Doing the right thing when things go wrong

UMHS approach to medical errors and malpractice suits could be used by hospitals nationwide, new study indicates
 The University of Michigan Health System doesn't claim to be perfect. But its response to medical errors, near-misses, unexpected clinical problems and unintended outcomes is a model for the nation that other hospitals can and should copy, according to a new paper in a prestigious health care journal.
The "Michigan Model" for handling these situations, and preventing them from happening again, has not only helped patients and medical staff alike – it has also helped UMHS go against the grain of the costly, combative "deny and defend" medical malpractice culture.
In a paper in December issue of the Milbank Quarterly, and in a presentation today at a meeting of the U-M Board of Regents, the UMHS approach is once again in the spotlight for its potential to be emulated by hospitals across the country.
The new paper, authored mainly by Massachusetts-based researchers, lays out the fundamentals of the model for other hospitals to emulate. The authors, from Harvard Medical School and the Massachusetts Medical Society, report that key stakeholders across the medical and legal community see the Michigan approach as a feasible and promising approach for their state.
The presentation to the U-M Regents, given by UMHS chief medical officer Darrell A. Campbell, Jr, M.D. and executive director of clinical safety Rick Boothman, J.D., lays out further the details and results of the UMHS approach. They also featured video clips from actual patients and patient family members, who have told their unvarnished stories for a video aimed at every member of the UMHS care team.
"By handling unanticipated and unintended incidents, and patient injuries, honestly and proactively, we've virtually eliminated groundless legal claims, allowing us to focus on issues that demand attention with clear vision and no more excuses," says Boothman. "We fundamentally focus on putting patients and safety first, and we believe other hospitals can do the same."
Campbell and Boothman have led a decade-long effort to implement and measure the results of the Michigan Model. It's based on these key principles:

• Compensate patients quickly and fairly when inappropriate care causes injury
• Support clinical staff when the care was reasonable
• Reduce patient injuries (and claims) by learning from patients' experiences

In that decade, new malpractice claims per month have dropped, total liability costs have dropped, claims and potential claims are being resolved faster, and UMHS is increasingly avoiding litigation in both claims without merit and claims with merit.
The authors of the new paper, who interviewed 37 physicians, hospital executives, attorneys, public policymakers, insurers and others across Massachusetts, find a general consensus that the Michigan approach – also called DA&O for "disclose, apologize and offer" -- holds great potential to improve medical liability and patient safety.
They write: "It was viewed as more promising than any other liability reform option, both on its merits and because it would not be stymied by political gridlock in state legislatures, as other tort reforms frequently have been." They also note that it offers a "value proposition" to patients that's crucial in this age of federal health care reform.
The authors also note that their interviews indicate that experts across the board do see challenges in implementing the Michigan Model in other hospitals and health care settings.
But, they conclude, based on the evidence available, "DA&O programs may prove not only to constrain liability costs but also to improve access to compensation, strengthen linkages between the liability system and patient safety, increase health care organizations' accountability and patient advocacy, and promote transparency in regard to medical error."
Boothman, who is a co-author of the new paper, notes that the Michigan Model or DA&O has also been put forth as a model by the federal Agency for Health Care Research and Quality, which has issued grants for teams to study implementation of the Michigan Model as the leading response to the malpractice crisis. There have also been legislative and research efforts in Massachusetts, Washington, New York, Illinois, Oregon and Florida based in part on the DA&O approach, and interest from four other countries.
Source:University of Michigan Health System 

