
Dysregulation of apoptosis is implicated in cancer and neurodegenerative disease such as Alzheimer’s disease. Zinc is known to affect the process by inhibiting the activity of caspases, which are important drug targets for the treatment of the above conditions. The findings may help researchers design therapeutic agents that target zinc-caspase interaction to specifically control the activity of caspases, and hence, apoptosis.
“The work is unique in helping to open up a broad new area of research which we call the bioinorganic chemistry of apoptosis – understanding the role of essential metal ions in one of life’s fundamental processes,” said corresponding author Nicholas P. Farrell, Ph.D., member of the Developmental Therapeutics program at VCU Massey Cancer Center and professor of chemistry in the VCU College of Humanities and Sciences.
“Indeed, the zinc inhibition of apoptosis in fact contrasts with the role of its closely related neighbor copper, which is understood to enhance apoptosis,” he said.
In the study, Farrell and his research team, A. Gerard Daniel, Ph.D., and Erica J. Peterson, used conventional enzymology and biophysical techniques combined with state-of-the-art computational methods, to show evidence for a hitherto unrecognized interaction site with caspase-3.
According to Farrell, caspases were discovered in the mid-1990s. There are 11 caspases known humans, and seven of these are involved in cell death. The study suggests a regulatory zinc site that may be common to all caspases. Previous findings have shown other zinc binding sites in caspase-6 and -9. Now, Farrell said, the generality of the team’s observations must be extended and verified in other caspases.
“The [journal] cover epitomizes the contrasting but interdependent roles of the metal ions copper/zinc in the regulation of apoptosis and perfectly captures the duality of this most fundamental of biological processes,” Farrell said.](http://36.media.tumblr.com/0451b9689542006e73381dfdf76eaec8/tumblr_n3gtl7IjuE1rog5d1o1_500.jpg)
Researchers identify how zinc regulates a key enzyme involved in cell death
Findings may help develop targeted drug interventions and fight cancer and neurodegenerative diseases
The molecular details of how zinc, an essential trace element of human metabolism, interacts with the enzyme caspase-3, which is central to apoptosis or cell death, have been elucidated in a new study led by researchers at Virginia Commonwealth University. The study is featured on the cover of the April issue of the journal Angewandte Chemie’s International Edition.
Dysregulation of apoptosis is implicated in cancer and neurodegenerative disease such as Alzheimer’s disease. Zinc is known to affect the process by inhibiting the activity of caspases, which are important drug targets for the treatment of the above conditions. The findings may help researchers design therapeutic agents that target zinc-caspase interaction to specifically control the activity of caspases, and hence, apoptosis.
“The work is unique in helping to open up a broad new area of research which we call the bioinorganic chemistry of apoptosis – understanding the role of essential metal ions in one of life’s fundamental processes,” said corresponding author Nicholas P. Farrell, Ph.D., member of the Developmental Therapeutics program at VCU Massey Cancer Center and professor of chemistry in the VCU College of Humanities and Sciences.
“Indeed, the zinc inhibition of apoptosis in fact contrasts with the role of its closely related neighbor copper, which is understood to enhance apoptosis,” he said.
In the study, Farrell and his research team, A. Gerard Daniel, Ph.D., and Erica J. Peterson, used conventional enzymology and biophysical techniques combined with state-of-the-art computational methods, to show evidence for a hitherto unrecognized interaction site with caspase-3.
According to Farrell, caspases were discovered in the mid-1990s. There are 11 caspases known humans, and seven of these are involved in cell death. The study suggests a regulatory zinc site that may be common to all caspases. Previous findings have shown other zinc binding sites in caspase-6 and -9. Now, Farrell said, the generality of the team’s observations must be extended and verified in other caspases.
“The [journal] cover epitomizes the contrasting but interdependent roles of the metal ions copper/zinc in the regulation of apoptosis and perfectly captures the duality of this most fundamental of biological processes,” Farrell said.
