High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding

Main Category: Cardiovascular / Cardiology
Also Included In: Medical Devices / Diagnostics;  Blood / Hematology
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding

Patients who receive a drug-eluting stent (DES) and demonstrate high platelet reactivity on clopidogrel are more likely to have blood clots form on the stent and to suffer a heart attack; however, these patients are less likely to develop bleeding complications. One-year results of the ADAPT-DES trial was published online in The Lancet. The findings were first presented at last year's Transcatheter Cardiovascular Therapeutics (TCT) annual scientific symposium.

ADAPT-DES is the largest study ever to explore the overall treatment implications of platelet reactivity on patient outcomes after successful coronary drug-eluting stent implantation. Researchers investigated the relationship between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes such as stent thrombosis, major bleeding, and other adverse events.

The study enrolled 8,583 patients at 11 sites in the US and Germany who underwent a percutaneous coronary intervention (PCI) with at least one drug-eluting stent between January 7, 2008, and September 16, 2010. Researchers assessed platelet reactivity with the VerifyNow Aspirin, P2Y12, and IIb/IIIa tests. Patients were followed for one year to determine the relationship between platelet reactivity and subsequent events. At one year, stent thrombosis had occurred in 70 patients (0.8 percent), heart attack in 269 (3.1 percent), major bleeding in 531 (6.2 percent), and death in 161 (1.9 percent).

Platelet reactivity units (PRU), an index of platelet inhibition to clopidogrel, were measured by the VerifyNow P2Y12 test. High platelet reactivity, defined as a PRU of greater than 208, was present in 42.7 percent of patients. At one year, researchers found that high platelet reactivity was significantly associated with stent thrombosis (1.3 percent vs. 0.5 percent) and heart attack (3.9 percent vs. 2.7 percent), but was also found to be protective against major bleeding (5.6 percent vs. 6.7 percent). High platelet reactivity was also associated with one-year mortality (2.4 percent vs. 1.5 percent). However, because high platelet reactivity is also associated with other patient risk factors and baseline characteristics, multivariable modeling was also performed; it showed no independent association between high platelet reactivity and mortality.

"Results from the ADAPT-DES registry definitely demonstrate that high platelet reactivity after implantation of drug-eluting stents is an independent predictor of one-year stent thrombosis and heart attack, but it is also protective against major bleeding, both of which impact mortality," said lead investigator Gregg W. Stone, MD. Dr Stone is professor of medicine at Columbia University College of Physicians and Surgeons and Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian Hospital/Columbia University Medical Center. Dr. Stone is also co-director of the Medical Research and Education Division at the Cardiovascular Research Foundation (CRF).

"Because of the counteracting effects of ischemia and bleeding, platelet reactivity was not an independent predictor of one-year mortality. Therefore, overcoming high platelet reactivity with more potent antiplatelet agents is unlikely to improve survival unless the beneficial effect of reducing stent thrombosis and heart attack can be separated from the likely increase in bleeding that results from greater platelet inhibition," said Dr. Stone.

Dr. Stone added: "Platelet reactivity on aspirin was unrelated to stent thrombosis, heart attack, or death, but may be related to bleeding. This raises questions as to the utility of aspirin in patients treated with drug-eluting stents."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

The ADAPT-DES trial was sponsored by CRF with research support from Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi Sankyo, Eli Lilly, Volcano, and Accumetrics.

Cardiovascular Research Foundation

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Foundation, Cardiovascular Research. "High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'High platelet reactivity on clopidogrel predicts stent thrombosis, heart attack, and bleeding'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Hope for motion sickness victims: Key neurons identified that sense unexpected movement

Main Category: Neurology / Neuroscience
Also Included In: Public Health
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Hope for motion sickness victims: Key neurons identified that sense unexpected movement

It happens to all of us at least once each winter in Montreal. You're walking on the sidewalk and before you know it you are slipping on a patch of ice hidden under a dusting of snow. Sometimes you fall. Surprisingly often you manage to recover your balance and walk away unscathed. McGill researchers now understand what's going on in the brain when you manage to recover your balance in these situations. And it is not just a matter of good luck.

Prof. Kathleen Cullen and her PhD student Jess Brooks of the Dept of Physiology have been able to identify a distinct and surprisingly small cluster of cells deep within the brain that react within milliseconds to readjust our movements when something unexpected happens, whether it is slipping on ice or hitting a rock when skiing. What is astounding is that each individual neuron in this tiny region that is smaller than a pin's head displays the ability to predict and selectively respond to unexpected motion.