We're all living longer, but longevity increases not benefitting everybody

Global lifespans have risen dramatically in the past 40 years, but the increased life expectancy is not benefitting everybody equally, say University of Toronto researchers. In particular, adult males from low- and middle-income countries are losing ground.
People are living longer on average than they were in 1970, and those extra years of life are being achieved at lower cost, the researchers, led by U of T Chemical Engineering PhD candidate Ryan Hum, say in a paper published in the open access science journal eLife this month.
However, the costs for an extra year of life among adult males in lower-income countries are rising, Hum and his colleagues say, while the costs for an extra year of life among children worldwide and for adults in high-income countries continues to drop.
Hum, who is also a member of U of T's Centre for Global Engineering, co-wrote the paper with Professors Yu-Ling Cheng, director of the Centre, Prabhat Jha of the Dalla Lana School of Public Health and Anita McGahan of the Rotman School of Management.
The researchers made the discovery when they took the Michaelis-Menten (MM) equation – a well-known mathematical model first used to analyze enzyme kinetics in 1913 – and applied it to adult and child mortality at different incomes. They reasoned that just as chemical catalysts affect enzyme velocity; the public health catalysts react with income to affect life expectancy.
"We noticed the similarity in the curvature and became fascinated with the beauty of the analogy," said Hum. The MM equation is standard curriculum for biochemistry, biology and most chemical engineering undergraduate students and we knew there could be added knowledge that we could decipher purely from the math."
"Over the past few decades, research and development of new technologies (drugs, vaccines, policies) have focused mostly on childhood and infectious disease, with fewer worldwide investments for adult chronic diseases," the U of T researchers suggest. "Increasing coverage of inexpensive health interventions such as immunization, insecticide-treated nets, and case management of childhood infections could be contributing to decline in critical income for child survival."
Hum and his colleagues conclude by recommending that society invest in research and treatment of adult chronic disease, most notably the control of smoking and other risk factors for chronic diseases, and low-cost, widely useful treatments for these diseases.
In the paper, "Global divergence in critical income for adult and childhood survival: analyses of mortality using Michaelis-Menten", the authors expand on the analogy between enzymes and incomes: "Income directly enables certain technologies, immunization programs, epidemiological knowledge, education, and sanitation systems and other areas, which may themselves be interpreted as 'catalysts' – agents that accelerate the rate of a reaction without being fully consumed in the process," they write.
They came up with a new parameter, critical income, which they define as the level of income needed to achieve half of the maximal overall life expectancy found in high-income countries. For example, in 1970, the critical income for overall life expectancy (in inflation adjusted 2005 dollars) was $1.48 per day. By the year 2007, the critical income had fallen to $1.21 per day. In other words, a lower national income is needed to achieve a higher life expectancy now, compared to 40 years ago.
However, that good news is due mostly to improvements in children's health and to increased life expectancy in high-income countries, the researchers say. For adults (aged 15 to 59) in lower-income countries, critical income has actually risen since 1970. In other words, adults in low- and middle-income countries need to have higher incomes on average in order to add an extra year of life. Adult males in these countries are especially affected, though adult females also suffer.
"Under the current conditions, an approximate national income per capita of $2.20 per day would be required in 2007 to attain the same achievable adult male survival rate with $1.25 per day in 1970. Moreover, should the critical income costs for adults continue to rise (in line with current trends)," they warn.
Hum and his colleagues noted that increases in smoking, especially among adult males, and HIV prevalence are responsible for part of the life expectancy gap. By contrast, worldwide attention to childhood health including much research on new technologies, vaccines and political attention mean a rosier future for children – it's becoming less expensive to give children the chance for longer lives.
Source:University of Toronto Faculty of Applied Science & Engineering 

Study questions reasons for routine pelvic exams

The pelvic exam, a standard part of a woman's gynecologic checkup, frequently is performed for reasons that are medically unjustified, according to the authors of a UCSF study that may lay the groundwork for future changes to medical practice.
The research shows that many physicians mistakenly believe the exam is important in screening for ovarian cancer. The study, which surveyed obstetricians and gynecologists around the country, also shows that doctors continue to perform the exam in part because women have come to expect it.
The article is currently published online in the American Journal of Obstetrics and Gynecology.
The pelvic examination has been the foundation of the annual checkup for women for many decades, yet very little has been known about why clinicians perform it and if they believe it is useful,'' said senior author George Sawaya, MD, a UCSF professor of obstetrics, gynecology and reproductive sciences, and epidemiology and biostatistics. "We set out to better understand their practices and beliefs.''
Well-woman annual medical checkups generally are recommended because they allow physicians to assess overall health and pinpoint potential problems early. Traditionally, these have included, among other assessments, a manual inspection of a woman's cervix and uterus and a Pap smear.
Under updated preventive care guidelines by the American Cancer Society, the American Congress of Obstetricians and Gynecologists (ACOG), and the U.S. Preventive Services Task Force, most women no longer need annual Pap smears, which screen for cervical cancer. Now, questions are being raised by the medical community about the necessity of the annual pelvic exam for women with no gynecologic problems such as pelvic pain or unscheduled bleeding.
"The bimanual pelvic exam is not recommended for ovarian cancer screening, so we wondered under what circumstances the exam is being performed and why,'' said lead author Jillian T. Henderson, PhD, MPH, who performed the research while based at UCSF. She is now at the Kaiser Permanente Center for Health Research in Portland, Oregon.
The study consisted of a nationwide survey of 521 practicing physicians specializing in obstetrics and gynecology, or gynecology alone. The doctors were asked to indicate whether they would perform a bimanual pelvic exam in vignettes of female patients aged 18, 35, 55, and 70 years who had no symptoms of gynecologic diseases and did not require a Pap test. The study centered on the bimanual exam, not other components of a pelvic checkup such as a speculum exam and visual inspection of external genitalia which are often performed.

