If you throw a ball underwater, you’ll find that the smaller it is, the faster it moves: A larger cross-section greatly increases the water’s resistance. Now, a team of MIT researchers has figured out a way to use this basic principle, on a microscopic scale, to carry out biomedical tests that could eventually lead to fast, compact and versatile medical-testing devices.
The results is based on work by graduate student Elizabeth Rapoport and assistant professor Geoffrey Beach, of MIT’s Department of Materials Science and Engineering (DMSE).
The balls used here are microscopic magnetic beads that can be ‘decorated’ with biomolecules such as antibodies that cause them to bind to specific proteins or cells; such beads are widely used in biomedical research. The key to this new work was finding a way to capture individual beads and set them oscillating by applying a variable magnetic field. The rate of their oscillation can then be measured to assess the size of the beads.
When these beads are placed in a biological sample, biomolecules attach to their surfaces, making the beads larger — a change that can then be detected through the biomolecules effect on the beads’ oscillation. This would provide a way to detect exactly how much of a target biomolecule is present in a sample, and provide a way to give a virtually instantaneous electronic readout of that information.
This new technique, for the first time, allows these beads — each about one micrometer, or millionth of a meter, in diameter — to be used for precise measurements of tiny quantities of materials. This could, for example, lead to tests for disease agents that would need just a tiny droplet of blood and could deliver results instantly, instead of requiring laboratory analysis.
MIT
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New insights into certain muscle diseases, the filaminopathies, are reported by an international research team led by Dr. Rudolf Andre Kley of the RUB’s University Hospital Bergmannsheil in the journal Brain. The scientists from the Neuromuscular Centre Ruhrgebiet (headed by Prof. Matthias Vorgerd) at the Neurological University Clinic (Director: Prof. Martin Tegenthoff) cooperated with colleagues from eleven institutes in seven countries. Among other things they found that protection mechanisms to combat abnormal protein deposits do not work properly in filaminopathy patients. This opens up new starting points for therapies that the team aims to test on cell cultures.
Mutations in the filamin C gene (FLNC) cause filaminopathies, which are manifested through progressive muscle weakness to the point of loss of the ability to walk. Muscle fibres are composed of myofibrils, for the development and maintenance of which the protein filamin C is crucial. The mutations examined in the study bring about a so-called myofibrillar myopathy: the myofibrils disintegrate in certain places and mutant filamin C and other proteins aggregate massively in the muscle fibres.
The researchers showed that the diseased protein deposits interfere with the protein degradation usually occurring in cells. Normally, cells produce what are known as heat shock proteins, which promote the degradation of protein deposits and make sure that other proteins assume their correct three-dimensional structure. ‘However, these protection mechanisms only seem to be increasingly activated when the critical point is exceeded. It looks as if the ‘fire brigade’ was called too late’, says Dr. Kley. ‘We hope to positively influence the course of the disease by means of early treatment with substances that stimulate the production of heat shock proteins or affect the protein degradation in other ways. To study this, we have developed a cell culture model that allows us to carry out the first therapy studies in the laboratory.’
The study of filaminopathy patients also enables the researchers to describe the disease more accurately now. The heart is more affected by the disease than previously thought, which may cause sudden cardiac death. It was also confirmed that pathological remodelling processes in the leg muscles conform to a specific pattern, which is visible on magnetic resonance imaging pictures. ‘This enables us to distinguish filaminopathies from other muscle diseases within the group of myofibrillar myopathies’, explains Dr. Kley.
Ruhr-University Bochum
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A current focus in global health research is to make medical tests that are not just cheap, but virtually free. One such strategy is to start with paper – one of humanity’s oldest technologies – and build a device like a home-based pregnancy test that might work for malaria, diabetes or other diseases.
A University of Washington bioengineer recently developed a way to make regular paper stick to medically interesting molecules. The work produced a chemical trick to make paper-based diagnostics using plain paper, the kind found at office supply stores around the world.
‘We wanted to go for the simplest, cheapest starting material, and give it more capability,’ said Daniel Ratner, a UW assistant professor of bioengineering and lead author of the paper
‘We also wanted to make the system as independent of the end applications as possible, something any researcher could plug into.’
Many paper-based diagnostics are made from nitrocellulose, a sticky membrane used in pregnancy tests and by medical researchers to detect proteins, DNA or antibodies in the human immune system.
Ratner hopes to replace that specialised membrane with cheap, ubiquitous paper, and to use it for any type of medical test – not just the big, biological molecules.
The UW technique uses minimal equipment or know-how. The researchers used a cheap, industrial solvent called divinyl sulfone that can be bought by the gallon and has been used for decades as an adhesive. Ratner’s group discovered they could dilute the chemical in water, carefully control the acidity, then pour it into a Ziploc bag and add a stack of paper, shake for a couple of hours, and finally rinse the paper and let it dry.
The dried paper feels smooth to the touch but is sticky to all kinds of chemicals that could be of medical interest: proteins, antibodies and DNA, for example, as well as sugars and the small-molecule drugs used to treat most medical conditions.
‘We want to develop something to not just ask a single question but ask many personal health questions,’ Ratner said. ‘‘Is there protein in the urine? Is this person diabetic? Do they have malaria or influenza?’’