This finding both overturns current theories about how we learn to maintain our balance as we move through the world, and also has significant implications for understanding the neural basis of motion sickness.

Scientists have theorized for some time that we fine-tune our movements and maintain our balance, thanks to a neural library of expected motions that we gain through "sensory conflicts" and errors. "Sensory conflicts" occur when there is a mismatch between what we think will happen as we move through the world and the sometimes contradictory information that our senses provide to us about our movements.

This kind of "sensory conflict" may occur when our bodies detect motion that our eyes cannot see (such as during plane, ocean or car travel), or when our eyes perceive motion that our bodies cannot detect (such as during an IMAX film, when the camera swoops at high speed over the edge of steep cliffs and deep into gorges and valleys while our bodies remain sitting still). These "sensory conflicts" are also responsible for the feelings of vertigo and nausea that are associated with motion sickness.

But while the areas of the brain involved in estimating spatial orientation have been identified for some time, until now, no one has been able to either show that distinct neurons signaling "sensory conflicts" existed, nor demonstrate exactly how they work. "We've known for some time that the cerebellum is the part of the brain that takes in sensory information and then causes us to move or react in appropriate ways," says Prof. Cullen. "But what's really exciting is that for the first time we show very clearly how the cerebellum selectively encodes unexpected motion, to then send our body messages that help us maintain our balance. That it is such a very exact neural calculation is exciting and unexpected."

By demonstrating that these "sensory conflict" neurons both exist and function by making choices "on the fly" about which sensory information to respond to, Cullen and her team have made a significant advance in our understanding of how the brain works to keep our bodies in balance as we move about.

The research was done by recording brain activity in macaque monkeys who were engaged in performing specific tasks while at the same time being unexpectedly moved around by flight-simulator style equipment.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our neurology / neuroscience section for the latest news on this subject.

To read the full paper in Current Biology click here.

The research was funded by the Fonds de Recherche du Québec Nature et Technologies and Canadian Institutes of Health Research as well as through a National Institutes of Health grant.

McGill University

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University, McGill. "Hope for motion sickness victims: Key neurons identified that sense unexpected movement." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Hope for motion sickness victims: Key neurons identified that sense unexpected movement'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Hospital screening tool for suicide risk among self-harmers should be ditched, UK

Main Category: Mental Health
Also Included In: Psychology / Psychiatry;  Medical Devices / Diagnostics
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Hospital screening tool for suicide risk among self-harmers should be ditched, UK

A screening tool used in general hospitals to detect suicide risk among patients who have self harmed should be ditched, concludes a study published online in Emergency Medicine Journal.

The technique (SADPERSONS Scale) fails to pick up most of those who require admission to a psychiatric unit, community psychiatric aftercare, or to determine those at risk of self harming again, say the researchers.

The SADPERSONS Scale was developed in the USA in 1983 as a means of assessing suicide risk among patients who had self harmed. It is based on 10 major risk factors, but has changed little since it was first devised, say the researchers.

National guidance in England stipulates that all patients who go to hospital after an episode of self harm should be given a full psychosocial assessment. But current pressures in hospitals to meet waiting time targets, combined with a reduction in the availability of mental health services, mean that emergency care staff are increasingly minded to use rating scales to find out which patients can be discharged without a full psychosocial assessment, say the researchers.

They therefore assessed SADPERSONS scores that had been recorded for 126 patients consecutively admitted to one emergency medicine department in a major general hospital in Oxford during the summer of 2011, to see how accurate it was at predicting how these patients were subsequently managed and treated.

This included admission to a psychiatric unit, a proxy for psychosocial assessment; the provision of community psychiatric aftercare; and bouts of repeated self harm in the following six months.

Self harm was defined as any act of poisoning or injury, irrespective of its purpose. Most of the patients (102; 81%) had taken an overdose; around one in 10 (11%) had cut themselves; and the remaining 10 patients (8%) had inflicted other forms of injury on themselves.

Admission to a psychiatric unit was required in five cases (4%) and community psychiatric aftercare in just over half (55%; 70). One in four patients (24.6%) self harmed again at least once.

The SADPERSONS Scale only picked up 2% of those requiring admission to a psychiatric unit, around 6% of those needing community psychiatric aftercare, and just over 6.5% of those likely to self harm again.