		Photo:  Jillian T. Henderson, Ph.D., M.P.H.

The researchers found that nearly all the physicians surveyed routinely would conduct the exam in asymptomatic, low-risk women. Furthermore, most of the doctors said they would perform the exam on a 55-year-old woman with no ovaries, uterus or cervix – and more than half considered such an exam to be very important for that woman.
Some 87 percent of the physicians said they would perform the exam on healthy 18-year-olds. ACOG recently recommended the exam not begin routinely until age 21.
Altogether, nearly half the physicians erroneously believe the exam is very important in screening for ovarian cancer, despite longstanding recommendations discouraging its use for this purpose.
Notably, many doctors said they conduct the exam in part for non-clinical reasons: because it reassures patients, because patients expect it, because it ensures adequate compensation for routine gynecologic care.
There were clear geographic patterns: doctors in the northeast and the south were more likely to consider the exams very important and to believe they "reassure patients of their health.''
The researchers said their study shows a need to educate doctors about the appropriateness of the exam, especially to clarify its role in ovarian cancer screening. The study also should prompt a closer look at the evidence that supports the exam's usefulness for the reasons cited by surveyed physicians, they said.
"These exams could result in unnecessary surgeries or women being falsely reassured,'' Henderson said. "We need to have more discussion over whether the benefits of these exams outweigh the harms, and if they should be part of a woman's annual checkup.''
Source:

University of California - San Francisco 

 

Aerobic exercise trumps resistance training for weight and fat loss

Aerobic training is the best mode of exercise for burning fat, according to Duke researchers who compared aerobic training, resistance training, and a combination of the two.
The study, which appears Dec. 15, 2012, in the Journal of Applied Physiology, is the largest randomized trial to analyze changes in body composition from the three modes of exercise in overweight or obese adults without diabetes.
Aerobic exercise – including walking, running, and swimming – has been proven to be an effective way to lose weight. However, recent guidelines have suggested that resistance training, which includes weight lifting to build and maintain muscle mass, may also help with weight loss by increasing a person's resting metabolic rate. Research has demonstrated health benefits for resistance training, such as improving glucose control, but studies on the effects of resistance training on fat mass have been inconclusive.
"Given that approximately two-thirds of adults in the United States are overweight due to excess body fat, we want to offer clear, evidence-based exercise recommendations that will truly help people lose weight and body fat," said Leslie H. Willis, MS, an exercise physiologist at Duke Medicine and the study's lead author.
Researchers enrolled 234 overweight or obese adults in the study. Participants were randomly assigned to one of three exercise training groups: resistance training (three days per week of weight lifting, three sets per day, 8-12 repetitions per set), aerobic training (approximately 12 miles per week), or aerobic plus resistance training (three days a week, three set per day, 8-12 repetitions per set for resistance training, plus approximately 12 miles per week of aerobic exercise).
The exercise sessions were supervised in order to accurately measure adherence among participants. Data from 119 people who completed the study and had complete body composition data were analyzed to determine the effectiveness of each exercise regimen.
The groups assigned to aerobic training and aerobic plus resistance training lost more weight than those who did just resistance training. The resistance training group actually gained weight due to an increase in lean body mass.
Aerobic exercise was also a more efficient method of exercise for losing body fat. The aerobic exercise group spent an average of 133 minutes a week training and lost weight, while the resistance training group spent approximately 180 minutes exercising a week without shedding pounds.
The combination exercise group, while requiring double the time commitment, provided a mixed result. The regimen helped participants lose weight and fat mass, but did not significantly reduce body mass nor fat mass over aerobic training alone. This group did notice the largest decrease in waist circumference, which may be attributed to the amount of time participants spent exercising.
Resting metabolic rate, which determines how many calories are burned while at rest, was not directly measured in this study. While theories suggest that resistance training can improve resting metabolic rates and therefore aid in weight loss, in this study, resistance training did not significantly decrease fat mass nor body weight irrespective of any change in resting metabolic rate that might have occurred.
"No one type of exercise will be best for every health benefit," Willis added. "However, it might be time to reconsider the conventional wisdom that resistance training alone can induce changes in body mass or fat mass due to an increase in metabolism, as our study found no change."
Duke researchers added that exercise recommendations are age-specific. For older adults experiencing muscle atrophy, studies have found resistance training to be beneficial. However, younger, healthy adults or those looking to lose weight would see better results doing aerobic training.
"Balancing time commitments against health benefits, our study suggests that aerobic exercise is the best option for reducing fat mass and body mass," said Cris A. Slentz, PhD, a Duke exercise physiologist and study co-author. "It's not that resistance training isn't good for you; it's just not very good at burning fat."
Source:Duke University Medical Center 