To test their idea, the researchers ran the treated paper through an inkjet printer where the cartridge ink had been replaced with biomolecules, in this case a small sugar called galactose that attaches to human cells. They printed the biomolecules onto the sticky paper in an invisible pattern. Exposing that paper to fluorescent ricin, a poison that sticks to galactose, showed that the poison was present.
Now that they have proven their concept, Ratner said, they hope other groups will use the paper to develop actual diagnostic tests.
University of Washington
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The risk of death resulting from heart attack is higher in people with schizophrenia than in the general public, according to scientists at the Centre for Addiction and Mental Health (CAMH) and the Institute for Clinical Evaluative Sciences (ICES).
On average, people with schizophrenia have a life-span 20 years shorter than the general population. This is partly due to factors such as smoking, increased rates of diabetes, and metabolic problems brought on by the use of some anti-psychotic medications. These factors often worsen once a cardiac condition arises because people with schizophrenia are less likely to make the necessary lifestyle changes, such as diet and exercise, to offset the problem.
This study examined mortality and access to cardiac care after heart attacks (acute myocardial infarction) in those with schizophrenia.
Dr. Paul Kurdyak, Chief, Division of General and Health Systems Psychiatry at CAMH, analysed four years of Ontario-wide patient data and tracked all incidents of heart attack among people with schizophrenia, and compared results to people without schizophrenia.
‘When we looked at the data, we found that people with schizophrenia were 56 per cent more likely to die after discharge from hospital following a heart attack than those who did not have schizophrenia,’ says Dr. Kurdyak, also an Adjunct Scientist at ICES. ‘We also found that patients with schizophrenia, despite the increase in mortality risk after a heart attack, were half as likely to receive life-saving cardiac procedures and care from cardiologists than those without schizophrenia.’
Specifically, the study found that people with schizophrenia were 50 per cent less likely to receive cardiac procedures or to see a cardiologist within 30 days of discharge from hospital.
‘The numbers tell us that people with schizophrenia– the ones who are at most risk to develop and subsequently die from heart attacks — are not receiving adequate care,’ says Dr. Kurdyak. ‘The possible solutions are two-fold: prevention is one. We need to support patients whom we know are at risk of developing medication-related metabolic issues by working with them to provide strategies to offset weight gain, such as healthy eating and physical activity. The other part is aftercare – the mental health care team, primary care providers, and the cardiac specialists need to work together to ensure that patients are seen again after a first incident of heart attack.’
EurekAlert
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A technique that uses acoustic waves to sort cells on a chip may create miniature medical analytic devices that could make Star Trek’s tricorder seem a bit bulky in comparison, according to a team of researchers.
The device uses two beams of acoustic — or sound — waves to act as acoustic tweezers and sort a continuous flow of cells on a dime-sized chip, said Tony Jun Huang, associate professor of engineering science and mechanics, Penn State. By changing the frequency of the acoustic waves, researchers can easily alter the paths of the cells.
Huang said that since the device can sort cells into five or more channels, it will allow more cell types to be analysed simultaneously, which paves the way for smaller, more efficient and less expensive analytic devices.
‘Eventually, you could do analysis on a device about the size of a cell phone,’ said Huang. ‘It’s very doable and we’re making in-roads to that right now.’
Biological, genetic and medical labs could use the device for various types of analysis, including blood and genetic testing, Huang said.
Most current cell-sorting devices allow the cells to be sorted into only two channels in one step, according to Huang. He said that another drawback of current cell-sorting devices is that cells must be encapsulated into droplets, which complicates further analysis.
‘Today, cell sorting is done on bulky and very expensive devices,’ said Huang. ‘We want to minimise them so they are portable, inexpensive and can be powered by batteries.’
Using sound waves for cell sorting is less likely to damage cells than current techniques, Huang added.
In addition to the inefficiency and the lack of controllability, current methods produce aerosols, gases that require extra safety precautions to handle.
The researchers created the acoustic wave cell-sorting chip using a layer of silicone — polydimethylsiloxane. According to Huang, two parallel transducers, which convert alternating current into acoustic waves, were placed at the sides of the chip. As the acoustic waves interfere with each other, they form pressure nodes on the chip. As cells cross the chip, they are channelled toward these pressure nodes.
The transducers are tuneable, which allows researchers to adjust the frequencies and create pressure nodes on the chip.
The researchers first tested the device by sorting a stream of fluorescent polystyrene beads into three channels. Prior to turning on the transducer, the particles flowed across the chip unimpeded. Once the transducer produced the acoustic waves, the particles were separated into the channels.
Following this experiment, the researchers sorted human white blood cells that were affected by leukaemia. The leukaemia cells were first focused into the main channel and then separated into five channels.
The device is not limited to five channels, according to Huang.
‘We can do more,’ Huang said. ‘We could do 10 channels if we want, we just used five because we thought it was impressive enough to show that the concept worked.’
Penn State
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A research team led by the University of Iowa has created the most detailed, three-dimensional rendering of a mammal lung…Amidst the extraordinarily dense network of pathways in a mammal lung is a common destination. There, any road leads to a cul-de-sac of sorts called the pulmonary acinus. This place looks like a bunch of grapes attached to a stem (acinus means ‘berry’ in Latin).