The authors point out that for the purposes of suicide prevention, any technique designed to spot potential suicide risk must have a low rate of false negative results - in other words, it must be accurate and not miss most of those at risk of killing themselves.

While the small numbers of patients in this study don't allow any conclusions to be drawn about the Scale's usefulness in predicting suicide risk, the scores did not pick up very accurately those most at risk of further self harm, which is particularly associated with suicide risk, say the study authors.

Twenty three out of 31 of the episodes of self harm occurred within the first three months of the first visit to emergency care. But only two of these patients had high scores on the SADPERSONS Scale; the rest had low to moderate scores, suggesting they were not at high risk.

"The results clearly show that the SADPERSONS Scale has a very limited role, if any, to play in the assessment of patients presenting to the emergency department following an episode of self harm," write the authors.

"Indeed, arguably, our results show that reliance on the scale for determining who should receive a psychosocial assessment or otherwise using it for prediction is not only misleading, it could be dangerous," they add.

The use of rating scales has become increasingly widespread in response to the need to standardise practice for ever increasing numbers of patients. But these tools often overlook individual dynamics, they say.

"A greater focus on clinical judgement is needed, accompanied by the necessary education, training and supervision, if we are to more accurately fully identify and intervene with those who are at greatest risk following self harm," they conclude.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our mental health section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

MLA

BMJ. "Hospital screening tool for suicide risk among self-harmers should be ditched, UK." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Hospital screening tool for suicide risk among self-harmers should be ditched, UK'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

Main Category: Urology / Nephrology
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

A team led by researchers at the National Institutes of Health has overcome a major biological hurdle in an effort to find improved treatments for patients with a rare disease called methylmalonic acidemia (MMA). Using genetically engineered mice created for their studies, the team identified a set of biomarkers of kidney damage - a hallmark of the disorder - and demonstrated that antioxidant therapy protected kidney function in the mice.

Researchers at the National Human Genome Research Institute (NHGRI), part of NIH, validated the same biomarkers in 46 patients with MMA seen at the NIH Clinical Center. The biomarkers offer new tools for monitoring disease progression and the effects of therapies, both of which will be valuable in the researchers' design of clinical trials for this disease.

The discovery, reported in the July 29, 2013, advance online issue of the Proceedings of the National Academy of Sciences, paves the way for use of antioxidant therapy in a clinical trial for patients with MMA. It also illustrates the mechanisms by which dysfunction of mitochondria - the power generators of the cell - affects kidney disease. Mitochondrial dysfunction is a factor not only in rare disorders, such as MMA, but also in a wide variety of common conditions, such as obesity, diabetes and cancer.

MMA affects as many as one in 67,000 children born in the United States. It can have several different causes, all involving loss of function of a metabolic pathway that moderates levels of an organic compound called methylmalonic acid. Affected children are unable to properly metabolize certain amino acids consumed in their diet, which damages a number of organs, most notably the kidneys.

"Metabolic disorders like MMA are extremely difficult to manage because they perturb the delicate balance of chemicals that our bodies need to sustain health," said Daniel Kastner, M.D., Ph.D., NHGRI scientific director. "Given that every newborn in the United States is screened for a number of inherited metabolic disorders, including MMA, there is a critical need for better understanding of the disease mechanisms and therapies to treat them."

MMA is the most common organic acid disorder and invariably impairs kidney function, which can lead to kidney failure. The most common therapy is a restrictive diet, but doctors must resort to dialysis or kidney transplantation when the disease progresses. MMA patients also suffer from severe metabolic instability, failure to thrive, intellectual and physical disabilities, pancreatitis, anemia, seizures, vision loss and strokes.

"There are no definitive treatments for the management of patients with MMA," said Charles Venditti, M.D., Ph.D., senior author and investigator in the Organic Acid Research Section of NHGRI's Genetics and Molecular Biology Branch. "This study is the culmination of collaboration with the patient community. It uses mouse modelling, coupled with innovations in genomics and biochemical analyses, to derive new insights into the causes of renal injury in MMA. Our studies have improved our understanding of the basic biology underlying MMA, created a novel animal model for testing interventions and, now, led us to the promise of a new therapy."