Study shows COPD is not independent risk factor for lung cancer

Chronic obstructive pulmonary disease (COPD) and lung cancer are two of the most important smoking-related diseases worldwide, with a huge combined mortality bur¬den. Many consider the presence of COPD itself to be an independent risk factor for lung cancer. Others argue that smoking contributes to both COPD and lung cancer. A recent study published in the January 2013 issue of the International Association for the Study of Lung Cancer's (IASLC) Journal of Thoracic Oncology, concludes that COPD is not an independent risk factor for lung cancer.
Researchers from the University of Nottingham looked at patients with lung cancer between January 2000 and July 2009 from The Health Improvement Network, a general practice database, in the United Kingdom.
Researchers, "found evidence of a strong association between COPD and lung cancer, but this was largely explained by the effect of smoking and is most apparent in recently diagnosed cases of COPD, suggesting a strong element of ascertainment bias."
They go on to say that there is "an extremely strong unadjusted relationship between both COPD and pneu¬monia and lung cancer in the 6 months immediately before lung cancer diagnosis. This is useful in a clinical context, high¬lighting the need to consider a diagnosis of lung cancer when making new diagnoses of COPD or pneumonia."
The researchers support the current recommendations of the American Thoracic Society and the U.K. National Institute for Health Research, that all patients should have a chest radiograph looking for evi¬dence of lung cancer at the time of COPD diagnosis.
The lead author of this work is Dr. Helen Powell. Co-authors include IASLC member Dr. David Baldwin.

Source:International Association for the Study of Lung Cancer 

ASE and GE Healthcare to educate use of ultrasound in remote areas

American Society of Echocardiography (ASE) and GE Healthcare (GE) are in rural northwest India again to utilise advances in cardiovascular ultrasound technology to enhance medical education for healthcare providers caring for the underserved populations in India.An organised team of ASE member sonographers and physicians have travelled to New Delhi to train Indian physicians in image acquisition while testing the possibilities of remote medical education. The educational event is a collaboration with Medanta – The Medicity, one of India’s largest multi-specialty medical institutes located in Gurgaon, in the National Capital Region.
An additional team of ASE sonographers is assisting in training via the internet and StatVideo’s EchoBoxes, equipment designed to stream cardiac ultrasound images over the Web. Twenty Indian physicians are receiving training on-site, while half of the physicians are also benefitting from additional training by ASE sonographers providing real-time instruction remotely from the US. This technology, is assisting them to see the images the Indian physicians scanned, providing the ability to instruct the physicians on improved acquisition in real-time.
After a successful medical camp in January 2012, healthcare providers for  this year’s project have included two new corporate sponsors CoreSound Imaging and StatVideo, to expand the reach from the rural setting with long-distance, web-based technology to the remote sonographers. The project was organised by Dr Partho P Sengupta, a New York-based cardiologist, a member of the Board of ASE, and the India liaison for ASE. The local training was co-ordinated by Dr Manish Bansal, Medanta – The Medicity.
“This educational activity sets a benchmark in delivering innovative internet-based tele-consultation and tele-education programme to physicians,” said Dr Sengupta.
“The physicians registered for a novel training module: ASE-VISION (Value of Interactive Scanning for Improving Outcome of New Learners). This programme ushers newer training possibilities in integration of tele-echocardiography with activities that range from real-time online assessments, long distance consultations, information sharing and education of physicians in remote areas of the world,” he added.
Clinicians will leverage GE Healthcare ultrasound technology, including the laptop-sized Vivid i and Vivid q plus the Vscan pocket-sized visualisation tool to facilitate the acquisition of the images and provide an educational and awareness vehicle for India-based physicians. The systems will be used on loan from GE Healthcare, which also provided an educational grant for the project to help support travel for sonographers. Vscan leverages ultrasound technology to provide clinicians with an immediate, non-invasive method to help obtain visual information about what is happening inside the body.