Scientists have struggled to understand more specifically what happens in this microscopic, labyrinthine intersection of alleys and dead ends. To find out, a research team led by the University of Iowa created the most detailed, three-dimensional rendering of the pulmonary acinus. The computerised model, derived from mice, faithfully mimics each twist and turn in this region, including the length, direction and angles of the respiratory branches that lead to the all-important air sacs called alveoli.
The model is important, because it can help scientists understand where and how lung diseases emerge as well as the role the pulmonary acinus plays in the delivery of drugs, such as those commonly administered with inhalers.
‘These methods allow us to understand where in the lung periphery disease begins and how it progresses,’ says Eric Hoffman, professor in the departments of radiology, medicine, and biomedical engineering at the UI and corresponding author on the paper. ‘How do gases and inhaled substances get there and do they accumulate in one or another acinus? How do they swirl around and clear out? We just don’t have a complete understanding how that happens.’
As an example, Hoffman said the model could be used to determine how smoking-induced emphysema originates. ‘It has been hypothesised recently that it begins with the loss of peripheral airways rather than the lung air sacs,’ he says, citing ongoing research by James Hogg at the University of British Columbia, who was not involved in this study. It also could shed light and lead to more effective treatment of chronic obstructive pulmonary disease, which causes irreversible damage to the lung, says Dragos Vasilescu, first author on the paper who based his thesis on the research while a graduate student at the UI.
For years, the best that lung anatomy pioneers such as study co-corresponding author Ewald Weibel, professor emeritus of anatomy at the University of Bern, could do to study specific areas of a lung was to make measurements in two dimensions or create 3D casts of a lung’s air spaces. The techniques, while giving the earliest insights into a lungs’s makeup and functioning, had their limitations. For one, they did not directly replicate a lung’s structure in real life, and they could not convey how various parts act together as a whole. Yet advances in imaging and computation have enabled researchers to more fully explore how gases and other inhaled substances act in the lung’s furthest recesses.
In this study, the team worked with 22 pulmonary acini culled from young and old mice. They then set to ‘reconstruct’ the acini based on micro computed tomography imaging of scanned lungs in mice and extracted from them. The extracted lungs were preserved in a way that kept the anatomy intact—including the tiny air spaces required for successful imaging. From that, the researchers were able to measure an acinus, estimate the number of acini for each mouse lung and even count the alveoli and measure their surface area.
The mouse lung, in its structure and function, is remarkably similar to the human lung. That means researchers can alter the genetics of a mouse and see how those changes affect the peripheral structure of the lung and its performance.
Already, the researchers found in the current study that mouse alveoli increase in number long past the two weeks that at least one previous study had indicated. Hoffman adds that a separate study is needed to determine whether humans, too, increase the number of air sacs past a certain, predetermined age.
The researchers next aim to use the model to more fully understand how gases interact with the bloodstream within the acini and the alveoli.
University of Iowa
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Researchers at Mount Sinai School of Medicine have shown for the first time in an animal model that vitamin C actively protects against osteoporosis, a disease affecting large numbers of elderly women and men in which bones become brittle and can fracture.
‘This study has profound public health implications, and is well worth exploring for its therapeutic potential in people,’ said lead researcher Mone Zaidi, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease, and of Structural and Chemical Biology, and Director of the Mount Sinai Bone Program.
‘The medical world has known for some time that low amounts of vitamin C can cause scurvy and brittle bones, and that higher vitamin C intake is associated with higher bone mass in humans, ‘said Dr. Zaidi. ‘What this study shows is that large doses of vitamin C, when ingested orally by mice, actively stimulate bone formation to protect the skeleton. It does this by inducing osteoblasts, or premature bone cells, to differentiate into mature, mineralising speciality cells.’
The researchers worked with groups of mice whose ovaries had been removed, a procedure known to reduce bone density, and compared them with control mice that had ‘sham’ operations, which left their ovaries intact. The mice with ovariectomies were divided into two groups, one of which was given large doses of vitamin C over eight weeks. The scientists measured the bone mineral density in the lumbar spine, femur, and tibia bones.
The mice who received an ovariectomy – and no vitamin C – had a much lower bone mineral density (BMD) versus controls, whereas mice who received a ovariectomy and large doses of vitamin C, had roughly the same BMD as the controls, suggesting vitamin C prevented BMD loss in this group.
‘Further research may discover that dietary supplements may help prevent osteoporosis in humans,’ said Dr. Zaidi. ‘If so, the findings could be ultimately useful to developing nations where osteoporosis is prevalent and standard medications are sparse and expensive.’
The Mount Sinai Medical Center
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Chronic kidney disease changes the composition of intestinal bacterial microbes that normally play a crucial role in staving off disease-causing pathogens and maintaining micro-nutrient balance, according to UC Irvine researchers.
This profound alteration of the gut microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in patients with advanced renal disease, they said.
Study leader Dr. N.D. Vaziri of the UCI School of Medicine’s Division of Nephrology & Hypertension noted that consumption of high-fibre foods and better control of uremia — a disease common in kidney failure — by diet and dialysis may improve the composition of gut microbes and the well-being of patients.
The researchers studied microbial DNA extracted from the stool samples of a group of renal failure patients and healthy control individuals. They found marked differences in the abundance of some 190 types of bacteria in the gut microbiome of those with kidney disease — and confirmed the results in a concurrent study of rats with and without chronic kidney disease.