The researchers performed the studies using mice bred to carry gene alterations that disrupt the production of the same mitochondrial enzyme that is defective in patients with MMA. These are called transgenic mice. The enzyme, called methylmalonyl-CoA mutase (MUT), is an important component of the chemical process that metabolizes organic acids, specifically methylmalonic acid.

By measuring gene expression in the transgenic mice using DNA microarrays, researchers discovered 50 biomarkers of gene expression that each indicated declining kidney function. DNA microarrays are silicon chips with many spots to which a given molecule may bind. In this case, the DNA microarrays were used to precisely generate, with the aid of a computer program, a profile of gene expression in a kidney cell.

The researchers chose one of the biomarkers, called lipocalin-2, to test how it correlated with kidney function in 46 MMA patients. Plasma levels of this biomarker rose with kidney deterioration in patients with MMA, and may serve as a valuable indicator of MMA kidney disease progression in the clinic.

"The detection of biomarkers through microarray technology is immensely helpful in pointing to downstream pathways affected by the defective MUT activity," said Irini Manoli, M.D., Ph.D., lead author and a physician scientist and staff clinician in NHGRI's Genetics and Molecular Biology Branch. "The biomarkers provide new plasma or serum tests to follow disease progression in our patients."

Having discovered these important biomarkers of kidney function, the authors turned to kidney physiology experts on their team to explore the structural changes that occur in MMA disease. They analyzed the rate at which the kidneys filter waste from the blood. Co-author and renal physiology expert Jurgen Schnermann, M.D., and members of his laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), also part of NIH, demonstrated the early and significant decrease in this rate in MMA mice.

With further studies, the researchers identified increased production of free radicals in tissues from the mice, as well as in the MMA patients. Detection of free radicals indicates chemical instability in cells, which the researchers sought to remedy with antioxidant therapy. After treating the mice with two forms of dietary antioxidants, the researchers observed that the biomarkers of kidney damage diminished and the faltering kidney filtration rate tapered off. The findings demonstrated that readily available antioxidants can significantly affect the rate of decline of kidney function in transgenic mice, which replicate the kidney disease of MMA.

"The next step will be to translate these findings to the clinic," Dr. Venditti said. "With a progressive disorder like MMA, we are hopeful that we have achieved a laboratory success that our patients will benefit from in the near future."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our urology / nephrology section for the latest news on this subject.

Irini Manoli, Justin R. Sysol, Lingli Li, Pascal Houillier, Caterina Garone, Cindy Wang, Patricia M. Zerfas, Kristina Cusmano-Ozog, Sarah Young, Niraj S. Trivedi, Jun Cheng, Jennifer L. Sloan, Randy J. Chandler, Mones Abu-Asab, Maria Tsokos, Abdel G. Elkahloun, Seymour Rosen, Gregory M. Enns, Gerard T. Berry, Victoria Hoffmann, Salvatore DiMauro, Jurgen Schnermann, and Charles P. Venditti, "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia", Published online before print July 29, 2013, doi: 10.1073/pnas.1302764110

For information about the MMA clinical trial, go to ClinicalTrials.gov and search with NCT00078078.

Learn more about the study

NIH/National Human Genome Research Institute

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

NIH/National Human Genome Research Institute. "Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Investing in cardiovascular research benefits economy

Main Category: Cardiovascular / Cardiology
Also Included In: Public Health
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
Investing in cardiovascular research benefits economy

Investing in cardiovascular disease research in Canada provides economic and societal benefits to Canadians, according to new research published in CMAJ Open.

"Our main goal was to understand how much "bang" we were getting from our research "buck" and whether investing in cardiovascular disease research is worthwhile from a population health perspective," writes Dr. Claire de Oliveira, scientist and health economist with the Centre for Addiction and Mental Health (CAMH), Toronto, with coauthors.

Cardiovascular disease is the number one cause of hospitalization and death in Canada. For every $69 spent on cardiovascular health care in the country, $1 was spent on research through public and charitable sector funding.

"We found an internal rate of return of 20.6% for investment in cardiovascular disease research by the public and charitable sectors," the authors write. "Thus, for every $1 spent on public or charitable sources, Canadians receive an income stream of about $0.21 per year in perpetuity. Considering a minimum acceptable rate of return of 12%, this investment is quite attractive."

The internal rate of return is "the annual monetary benefit to the economy for each dollar invested in cardiovascular disease research."

Spending on cardiovascular disease research in Canada has increased from roughly $13 million in 1975 to $41 million in 1990 and $96 million in 2005.