 “Through the use of portable GE ultrasound technology and the collaboration with local healthcare providers, ASE and its physician members are helping improve the overall quality of care for thousands of people in this rural part of India,” said Al Lojewski, general manager, Cardiovascular Ultrasound, GE Healthcare.

Source:Pharmabiz

Intensive Programs Not Necessary to Help Overweight People Bring Lifestyle Changes to Avoid Diabetes

Researchers from Stanford University School of Medicine and the Palo Alto Medical Foundation Research Institute reveal that an intensive one-on-one program is not necessary to ensure that overweight patients reduce the risk of diabetes by bringing in lifestyle changes. 
The study, to be published Dec. 10 in the Archives of Internal Medicine, opens up a practical way for primary care physicians to help their patients at high risk for developing diabetes.Researchers have known for 10 years that intensive intervention programs led by lifestyle coaches to encourage weight loss through healthier diet and exercise help reduce type-2 diabetes incidence. The Diabetes Prevention Program clinical research study, the results of which were published in 2002, found this strategy led to a 58 percent decrease in the incidence of type-2 diabetes, a result that surpassed the benefit of drug treatment. The new study — headed by Jun Ma, MD, PhD, an associate investigator at the research institute and an affiliate member of the Stanford Prevention Research Center — builds off the DPP's strategy but makes full use of online resources and, in one group, a take-home DVD. If implemented, the new interventions could increase the accessibility and reach of existing educational, coach-based diabetes prevention programs, and free up time for primary care doctors, who are often frustrated with high patient loads that prevent them from providing the individualized care these patients need. 
"The big issue in diabetes prevention is how to take what clearly worked for DPP — which was very intensive and one-on-one focused — and get it to the point where it could be established as a program in large group practices," said Randall Stafford, MD, PhD, professor of medicine at the Stanford Prevention Research Center and a senior investigator on the study. 
Diabetes currently affects 25.8 million people in the United States, or 8.3 percent of the population. The disease is a major cause of heart disease and stroke, and is the leading cause of kidney failure, nontraumatic lower-limb amputation and new cases of blindness among adults. In 2007, diabetes-related medical costs in the United States were estimated at $174 billion. Effective health interventions that reach a maximum amount of pre-diabetic patients — those at the highest risk for developing diabetes — are urgently needed to curb the burden of the disease. 
What the DPP sported in effectiveness, it lacked in its ability to broadly reach patients at the level of primary care. In the new study, Ma and Stafford set out to determine whether restructuring the DPP to take advantage of online connectivity and health monitoring could be achieved without sacrificing the benefits seen in the original program. 
Pre-diabetic patients were recruited from Palo Alto Medical Foundation and randomized into three groups: a coach-led group intervention, a self-directed DVD intervention or usual care. In addition to offering practical ways to start eating healthier foods and exercising more, the curriculum in both the coach-led and DVD-based interventions also focused on the mental and behavioral strategies necessary to make the changes stick. This lifestyle instruction was delivered over a three-month intensive intervention phase. 
Following the first three months of intervention, the participants regularly received encouraging messages to help them follow through with what they had learned in the initial intervention phase. During this 12-month maintenance phase, participants received supportive emails within an electronic health-record system, and monitored their health goals through the publicly available American Heart Association's Heart360 website. The primary outcome tested in the study was a change in body mass index (a calculation based on a person's height and weight), although other factors, including weight loss, waist circumference, blood pressure and blood glucose, were also measured. 
The results show that participants responded to both the coach-led and self-directed interventions, although the coach-led group fared slightly better. At the beginning of the study, the participants had an average BMI of 32; a BMI of 30 or more is considered obese. After the 15-month trial, the average drop in BMI was 2.2 for the coach-led group, 1.6 for the self-directed group and 0.9 for the group that received usual care. The average weight loss was 13.9 pounds for the coach-led group, 9.9 pounds for the self-directed group and 5.3 pounds for usual care. Both interventions also led to a dip in waistline circumference as compared to the usual-care group. 
Though the study was too small to generate statistically significant findings along gender lines, they turned up a hint of a gender difference: While men responded with equal success to both the coach-led and self-directed interventions, women responded better to the coach-led approach. 
Stafford points out that the suggested differences between genders highlights the need for options when it comes to lifestyle interventions. "It suggests that a one-size-fits-all program isn't necessarily what we need. We need some way to offer people different styles of intervention," said Stafford. 
Narrow demographics were a primary limitation of the study. Participants were all from a single clinic in Silicon Valley, and a large majority were white (78 percent), college-educated (97 percent) and earned more than $75,000 per year (88 percent). Stafford acknowledged the limited demographics of the study, but said he hopes that similar lifestyle interventions will work in more diverse populations. His group is currently conducting a National Institutes of Health-funded study testing the effectiveness of weight-loss interventions in a low-income, Latino population. 
If implemented, the approaches — especially the self-directed DVD — could extend the reach and lower the cost of lifestyle intervention programs. In addition to the cost-benefit of the intervention programs themselves, the real savings will come from diabetes prevention. "Diabetes is an expensive disease to treat and its complications are both personally devastating and societally costly," said Stafford. If patients respond to self-directed programs by losing a modest amount of weight, this could be enough to prevent or significantly delay the onset of type-2 diabetes in high-risk populations, ultimately reducing the burden of this chronic disease.
Source:Stanford University School of Medicine and the Palo Alto Medical Foundation
 