Vaziri explained that nitrogen-rich waste products — particularly urea and uric acid, which are usually excreted by the kidneys — accumulate in the body fluids of patients with renal failure. This leads to the massive release of these waste products in the gastrointestinal tract, supporting the growth and dominance of microbial species that can utilise these compounds.
The impact of this flooding of the gut by nitrogenous waste products in patients with advanced kidney disease, Vaziri added, is compounded by dietary restrictions on fruits and vegetables, which contain the indigestible fibres that favourable gut microbes feed on. This is because fruits and vegetables contain large amounts of potassium, a mineral normally excreted by the kidneys. In cases of renal failure, potassium levels are high, increasing the risk of cardiac arrest.
One solution, Vaziri said, is to provide longer, more frequent dialysis treatments. This would let more potassium be removed by dialysis and allow for more potassium in the diet. Alternatively, packaged fibre foods that do not contain potassium could be used as a dietary supplement.
The work adds to a growing body of evidence pointing to the role of gut bacteria in disease and health. Recent research by other groups has identified changes in the composition of intestinal microbial flora in people with diabetes, colorectal cancer, obesity and inflammatory bowel disease, among other conditions.
University of California, Irvine
A newly discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent pre-clinical study suggests.
The team, led by Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression. PARP inhibition in various models was found to suppress AR activity, which fuels prostate growth.
Researchers believe that the dual functions of PARP-1—as both a regulator of AR as well as critical for DNA damage repair—could be leveraged for therapeutic benefit. PARP inhibitors could slow down advanced-stage prostate cancer and shrink tumours, the team surmises.
‘We hope to capitalise on this previously unknown function in PARP-1 in prostate cancer,’ said Dr. Knudsen. ‘Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumour effects of castration and delayed onset to castration resistance. ‘
‘This is the basis to support a clinical trial investigating PARP-1 inhibitors in patients with advanced disease,’ she added.
Today, PARP-1 is seen as a valuable target because of its involvement in DNA damage repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumour growth by stopping DNA repair in various cancers.
Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumours arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.
Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, PARP inhibitors targeting both functions could sensitise prostate cancer cells to DNA damage, and potentially improve the efficacy of AR-directed therapies in these patients, the researchers suggest in the paper.
Almost 40 percent of men with prostate cancer progress into an advanced stage, termed castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.
Using various in vitro and in vivo model systems, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer. Additionally, inhibiting PARP-1 suppressed proliferation of cultured, primary human tumour specimens in a state-of-the-art system.
Jefferson’s Kimmel Cancer Center
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Scientists at the Montreal Neurological Institute and Hospital – The Neuro, McGill University working with a team at Oxford University have uncovered the genetic defect underlying a group of rare genetic disorders.
Using a new technique that has revolutionised genetic studies, the teams determined that mutations in the RMND1 gene were responsible for severe neurodegenerative disorders, in two infants, ultimately leading to their early death. Although the teams’ investigations dealt with an infant, their discovery also has implications for understanding the causes of later-onset neurological diseases.
The RMND1 gene encodes a protein that is an important component of the machinery in mitochondria which generates the chemical energy that all cells need to function. Mutations in genes affecting mitochondrial function are common causes of neurological and neuromuscular disorders in adults and children. It is estimated that one newborn baby out of 5000 is at risk for developing one of these disorders. Mortality among such cases is very high.
‘Mitochondria are becoming a focus of research because it’s clear they’re involved in neurodegenerative disorders in a fairly big way,’ says Dr. Eric Shoubridge, an internationally recognised specialist on mitochondrial diseases at The Neuro and lead author of the paper published.
‘For instance, we’re finding that dysfunctional mitochondria may be at the heart of adult-onset disorders like Parkinson’s and Alzheimer’s disease.’
Discovery of the mutations in the RMND1 gene involved using whole-exome sequencing at the McGill University and Genome Québec Innovation Centre. This technique allows all of the genes in the body that code for proteins to be sequenced and analysed in a single experiment. At a cost of about $1000, whole-exome sequencing is much more economical than previous techniques in which lists of candidate genes had to be screened in the search for mutations. The technique is poised to change the face of genetic diagnosis, making testing more efficient and available.
‘Parents who have had a child with a mitochondrial disorder and who are hesitating to have another child now have the possibility to know the cause of the disease. With genetic information, they have reproductive options like in vitro fertilisation,’ says Dr. Shoubridge. The discovery of the RMND1 gene’s role sheds light on disorders of mitochondrial energy metabolism, but therapies to alleviate or cure such disorders remain elusive. Dr. Shoubridge is hopeful that the discovery will encourage pharmaceutical interest. ‘Drug companies are starting to be interested in rare diseases and metabolic disorders like this. They’re picking some genes as potential drug candidates.’
EurekAlert
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Oscillating microscopic beads could be key to biolab on a chip
, /in E-News /by 3wmediaIf you throw a ball underwater, you’ll find that the smaller it is, the faster it moves: A larger cross-section greatly increases the water’s resistance. Now, a team of MIT researchers has figured out a way to use this basic principle, on a microscopic scale, to carry out biomedical tests that could eventually lead to fast, compact and versatile medical-testing devices.