New Method Could Improve Ultrasound Imaging
One day while casually reading a review article, Caltech chemical engineer Mikhail Shapiro came across a mention of gas vesicles—tiny gas-filled structures used by some photosynthetic microorganisms to control buoyancy. It was a light-bulb moment. Shapiro is always on the lookout for new ways to enhance imaging techniques such as ultrasound or MRI, and the natural nanostructures seemed to be just the ticket to improve ultrasound imaging agents.
Now Shapiro and his colleagues from UC Berkeley and the University of Toronto have shown that these gas vesicles, isolated from bacteria and from archaea (a separate lineage of single-celled organisms), can indeed be used for ultrasound imaging. The vesicles could one day help track and reveal the growth, migration, and activity of a variety of cell types—from neurons to tumor cells—using noninvasive ultrasound, one of the most widely used imaging modalities in biomedicine.
A paper describing the work appears as an advance online publication in the journal Nature Nanotechnology.
"People have struggled to make synthetic nanoscale imaging agents for ultrasound for many years," says Shapiro. "To me, it’s quite amazing that we can borrow something that nature has evolved for a completely different purpose and use it for in vivo ultrasound imaging. It shows just how much nature has to offer us as engineers."
Anaesthetic technique important to prevent damage to brain
Researchers at the University of Adelaide have discovered that a commonly used anaesthetic technique to reduce the blood pressure of patients undergoing surgery could increase the risk of starving the brain of oxygen.
Reducing blood pressure is important in a wide range of surgeries - such as sinus, shoulder, back and brain operations - and is especially useful for improving visibility for surgeons, by helping to remove excess blood from the site being operated on.
There are many different techniques used to lower patients’ blood pressure for surgery - one of them is known as hypotensive anaesthesia, which slows the arterial blood pressure by up to 40%.
Professor PJ Wormald, a sinus, head and neck surgeon from the University’s Discipline of Surgery, based at the Queen Elizabeth Hospital, led a world-first study looking at both the effectiveness of hypotensive anaesthesia from the surgeon’s point of view and its impact on the patients.
The study followed 32 patients who underwent endoscopic sinus surgery. The results have now been published online in the journal The Laryngoscope.
"There is an important balance in anaesthesia where the blood pressure is lowered so that the surgeon has good visibility and is able to perform surgery safely. There are numerous sensitive areas in sinus surgery - the brain, the eye and large vessels such as the carotid. However, if the blood pressure is lowered too far this may cause damage to the brain and other organs," says Professor Wormald.
"We know from previous research that a person’s brain undergoing anaesthesia has lower metabolic requirements than the awake brain, and therefore it can withstand greater reductions in blood flow.
"There is also a widely accepted concept that the brain has the ability to autoregulate - to adapt and maintain a constant blood flow as needed, despite a wide range of blood pressure conditions. Our studies challenge this; they show that the brain can only autoregulate up to a point, and cannot completely adapt to such low blood pressures.
"This drop in blood pressure poses a risk of starving the brain of much-needed oxygen and nutrients, which could result in injury. There have been cases, for example, where patients have reported memory loss following surgery.
"Given that hypotensive anaesthesia is a widely used technique, not just in sinus surgery but in many different types of surgery, we’ve made recommendations in our paper that suggest a safer approach to this technique. This would reduce risk to the patient while enabling the surgeon to carry out their work effectively," Professor Wormald says.
(Image: Shutterstock)
Researchers Reveal a New Pathway Through the Sodium Pump
A study in The Journal of General Physiology provides new evidence that the ubiquitous sodium pump is more complex—and more versatile—than we thought.
(Image caption: Structure of the sodium pump, which researchers reveal to be more versatile than previously thought)
The sodium pump is present in the surface membrane of all animal cells, using energy derived from ATP to transport sodium and potassium ions in opposite directions across the cell boundary. By setting up transmembrane gradients of these two ions, the pump plays a vital role in many important processes, including nerve impulses, heartbeats, and muscular contraction.
Now, Rockefeller University researchers Natascia Vedovato and David Gadsby demonstrate that, in addition to its role as a sodium and potassium ion transporter, the pump can simultaneously import protons into the cell. Their study not only provides evidence of “hybrid” function by the pump, it also raises important questions about whether the inflow of protons through sodium pumps might play a role in certain pathologies.