Genetically Engineering Algae Used to Make Complex Anti-cancer Drug

To treat cancer, biologists at UC San Diego have succeeded in genetically engineering algae to produce a complex and expensive human therapeutic drug. 
Their achievement, detailed in a paper in this week's early online issue of The Proceedings of the National Academy of Sciences, opens the door for making these and other "designer" proteins in larger quantities and much more cheaply than can now be made from mammalian cells.v "Because we can make the exact same drug in algae, we have the opportunity to drive down the price down dramatically," said Stephen Mayfield, a professor of biology at UC San Diego and director of the San Diego Center for Algae Biotechnology or SD-CAB, a consortium of research institutions that is also working to develop new biofuels from algae. Their method could even be used to make novel complex designer drugs that can't be produced in any other systems--drugs that could be used to treat cancer or other human diseases in new ways. "You can't make these drugs in bacteria, because bacteria are incapable of folding these proteins into these complex, three-dimensional shapes," said Mayfield. "And you can't make these proteins in mammalian cells because the toxin would kill them."
The advance is the culmination of seven years of work in Mayfield's laboratory to demonstrate that Chlamydomonas reinhardtii, a green alga used widely in biology laboratories as a genetic model organism, can produce a wide range of human therapeutic proteins in greater quantity and more cheaply than bacteria or mammalian cells. Mayfield and his colleagues achieved their first breakthrough five years ago when they demonstrated they could produce a mammalian serum amyloid protein in algae. 
The following year, they succeeded in getting algae to produce a human antibody protein. In 2010, they demonstrated that more complex proteins—human therapeutic drugs, such as human vascular endothelial growth factor, or VEGF, used to treat patients suffering from pulmonary emphysema—could be produced in algae. Then in May of this year, Mayfield's group working with another team headed by Joseph Vinetz from UC San Diego's School of Medicine, engineered algae to produce an even more complex protein—a new kind of vaccine that, preliminary experiments suggest, could protect billions of people from malaria, one of the world's most prevalent and debilitating diseases. "What the development of the malarial vaccine showed us was that algae could produce proteins that were really complex structures, containing lots of disulfide bonds that would still fold into the correct three-dimensional structures," said Mayfield. "Antibodies were the first sophisticated proteins we made. But the malarial vaccine is complex, with disulfide bonds that are pretty unusual. So once we made that, we were convinced we could make just about anything in algae. "In their latest development, the scientists genetically engineered algae to produce a complex, three-dimensional protein with two "domains"—one of which contains an antibody, which can home in on and attach to a cancer cell and another domain that contains a toxin that kills the bound cancer cells. Such "fusion proteins" are presently created by pharmaceutical companies in a complex, two-step process by first developing the antibody domain in a Chinese hamster, or CHO, cell. 
The antibody is purified, then chemically attached to a toxin outside of the cell. Then the final protein is repurified. "We have a two-fold advantage over that process," said Mayfield. "First, we make this as a single protein with the antibody and toxin domains fused together in a single gene, so we only have to purify it one time. And second, because we make this in algae rather than CHO cells, we get an enormous cost advantage on the production of the protein. "The fusion protein the researchers in his laboratory produced from algae is identical to one that is under development by pharmaceutical companies with a proposed cost of more than $100,000. 
This same protein could be produced in algae for a fraction of that price, they report in their paper. And the UCSD researchers—Miller Tran, Christina Van, Dan Barrera and Jack Bui at the UC San Diego Medical School—confirmed that the compound worked like the more expensive treatment: it homed in on cancer cells and inhibited the development of tumors in laboratory mice. Mayfield said such a fusion protein could not have been produced in a mammalian CHO cell, because the toxin would have killed it. 
But because the protein was produced in the algae's chloroplasts—the part of algal and plant cells where photosynthesis takes place—it did not kill the algae."The protein was sequestered inside the chloroplast," Mayfield said. "And the chloroplast has different proteins from the rest of the cell, and these are not affected by the toxin. If the protein we made were to leak out of the chloroplast, it would have killed the cell. So it's amazing to think that not one molecule leaked out of the chloroplasts. There are literally thousands of copies of that protein inside the chloroplasts and not one of them leaked out."Mayfield said producing this particular fusion protein was fairly straightforward because it involved fusing two domains—one to recognize and bind to cancer cells and another to kill them. 
But in the future, he suspects this same method could be used to engineer algae to produce more complex proteins with multiple domains. "Can we string together four or five domains and produce a designer protein in algae with multiple functions that doesn't exist in nature? I think we can?" he added. "Suppose I want to couple a receptor protein with a series of activator proteins so that I could stimulate bone production or the production of neurons? At some point you can start thinking about medicine the same way we think about assembling a computer, combining different modules with specific purposes. We can produce a protein that has one domain that targets the kind of cell you want to impact, and another domain that specifies what you want the cell to do."
Source:UCSD