The results is based on work by graduate student Elizabeth Rapoport and assistant professor Geoffrey Beach, of MIT’s Department of Materials Science and Engineering (DMSE).
The balls used here are microscopic magnetic beads that can be ‘decorated’ with biomolecules such as antibodies that cause them to bind to specific proteins or cells; such beads are widely used in biomedical research. The key to this new work was finding a way to capture individual beads and set them oscillating by applying a variable magnetic field. The rate of their oscillation can then be measured to assess the size of the beads.
When these beads are placed in a biological sample, biomolecules attach to their surfaces, making the beads larger — a change that can then be detected through the biomolecules effect on the beads’ oscillation. This would provide a way to detect exactly how much of a target biomolecule is present in a sample, and provide a way to give a virtually instantaneous electronic readout of that information.
This new technique, for the first time, allows these beads — each about one micrometer, or millionth of a meter, in diameter — to be used for precise measurements of tiny quantities of materials. This could, for example, lead to tests for disease agents that would need just a tiny droplet of blood and could deliver results instantly, instead of requiring laboratory analysis. MIT
When the ‘fire brigade’ arrives too late
, /in E-News /by 3wmediaNew insights into certain muscle diseases, the filaminopathies, are reported by an international research team led by Dr. Rudolf Andre Kley of the RUB’s University Hospital Bergmannsheil in the journal Brain. The scientists from the Neuromuscular Centre Ruhrgebiet (headed by Prof. Matthias Vorgerd) at the Neurological University Clinic (Director: Prof. Martin Tegenthoff) cooperated with colleagues from eleven institutes in seven countries. Among other things they found that protection mechanisms to combat abnormal protein deposits do not work properly in filaminopathy patients. This opens up new starting points for therapies that the team aims to test on cell cultures.
Mutations in the filamin C gene (FLNC) cause filaminopathies, which are manifested through progressive muscle weakness to the point of loss of the ability to walk. Muscle fibres are composed of myofibrils, for the development and maintenance of which the protein filamin C is crucial. The mutations examined in the study bring about a so-called myofibrillar myopathy: the myofibrils disintegrate in certain places and mutant filamin C and other proteins aggregate massively in the muscle fibres.
The researchers showed that the diseased protein deposits interfere with the protein degradation usually occurring in cells. Normally, cells produce what are known as heat shock proteins, which promote the degradation of protein deposits and make sure that other proteins assume their correct three-dimensional structure. ‘However, these protection mechanisms only seem to be increasingly activated when the critical point is exceeded. It looks as if the ‘fire brigade’ was called too late’, says Dr. Kley. ‘We hope to positively influence the course of the disease by means of early treatment with substances that stimulate the production of heat shock proteins or affect the protein degradation in other ways. To study this, we have developed a cell culture model that allows us to carry out the first therapy studies in the laboratory.’
The study of filaminopathy patients also enables the researchers to describe the disease more accurately now. The heart is more affected by the disease than previously thought, which may cause sudden cardiac death. It was also confirmed that pathological remodelling processes in the leg muscles conform to a specific pattern, which is visible on magnetic resonance imaging pictures. ‘This enables us to distinguish filaminopathies from other muscle diseases within the group of myofibrillar myopathies’, explains Dr. Kley. Ruhr-University Bochum
Sticky paper offers cheap, easy solution for paper-based diagnostics
, /in E-News /by 3wmediaA current focus in global health research is to make medical tests that are not just cheap, but virtually free. One such strategy is to start with paper – one of humanity’s oldest technologies – and build a device like a home-based pregnancy test that might work for malaria, diabetes or other diseases.
A University of Washington bioengineer recently developed a way to make regular paper stick to medically interesting molecules. The work produced a chemical trick to make paper-based diagnostics using plain paper, the kind found at office supply stores around the world.
‘We wanted to go for the simplest, cheapest starting material, and give it more capability,’ said Daniel Ratner, a UW assistant professor of bioengineering and lead author of the paper
‘We also wanted to make the system as independent of the end applications as possible, something any researcher could plug into.’
Many paper-based diagnostics are made from nitrocellulose, a sticky membrane used in pregnancy tests and by medical researchers to detect proteins, DNA or antibodies in the human immune system.
Ratner hopes to replace that specialised membrane with cheap, ubiquitous paper, and to use it for any type of medical test – not just the big, biological molecules.
The UW technique uses minimal equipment or know-how. The researchers used a cheap, industrial solvent called divinyl sulfone that can be bought by the gallon and has been used for decades as an adhesive. Ratner’s group discovered they could dilute the chemical in water, carefully control the acidity, then pour it into a Ziploc bag and add a stack of paper, shake for a couple of hours, and finally rinse the paper and let it dry.
The dried paper feels smooth to the touch but is sticky to all kinds of chemicals that could be of medical interest: proteins, antibodies and DNA, for example, as well as sugars and the small-molecule drugs used to treat most medical conditions.
‘We want to develop something to not just ask a single question but ask many personal health questions,’ Ratner said. ‘‘Is there protein in the urine? Is this person diabetic? Do they have malaria or influenza?’’
To test their idea, the researchers ran the treated paper through an inkjet printer where the cartridge ink had been replaced with biomolecules, in this case a small sugar called galactose that attaches to human cells. They printed the biomolecules onto the sticky paper in an invisible pattern. Exposing that paper to fluorescent ricin, a poison that sticks to galactose, showed that the poison was present.