The sodium pump exports three sodium ions out of the cell and imports two potassium ions into the cell during each transport cycle. Vedovato and Gadsby show that, during this normal cycle, the pump develops a passageway that enables protons to cross the membrane. When the pump releases the first of the three sodium ions to the cell exterior, a newly emptied binding site becomes available for use by an external proton, allowing it to then make its way into the cytoplasm. The protons travel a distinct route, and proton inflow is not required for successful transport of sodium and potassium.
Import of protons is high when their extracellular concentration is high (pH is low) and membrane potential is negative. The authors therefore speculate that proton inflow might have important implications under conditions in which extracellular pH is lowered, such as in muscle during heavy exercise, in the heart during a heart attack, or in the brain during a stroke.
(Source: newswise.com)
Neurosurgeons successfully implant 3D printed skull
A 22-year-old woman from the Netherlands who suffers from a chronic bone disorder — which has increased the thickness of her skull from 1.5cm to 5cm, causing reduced eyesight and severe headaches — has had the top section of her skull removed and replaced with a 3D printed implant.
The operation was performed by a team of neurosurgeons at the University Medical Centre Utrecht and the university claims this is this first instance of a successful 3D printed cranium that has not been rejected by the patient.
The operation, which took 23 hours, was led by Dr Bon Verweij. The patient’s skull was so thick, that had the operation not been performed, serious brain damage or death may have occurred in the near future.
Cell-saving drugs could reduce brain damage after stroke
Long-term brain damage caused by stroke could be reduced by saving cells called pericytes that control blood flow in capillaries, suggest researchers from Oxford University, UCL and the University of Copenhagen.
Until now, many scientists believed that blood flow within the brain was solely controlled by changes in the diameter of arterioles, blood vessels that branch out from arteries into smaller capillaries.
In this new study, the UK and Danish researchers reveal that the brain’s blood supply is in fact chiefly controlled by the narrowing or widening of capillaries as pericytes tighten or loosen around them.
Their study, published this week in the journal Nature, shows not only that pericytes are the main regulator of blood flow to the brain, but also that they tighten and die around capillaries after stroke. This significantly impairs blood flow in the long term, causing lasting damage to brain cells.
The scientists showed that certain chemicals can halve pericyte death from simulated stroke in the lab, and they hope to develop these into drugs to treat stroke victims.
'This discovery offers radically new treatment approaches for stroke,' says study co-author Professor Alastair Buchan, Dean of Medicine and Head of the Medical Sciences Division at Oxford University. 'Importantly, we should now be able to identify drugs that target these cells. If we are able to prevent pericytes from dying, it should help restore blood flow in the brain to normal and prevent the ongoing slow damage we see after a stroke which causes so much neurological disability in our patients.'
Professor David Attwell of UCL, who led the study, explains: ‘At present, clinicians can remove clots blocking blood flow to the brain if stroke patients reach hospital early enough. However, the capillary constriction produced by pericytes may, by restricting the blood supply for a long time, cause further damage to nerve cells even after the clot is removed. Our latest research suggests that devising drugs to prevent capillary constriction may offer new therapies for reducing the disability caused by stroke.’
The new research also gives insight into the mechanisms underlying the use of functional magnetic resonance imaging to detect blood flow changes in the brain.
'Functional imaging allows us to see the activity of nerve cells within the human brain but until now we didn't quite know what we were looking at,' says Professor Martin Lauritzen of the University of Copenhagen. 'We have shown that pericytes initiate the increase in blood flow seen when nerve cells become active. So we now know that functional imaging signals are caused by a pericyte-mediated increase of capillary diameter. Knowing exactly what functional imaging shows will help us to better understand and interpret what we see.'
(Source: ox.ac.uk)
Neurologists at LMU have studied the role of the vestibular system, which controls balance, in optimizing how we direct our gaze. The results could lead to more effective rehabilitation of patients with vestibular or cerebellar dysfunction.