 

Millions of patients still waiting for medical 'breakthroughs' against neglected diseases

 Despite important progress in research and development (R&D) for global health over the past decade, only a small fraction of new medicines developed between 2000 and 2011 were for the treatment of neglected diseases, highlighting the 'fatal imbalance' between global disease burden and drug development for some of the world most devastating illnesses, said Doctors Without Borders/Médecins Sans Frontières (MSF) and the Drugs for Neglected Diseases initiative (DNDi), in an analysis to be presented today at an international conference aimed at spurring medical innovations for these diseases.
DNDi and MSF found that between 2000 and 2011, 3.8 percent of newly approved drugs (excluding vaccines) were for tropical diseases, TB, and other neglected infections, which together account for 10.5 percent of the global disease burden. Much of the progress in the treatment of neglected diseases and important patient benefit during this time came about through drug reformulations and repurposing of existing drugs against these illnesses. However, only four of the 336 brand-new medicines (new chemical entities) developed between 2000 and 2011 were for the treatment of neglected diseases.
"We have to ask ourselves, how much progress have we really made over the past decade?" said Dr. Unni Karunakara, MSF International President. "People are still dying of archaic diseases. Doctors and nurses are still handcuffed by the shortcomings of available medicines, forced to treat their patients with decades-old, often brutal drugs. As we speak, there are drug-resistant TB patients enduring two years on an absolutely horrific course of treatment—debilitating nausea and pain, depression, social isolation, hearing loss, and even psychosis, are just some of the few side effects they can have while on these medicines. Our patients are still waiting for real scientific breakthroughs."
The two-day conference, Lives in the Balance: Delivering Medical Innovations for Neglected Patients and Populations, also hosted by the Mount Sinai School of Medicine's Global Health Program, will look at the progress and shortcomings of the last decade of medical R&D to fight neglected diseases—a period during which there has been an increase in new neglected disease R&D initiatives and funders— and will focus in particular on the need to accelerate development and delivery of new health technologies to fight Chagas disease and drug-resistant tuberculosis (DR-TB). It will also examine the need for field-adapted vaccines to reach the 22.4 million children who are still not receiving even the most basic package of immunizations every year.
According to the DNDi and MSF analysis, three of the four brand-new medicines approved for neglected diseases in the past decade were for malaria, with none for the 17 neglected tropical diseases (NTDs) defined by the World Health Organization (WHO), nor TB. Furthermore, as of December 2011, only 1.4 percent of a total of nearly 150,000 registered clinical trials were focused on neglected diseases.
The conference is taking place 10 years after MSF hosted a major conference in New York to examine the crisis in R&D for neglected diseases and lay the groundwork for the creation of DNDi in 2003. In a 2001 study carried out by MSF and the Drugs for Neglected Diseases Working Group, the precursor to DNDi, only 1.1 percent of new drugs approved between 1975 and 1999 were for neglected diseases, including NTDs, malaria, and TB, though they accounted for 12 percent of the global disease burden.
Some individual successes have emerged from the proliferation of global R&D actors over the last decade. For example, product development partnerships (PDPs) were responsible for over 40 percent of neglected disease products registered between 2000 and 2011, including new TB diagnostics and malaria combination treatments.
"There have been advances, but for many diseases we have yet to see the kind of 'game-changers' that are truly needed," said Dr. Bernard Pécoul, Executive Director of DNDi. "Product development partnerships and ad hoc R&D initiatives cannot be 'the' solution to the systemic lack of innovation. We must make patient needs the driving force for R&D. This is the only way to build on the successes we have seen in the past ten years and overcome the fatal imbalance that still exists between drug R&D and global health needs. Governments must put in place a R&D framework to sustainably coordinate, finance, and stimulate medical innovation for new drugs, diagnostics and vaccines for the people who need them most."
The conference comes on the heels of a recent decision by governments to further delay a WHO-led, 10-year effort to develop a global framework to strengthen priority-setting, coordination, and financing of R&D for diseases that affect millions worldwide. Today's system for medical R&D is flawed in that it is predominantly driven by commercial rewards rather than global health priorities. This means that research is steered towards areas that are the most profitable, leaving fundamental medical needs—particularly those that disproportionately affect developing countries like NTDs or TB—unaddressed.
The conference, which will bring together a broad range of researchers, medical professionals, global health experts, policymakers, pharmaceutical and biotechnology experts, donors, activists, patient advocates, and journalists, will feature a keynote address from Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, and a video address by World Bank President Dr. Jim Yong Kim.
Source:Drugs for Neglected Diseases Initiative 