Now that they have proven their concept, Ratner said, they hope other groups will use the paper to develop actual diagnostic tests. University of Washington
People with schizophrenia more likely to die of heart attack
, /in E-News /by 3wmediaThe risk of death resulting from heart attack is higher in people with schizophrenia than in the general public, according to scientists at the Centre for Addiction and Mental Health (CAMH) and the Institute for Clinical Evaluative Sciences (ICES).
On average, people with schizophrenia have a life-span 20 years shorter than the general population. This is partly due to factors such as smoking, increased rates of diabetes, and metabolic problems brought on by the use of some anti-psychotic medications. These factors often worsen once a cardiac condition arises because people with schizophrenia are less likely to make the necessary lifestyle changes, such as diet and exercise, to offset the problem.
This study examined mortality and access to cardiac care after heart attacks (acute myocardial infarction) in those with schizophrenia.
Dr. Paul Kurdyak, Chief, Division of General and Health Systems Psychiatry at CAMH, analysed four years of Ontario-wide patient data and tracked all incidents of heart attack among people with schizophrenia, and compared results to people without schizophrenia.
‘When we looked at the data, we found that people with schizophrenia were 56 per cent more likely to die after discharge from hospital following a heart attack than those who did not have schizophrenia,’ says Dr. Kurdyak, also an Adjunct Scientist at ICES. ‘We also found that patients with schizophrenia, despite the increase in mortality risk after a heart attack, were half as likely to receive life-saving cardiac procedures and care from cardiologists than those without schizophrenia.’
Specifically, the study found that people with schizophrenia were 50 per cent less likely to receive cardiac procedures or to see a cardiologist within 30 days of discharge from hospital.
‘The numbers tell us that people with schizophrenia– the ones who are at most risk to develop and subsequently die from heart attacks — are not receiving adequate care,’ says Dr. Kurdyak. ‘The possible solutions are two-fold: prevention is one. We need to support patients whom we know are at risk of developing medication-related metabolic issues by working with them to provide strategies to offset weight gain, such as healthy eating and physical activity. The other part is aftercare – the mental health care team, primary care providers, and the cardiac specialists need to work together to ensure that patients are seen again after a first incident of heart attack.’ EurekAlert
Acoustic cell-sorting chip may lead to cell phone-sized medical labs
, /in E-News /by 3wmediaA technique that uses acoustic waves to sort cells on a chip may create miniature medical analytic devices that could make Star Trek’s tricorder seem a bit bulky in comparison, according to a team of researchers.
The device uses two beams of acoustic — or sound — waves to act as acoustic tweezers and sort a continuous flow of cells on a dime-sized chip, said Tony Jun Huang, associate professor of engineering science and mechanics, Penn State. By changing the frequency of the acoustic waves, researchers can easily alter the paths of the cells.
Huang said that since the device can sort cells into five or more channels, it will allow more cell types to be analysed simultaneously, which paves the way for smaller, more efficient and less expensive analytic devices.
‘Eventually, you could do analysis on a device about the size of a cell phone,’ said Huang. ‘It’s very doable and we’re making in-roads to that right now.’
Biological, genetic and medical labs could use the device for various types of analysis, including blood and genetic testing, Huang said.
Most current cell-sorting devices allow the cells to be sorted into only two channels in one step, according to Huang. He said that another drawback of current cell-sorting devices is that cells must be encapsulated into droplets, which complicates further analysis.
‘Today, cell sorting is done on bulky and very expensive devices,’ said Huang. ‘We want to minimise them so they are portable, inexpensive and can be powered by batteries.’
Using sound waves for cell sorting is less likely to damage cells than current techniques, Huang added.
In addition to the inefficiency and the lack of controllability, current methods produce aerosols, gases that require extra safety precautions to handle.
The researchers created the acoustic wave cell-sorting chip using a layer of silicone — polydimethylsiloxane. According to Huang, two parallel transducers, which convert alternating current into acoustic waves, were placed at the sides of the chip. As the acoustic waves interfere with each other, they form pressure nodes on the chip. As cells cross the chip, they are channelled toward these pressure nodes.
The transducers are tuneable, which allows researchers to adjust the frequencies and create pressure nodes on the chip.
The researchers first tested the device by sorting a stream of fluorescent polystyrene beads into three channels. Prior to turning on the transducer, the particles flowed across the chip unimpeded. Once the transducer produced the acoustic waves, the particles were separated into the channels.
Following this experiment, the researchers sorted human white blood cells that were affected by leukaemia. The leukaemia cells were first focused into the main channel and then separated into five channels.
The device is not limited to five channels, according to Huang.
‘We can do more,’ Huang said. ‘We could do 10 channels if we want, we just used five because we thought it was impressive enough to show that the concept worked.’ Penn State
A mammal lung, in 3D
, /in E-News /by 3wmediaA research team led by the University of Iowa has created the most detailed, three-dimensional rendering of a mammal lung…Amidst the extraordinarily dense network of pathways in a mammal lung is a common destination. There, any road leads to a cul-de-sac of sorts called the pulmonary acinus. This place looks like a bunch of grapes attached to a stem (acinus means ‘berry’ in Latin).