When we shift the direction of our gaze, head and eye movements are normally highly coordinated with each other. Indeed, from the many possible combinations of speed and duration for such movements, the brain chooses the one that minimizes the error in reaching the intended line of sight. Dr. Nadine Lehnen, who heads a research group based at LMU’s Center for Vertigo and Balance Disorders, in collaboration with her colleague Dr. Murat Saglam and Professor Stefan Glasauer of the Center for Sensorimotor Diseases at LMU, have now published a paper in the latest issue of the journal of Brain which investigates the significance of the vestibular system for this optimization of motor coordination. The vestibular system in the brain is mainly responsible for the maintenance of balance and posture. The new work focused on subjects suffering from bilateral defects in the vestibular system (a complete vestibulopathy) or lesions in the cerebellum, which is functionally linked to it.
The authors of the new study had previously developed a mathematical model that enabled them to predict the horizontal movements of the head and eyes in response to the presentation of an off-center stimulus. “When subjected to repeated trials, healthy subjects are able to select the combination of eye and head movements that minimizes gaze shift variability,” says Glasauer. They unconsciously choose the set of movements associated with the least error in the endpoint. Moreover, they can do this even when wearing a helmet with weights attached, which alters the moment of inertia of the head.
Learning to find the endpoint
However, patients who show defects in the vestibular system or the cerebellum have greater difficulty in controlling the direction of gaze in response to changes in their environment. “It turns out that information relayed from the balance organs to the vestibular system is essential for the optimization of gaze shifts,” says Nadine Lehnen. Patients with complete bilateral vestibular loss are therefore unable to perform such shifts in the most efficient way. “In striking contrast, patients with cerebellar damage can, to a certain extent, learn to optimize certain parameters of head and eye movements, by adjusting the velocity of head movement, for instance,” says Glasauer.
"These results provide the first evidence that the vestibular system is critical for optimizing voluntary movements“, says Dr. Kathleen E. Cullen from McGill University in Montreal in a scientific commentary to the study appearing in the print issue of Brain. The new findings are of relevance for the rehabilitation of patients who have suffered damage to the cerebellum and patients with incomplete vestibulopathies. “We assume that gaze shift control in these patients can be enhanced by a rehabilitation training based on active head movements,” says Nadine Lehnen. Head movements provide the vestibular feedback which generates the sensorimotor error messages that underlie the ability to learn how to optimize the coordination of eye and head movements. Instead of trying to hold their heads steady, these patients should be encouraged to actively move their heads, when they shift their gaze.
The question if patients with partial vestibulopathy can optimize gaze shift behavior by engaging in active head movements is now under investigation. This work forms part of a rehabilitation study which is being carried out at the Center for Vertigo and Balance Disorders at Munich University Hospitals, and is financed by the Federal Ministry for Education and Research.
Nasal spray delivers new type of depression treatment
A nasal spray that delivers a peptide to treat depression holds promise as a potential alternative therapeutic approach, research from the Centre for Addiction and Mental Health (CAMH) shows.
The study, led by CAMH’s Dr. Fang Liu, is published online in Neuropsychopharmacology.
In a previous study published in Nature Medicine in 2010, Dr. Liu developed a protein peptide that provided a highly targeted approach to treating depression that she hopes will have minimal side effects. The peptide was just as effective in relieving symptoms when compared to a conventional antidepressant in animal testing. However, the peptide had to be injected into the brain. Taken orally, it would not cross the blood-brain barrier in sufficient concentrations.
"Clinically, we needed to find a non-invasive, convenient method to deliver this peptide treatment," says Dr. Liu, Senior Scientist in the Campbell Family Mental Health Research Institute at CAMH. With the support of a Proof of Principle grant from the Canadian Institutes of Health Research (CIHR), Dr. Liu’s team was able to further explore novel delivery methods.
The nasal delivery system, developed by U.S. company Impel NeuroPharma, was shown to deliver the peptide to the right part of the brain. It also relieved depression-like symptoms in animals.
"This study marks the first time a peptide treatment has been delivered through nasal passageways to treat depression," says Dr. Liu, Professor in the University of Toronto’s Department of Psychiatry.
The peptide treatment interferes with the binding of two dopamine receptors – the D1 and D2 receptor complex. Dr. Liu’s team had found that this binding was higher in the brains of people with major depression. Disrupting the binding led to the anti-depressant effects.