The authors hope this study will help funders determine the return on investment and whether they are spending appropriately.

"Our estimates provide evidence that investing in cardiovascular disease research is valuable and that investments in medical research are returned many times over in societal benefits," conclude the authors.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

Estimating the payoffs from cardiovascular disease research in Canada: an economic analysis

CMAJ Open - doi: 10.9778/cmajo.20130003

Authors: Claire de Oliveira, MA, PhD, Hai V. Nguyen, PhD, Harindra C. Wijeysundera, MD, PhD, William W.L. Wong, PhD, Gloria Woo, PhD, Paul Grootendorst, PhD, Peter P. Liu, MD, MSc, Murray D. Krahn, MD, MSc

CMAJ Open

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Open, CMAJ. "Investing in cardiovascular research benefits economy." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Investing in cardiovascular research benefits economy'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Main Category: Liver Disease / Hepatitis
Also Included In: Stem Cell Research
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Researchers have generated functional hepatocytes from human stem cells, transplanted them into mice with acute liver injury, and shown the ability of these stem-cell derived human liver cells to function normally and increase survival of the treated animals. This promising advance in the development of cell-based therapies to treat liver failure resulting from injury or disease relied on the development of scalable, reproducible methods to produce stem cell-derived hepatocytes in bioreactors, as described in an article in Stem Cells and Development, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Stem Cells and Development website.

Massoud Vosough and coauthors demonstrate a large-scale, integrated manufacturing strategy for generating functional hepatocytes in a single suspension culture grown in a scalable stirred bioreactor. In the article "Generation of Functional Hepatocyte-Like Cells from Human Pluripotent Stem Cells in a Scalable Suspension Culture" the authors describe the method used for scale-up, differentiation of the pluripotent stem cells into liver cells, and characterization and purification of the hepatocytes based on their physiological properties and the expression of liver cell biomarkers.

David C. Hay, MRC Centre for Regenerative Medicine, University of Edinburgh, U.K., comments on the importance of Vosough et al.'s contribution to the scientific literature in his editorial in Stem Cells and Development entitled "Rapid and Scalable Human Stem Cell Differentiation: Now in 3D." The researchers "developed a system for mass manufacture of stem cell derived hepatocytes in numbers that would be useful for clinical application," creating possibilities for future "immune matched cell based therapies," says Hay. Such approaches could be used to correct mutated genes in stem cell populations prior to differentiation and transplantation, he adds.

"The elephant in the room for stem cell therapy rarely even acknowledged let alone addressed in the literature is that of scalable production of cells for translational application," says Editor-in-Chief Graham C. Parker, PhD, research professor, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine. "Baharvand's groups' landmark publication not only demonstrates but exquisitely describes the methodology required to scale up stem cell populations for clinical application with a rigor to satisfy necessary manufacturing standards."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our liver disease / hepatitis section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Liebert, Mary Ann. "Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

New understanding of actin filament growth in cells

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;  HIV / AIDS
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
New understanding of actin filament growth in cells

University of Oregon biochemists have determined how tiny synthetic molecules disrupt an important actin-related molecular machine in cells in one study and, in a second one, the crystal structure of that machine when bound to a natural inhibitor.

The accomplishments - done in the name of fundamental understanding, or basic science - provide new windows on the complexities of cellular structure and suggest a potential future route to therapeutic targeting, said Brad J. Nolen, a professor of chemistry and biochemistry at the UO, who was principal investigator on both studies.

The machinery is the actin-related protein 2/3 complex (Arp2/3), a large assembly of seven proteins that stick together. This complex is critical to cell motility - the ability to move and perform myriad duties - and for initializing the construction of a network of filaments known as the actin cytoskeleton that provides structural support for cells.

"In addition to cells having a lot of actin, they also have a lot of proteins that bind to actin to control its dynamics," said Nolen, who has just completed his second year as a Pew Scholar in the Biomedical Sciences. "And that's exactly what the complex does. It binds to the side of pre-existing actin filaments, where it nucleates the growth of new filaments. The Arp2/3 complex is very highly conserved, like actin. All of your cells are chock full of actin much like a yeast cell. There are very few differences between the molecule in yeast and in human cells."

The cell loses control of the actin cytoskeleton in various diseased states, including certain viral infections, such as HIV and cancer, he said.