Scientists have struggled to understand more specifically what happens in this microscopic, labyrinthine intersection of alleys and dead ends. To find out, a research team led by the University of Iowa created the most detailed, three-dimensional rendering of the pulmonary acinus. The computerised model, derived from mice, faithfully mimics each twist and turn in this region, including the length, direction and angles of the respiratory branches that lead to the all-important air sacs called alveoli.
The model is important, because it can help scientists understand where and how lung diseases emerge as well as the role the pulmonary acinus plays in the delivery of drugs, such as those commonly administered with inhalers.
‘These methods allow us to understand where in the lung periphery disease begins and how it progresses,’ says Eric Hoffman, professor in the departments of radiology, medicine, and biomedical engineering at the UI and corresponding author on the paper. ‘How do gases and inhaled substances get there and do they accumulate in one or another acinus? How do they swirl around and clear out? We just don’t have a complete understanding how that happens.’
As an example, Hoffman said the model could be used to determine how smoking-induced emphysema originates. ‘It has been hypothesised recently that it begins with the loss of peripheral airways rather than the lung air sacs,’ he says, citing ongoing research by James Hogg at the University of British Columbia, who was not involved in this study. It also could shed light and lead to more effective treatment of chronic obstructive pulmonary disease, which causes irreversible damage to the lung, says Dragos Vasilescu, first author on the paper who based his thesis on the research while a graduate student at the UI.
For years, the best that lung anatomy pioneers such as study co-corresponding author Ewald Weibel, professor emeritus of anatomy at the University of Bern, could do to study specific areas of a lung was to make measurements in two dimensions or create 3D casts of a lung’s air spaces. The techniques, while giving the earliest insights into a lungs’s makeup and functioning, had their limitations. For one, they did not directly replicate a lung’s structure in real life, and they could not convey how various parts act together as a whole. Yet advances in imaging and computation have enabled researchers to more fully explore how gases and other inhaled substances act in the lung’s furthest recesses.
In this study, the team worked with 22 pulmonary acini culled from young and old mice. They then set to ‘reconstruct’ the acini based on micro computed tomography imaging of scanned lungs in mice and extracted from them. The extracted lungs were preserved in a way that kept the anatomy intact—including the tiny air spaces required for successful imaging. From that, the researchers were able to measure an acinus, estimate the number of acini for each mouse lung and even count the alveoli and measure their surface area.
The mouse lung, in its structure and function, is remarkably similar to the human lung. That means researchers can alter the genetics of a mouse and see how those changes affect the peripheral structure of the lung and its performance.
Already, the researchers found in the current study that mouse alveoli increase in number long past the two weeks that at least one previous study had indicated. Hoffman adds that a separate study is needed to determine whether humans, too, increase the number of air sacs past a certain, predetermined age.
The researchers next aim to use the model to more fully understand how gases interact with the bloodstream within the acini and the alveoli. University of Iowa
Study shows Vitamin C prevents bone loss in animal models
, /in E-News /by 3wmediaResearchers at Mount Sinai School of Medicine have shown for the first time in an animal model that vitamin C actively protects against osteoporosis, a disease affecting large numbers of elderly women and men in which bones become brittle and can fracture.
‘This study has profound public health implications, and is well worth exploring for its therapeutic potential in people,’ said lead researcher Mone Zaidi, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease, and of Structural and Chemical Biology, and Director of the Mount Sinai Bone Program.
‘The medical world has known for some time that low amounts of vitamin C can cause scurvy and brittle bones, and that higher vitamin C intake is associated with higher bone mass in humans, ‘said Dr. Zaidi. ‘What this study shows is that large doses of vitamin C, when ingested orally by mice, actively stimulate bone formation to protect the skeleton. It does this by inducing osteoblasts, or premature bone cells, to differentiate into mature, mineralising speciality cells.’
The researchers worked with groups of mice whose ovaries had been removed, a procedure known to reduce bone density, and compared them with control mice that had ‘sham’ operations, which left their ovaries intact. The mice with ovariectomies were divided into two groups, one of which was given large doses of vitamin C over eight weeks. The scientists measured the bone mineral density in the lumbar spine, femur, and tibia bones.
The mice who received an ovariectomy – and no vitamin C – had a much lower bone mineral density (BMD) versus controls, whereas mice who received a ovariectomy and large doses of vitamin C, had roughly the same BMD as the controls, suggesting vitamin C prevented BMD loss in this group.
‘Further research may discover that dietary supplements may help prevent osteoporosis in humans,’ said Dr. Zaidi. ‘If so, the findings could be ultimately useful to developing nations where osteoporosis is prevalent and standard medications are sparse and expensive.’ The Mount Sinai Medical Center
Chronic kidney disease alters intestinal microbial flora
, /in E-News /by 3wmediaChronic kidney disease changes the composition of intestinal bacterial microbes that normally play a crucial role in staving off disease-causing pathogens and maintaining micro-nutrient balance, according to UC Irvine researchers.
This profound alteration of the gut microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in patients with advanced renal disease, they said.
Study leader Dr. N.D. Vaziri of the UCI School of Medicine’s Division of Nephrology & Hypertension noted that consumption of high-fibre foods and better control of uremia — a disease common in kidney failure — by diet and dialysis may improve the composition of gut microbes and the well-being of patients.