The peptide is an entirely new approach to treating depression, which has previously relied on medications that primarily block serotonin or norepinephrine transporters.
Depression, the most common form of mental illness, is one of the leading causes of disability globally. More than 50 per cent of people living with depression do not respond to first-line medication treatment.
"This research brings us one step closer to clinical trials," says Dr. Liu. In ongoing lab research, her team is experimenting to determine if they can make the peptide break down more slowly, and travel more quickly in the brain, to improve its anti-depressant effects.
The Hidden Dangers of Going Under
Anesthesia may have lingering side effects on the brain, even years after an operation
Two and a half years ago Susan Baker spent three hours under general anesthesia as surgeons fused several vertebrae in her spine. Everything went smoothly, and for the first six hours after her operation, Baker, then an 81-year-old professor at the Johns Hopkins Bloomberg School of Public Health, was recovering well. That night, however, she hallucinated a fire raging through the hospital toward her room. Petrified, she repeatedly buzzed the nurses’ station, pleading for help. The next day she was back to her usual self. “It was the most terrifying experience I have ever had,” she says.
Baker’s waking nightmare was a symptom of postoperative delirium, a state of serious confusion and memory loss that sometimes follows anesthesia. In addition to hallucinations, delirious patients may forget why they are in the hospital, have trouble responding to questions and speak in nonsensical sentences. Such bewilderment—which is far more severe than the temporary mental fog one might expect after any major operation that requires general anesthesia—usually resolves after a day or two.
Although physicians have known about the possibility of such confusion since at least the 1980s, they had decided, based on the then available evidence, that the drugs used to anesthetize a patient in the first place were unlikely to be responsible. Instead, they concluded, the condition occurred more often because of the stress of surgery, which might in turn unmask an underlying brain defect or the early stages of dementia. Studies in the past four years have cast doubt on that assumption, however, and suggest that a high enough dose of anesthesia can in fact raise the risk of delirium after surgery. Recent studies also indicate that the condition may be more pernicious than previously realized: even if the confusion dissipates, attention and memory can languish for months and, in some cases, years.
Researchers discover underlying genetics, marker for stroke, cardiovascular disease
Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke, and have also uncovered new details about an important metabolic pathway that plays a major role in several common diseases. Together, their findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies.
"Our findings have the potential to identify new targets in the prevention and treatment of stroke, cardiovascular disease and many other common diseases," said Stephen R. Williams, Ph.D., a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics, Charlottesville.
Dr. Williams, Michele Sale, Ph.D., associate professor of medicine, Brad Worrall, M.D., professor of neurology and public health sciences, all at the University of Virginia, and their team reported their findings March 20, 2014 in PLoS Genetics. The investigators were supported by the National Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program (www.genome.gov/27541119).
Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke. “Our goals were to break down the risk factors for stroke,” Dr. Williams said.
The researchers focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.
But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels - and methionine metabolism gone awry - are not well defined.
Dr. Williams and his colleagues conducted genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism - the ability to convert methionine to homocysteine - in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.
In a genome-wide association study, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait - the ability to metabolize methionine into homocysteine.
Investigators identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one - the ALDH1L1 gene - was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival.
They also made important discoveries about the methionine-homocysteine process. “GNMT produces a protein that converts methionine to homocysteine. Of the five genes that we identified, it was the one most significantly associated with this process,” Dr. Williams said. “The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”
"It’s striking that the genes are in the same pathway, so we know that the genomic variants affecting that pathway contribute to the variability in disease and risk that we’re seeing," he said. "We may have found how genetic information controls the regulation of GNMT."
The group determined that the five genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5 percent of such differences.
"This is a great example of the kinds of successful research efforts coming out of the GARNET program," said program director Ebony Madden, Ph.D. "GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals."
The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease, Dr. Williams said.
"As genome sequencing becomes more widespread, clinicians may be able to determine if a person’s risk for abnormally high levels of homocysteine is elevated," he said. "Changes could be made to an individual’s diet because of a greater risk for stroke and cardiovascular disease."
The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.