Nolen, also a member of the UO's Institute of Molecular Biology, began studying the Arp2/3 complex's role in cytoskeletal network formation during postdoctoral research at Yale University, where he was part of a team that in 2009 identified two distinct classes of molecules that inhibited normal activity of the machinery. The discovery, reported in the journal Nature, opened the way for exploring how the complex works.

Reporting in a recent issue of the journal Chemistry & Biology, Nolen and a team of UO researchers, in a series of biochemical, biophysical and X-ray crystallography experiments, exposed the complex to the two tiny synthetic molecules, which turned off actin-filament initiation as anticipated. More importantly, they were able to capture exactly where the molecules docked, or bound, with the much larger macromolecular Arp2/3 complex.

That binding activity, they found, was enough to block the ability of the machinery to align properly for activating filament production. "We found that these small molecules throw a monkey wrench in this macromolecular machine and lock it into the off state," Nolen said. "By locking it into the off state it prevents it from nucleating branched filaments."

What was seen in the Arp2/3 complex, Nolen said, will help to understand precisely how actin is controlled in cells. "Cell motility requires actin inside the cell to constantly be remodeled," he said. "A lot of studies are showing that the Arp2/3 complex is very important for cell motility. So if we can figure out the Arp2/3 complex works, we can better understand how it affects things like cellular motility and, therefore, how we might affect things like metastasis of tumors.

In the second paper, placed online July 28 in advance of regular publication in the journal Nature Structural & Molecular Biology, Nolen and Quing Luan, a research technician in the UO's Institute of Molecular Biology, report the first crystal structure of the Arp2/3 complex while bound with a natural occurring inhibitor, glial maturation factor, known as GMF.

"We have determined the three-dimensional structure of all of the atoms that make up each of the sub-units of the Arp2/3 complex, and we've created a 3-D picture of where this regulator binds to the complex by using X-ray crystallography," Nolen said. "What this tells us is the structural basis for how GMF regulates the Arp2/3 complex. It binds to the complex and blocks the initiation of Y-shaped branches that create new filaments. It also binds to the pre-existing branches and causes them to pop off, so it is involved in the disassembly of these networks."

There is a difference, he noted, in how inhibitor molecules in the two studies worked. The synthetic versions in the first study, while binding to specific locations, did not block separate filament-building activators from also binding to the complex but instead stopped activation by locking the complex into a non-productive position. GMF while bound to the complex, on the other hand, blocked activators from also locking on.

The different results, Nolen said, could guide future efforts therapeutic delivery of molecules, or drugs, to fight disease-related scenarios in damaged cells. His lab is now working with a computational chemist on the design of molecules that might drive desired alterations in the complex and related actin regulators without unintended consequences of toxicity.

"We are pursuing the potential clinical value," Nolen said. "It's basic research with a potential long-term payoff, or it may never happen. For now what we've provided is a basic-science tool."

"Researchers at the University of Oregon continue to further our understanding of the dynamic processes that inform multi-level health and well-being," said Kimberly Andrews Espy, vice president for research and innovation and dean of the UO graduate school. "By helping to elucidate the complexities of cellular structure, Dr. Nolen's research may eventually lead to more effective targeting of tumors and other diseases."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

Byron Hetrick, Min Suk Han, Luke A. Helgeson, Brad J. Nolen, Small Molecules CK-666 and CK-869 Inhibit Actin-Related Protein 2/3 Complex by Blocking an Activating Conformational Change, Chemistry & Biology, doi: 10.1016/j.chembiol.2013.03.019

Co-authors with Nolen on the Chemistry & Biology paper were postdoctoral researcher Byron Hetrick and graduate students Min Suk Han and Luke Helgeson. The National Institutes of Health (RO1-GM092917 to Nolen and F32-GM097913 to Hetrick, the lead author) and American Heart Association (10SDG2610189 to Nolen) supported the research.

The NIH (RO1-GM092917) and Pew Scholars in the Biomedical Sciences program of the Pew Charitable Trusts supported Nolen for the work in Nature Structural & Molecular Biology. Experiments were done at the Argonne National Laboratory's Advanced Photon Source, a U.S. Department of Energy-funded facility operated by the University of Chicago.

University of Oregon

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University of Oregon. "New understanding of actin filament growth in cells." Medical News Today. MediLexicon, Intl., 30 Jul. 2013. Web.
30 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'New understanding of actin filament growth in cells'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here