The researchers studied microbial DNA extracted from the stool samples of a group of renal failure patients and healthy control individuals. They found marked differences in the abundance of some 190 types of bacteria in the gut microbiome of those with kidney disease — and confirmed the results in a concurrent study of rats with and without chronic kidney disease.
Vaziri explained that nitrogen-rich waste products — particularly urea and uric acid, which are usually excreted by the kidneys — accumulate in the body fluids of patients with renal failure. This leads to the massive release of these waste products in the gastrointestinal tract, supporting the growth and dominance of microbial species that can utilise these compounds.
The impact of this flooding of the gut by nitrogenous waste products in patients with advanced kidney disease, Vaziri added, is compounded by dietary restrictions on fruits and vegetables, which contain the indigestible fibres that favourable gut microbes feed on. This is because fruits and vegetables contain large amounts of potassium, a mineral normally excreted by the kidneys. In cases of renal failure, potassium levels are high, increasing the risk of cardiac arrest.
One solution, Vaziri said, is to provide longer, more frequent dialysis treatments. This would let more potassium be removed by dialysis and allow for more potassium in the diet. Alternatively, packaged fibre foods that do not contain potassium could be used as a dietary supplement.
The work adds to a growing body of evidence pointing to the role of gut bacteria in disease and health. Recent research by other groups has identified changes in the composition of intestinal microbial flora in people with diabetes, colorectal cancer, obesity and inflammatory bowel disease, among other conditions. University of California, Irvine
Doubling up on advanced prostate cancer with PARP inhibitors
, /in E-News /by 3wmediaA newly discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent pre-clinical study suggests.
The team, led by Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression. PARP inhibition in various models was found to suppress AR activity, which fuels prostate growth.
Researchers believe that the dual functions of PARP-1—as both a regulator of AR as well as critical for DNA damage repair—could be leveraged for therapeutic benefit. PARP inhibitors could slow down advanced-stage prostate cancer and shrink tumours, the team surmises.
‘We hope to capitalise on this previously unknown function in PARP-1 in prostate cancer,’ said Dr. Knudsen. ‘Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumour effects of castration and delayed onset to castration resistance. ‘
‘This is the basis to support a clinical trial investigating PARP-1 inhibitors in patients with advanced disease,’ she added.
Today, PARP-1 is seen as a valuable target because of its involvement in DNA damage repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumour growth by stopping DNA repair in various cancers.
Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumours arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.
Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, PARP inhibitors targeting both functions could sensitise prostate cancer cells to DNA damage, and potentially improve the efficacy of AR-directed therapies in these patients, the researchers suggest in the paper.
Almost 40 percent of men with prostate cancer progress into an advanced stage, termed castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.
Using various in vitro and in vivo model systems, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer. Additionally, inhibiting PARP-1 suppressed proliferation of cultured, primary human tumour specimens in a state-of-the-art system. Jefferson’s Kimmel Cancer Center
Scientists discover gene behind rare disorders
, /in E-News /by 3wmediaScientists at the Montreal Neurological Institute and Hospital – The Neuro, McGill University working with a team at Oxford University have uncovered the genetic defect underlying a group of rare genetic disorders.
Using a new technique that has revolutionised genetic studies, the teams determined that mutations in the RMND1 gene were responsible for severe neurodegenerative disorders, in two infants, ultimately leading to their early death. Although the teams’ investigations dealt with an infant, their discovery also has implications for understanding the causes of later-onset neurological diseases.
The RMND1 gene encodes a protein that is an important component of the machinery in mitochondria which generates the chemical energy that all cells need to function. Mutations in genes affecting mitochondrial function are common causes of neurological and neuromuscular disorders in adults and children. It is estimated that one newborn baby out of 5000 is at risk for developing one of these disorders. Mortality among such cases is very high.
‘Mitochondria are becoming a focus of research because it’s clear they’re involved in neurodegenerative disorders in a fairly big way,’ says Dr. Eric Shoubridge, an internationally recognised specialist on mitochondrial diseases at The Neuro and lead author of the paper published.
‘For instance, we’re finding that dysfunctional mitochondria may be at the heart of adult-onset disorders like Parkinson’s and Alzheimer’s disease.’
Discovery of the mutations in the RMND1 gene involved using whole-exome sequencing at the McGill University and Genome Québec Innovation Centre. This technique allows all of the genes in the body that code for proteins to be sequenced and analysed in a single experiment. At a cost of about $1000, whole-exome sequencing is much more economical than previous techniques in which lists of candidate genes had to be screened in the search for mutations. The technique is poised to change the face of genetic diagnosis, making testing more efficient and available.
‘Parents who have had a child with a mitochondrial disorder and who are hesitating to have another child now have the possibility to know the cause of the disease. With genetic information, they have reproductive options like in vitro fertilisation,’ says Dr. Shoubridge. The discovery of the RMND1 gene’s role sheds light on disorders of mitochondrial energy metabolism, but therapies to alleviate or cure such disorders remain elusive. Dr. Shoubridge is hopeful that the discovery will encourage pharmaceutical interest. ‘Drug companies are starting to be interested in rare diseases and metabolic disorders like this. They’re picking some genes as potential drug candidates.’ EurekAlert