New Study Sheds Light on How Cells Transport Materials Along Crowded Intercellular 'Highways'

Published in the Proceedings of the National Academy of Sciences, the Study by Physicists at WPI and UMass Amherst Provides New Insights into a Cellular System Whose Failure Can Lead to Neurodegenerative Diseases and Cancer

Erkan Tüzel, assistant professor of physics

The interior of an animal cell is like a small city, with factories—called organelles—dedicated to manufacturing, energy production, waste processing, and other life functions. A network of intercellular "highways," called microtubules, enables bio-molecular complexes, products, and other cargo to move speedily about the cell to keep this vital machinery humming. A new paper published online in the journal Proceedings of the National Academy of Sciences sheds new light on how cells manage to keep traffic flowing smoothly along this busy transportation network that is vital to the survival of cells and whose failure can lead to a variety of diseases, including Alzheimer's and cancer.

The study, "Motor transport of self-assembled cargos in crowded environments", is co-authored by Jennifer Ross, assistant professor of physics at the University of Massachusetts Amherst, Erkan Tüzel, assistant professor of physics at Worcester Polytechnic Institute (WPI), and Leslie Conway and Derek Wood, graduate students of physics at UMass Amherst. It examines how proteins called motors (the trucks of the intercellular transport network) cooperate to minimize traffic jams and maximize the distance traveled by cargos.In the study, the researchers used quantum dots (nanometer-sized semiconductors that reflect brightly in microscopy images) as cargo. In the laboratory, they attached these tiny cargos to individual motor proteins and then allowed those proteins to attach to a microtubule. Motor proteins are able to "walk" along microtubules by attaching and detaching parts of their structure to the microtubule, much like the hand-over-hand motion of a person climbing a rope. The researchers observed how the quantum dots moved along the microtubule as they created more and more traffic by adding more and more motor proteins to the highways of this simplified transportation system.They found that the dots moved more slowly as the traffic increased, but that they were able to travel farther before becoming detached from the microtubule. They also observed the pausing of the quantum dots, with the number of pauses increasing, but the length of the pauses decreasing, as the concentration of motor proteins is increased. The authors hypothesize that as the concentration of motor proteins increased, several of them became bound to each quantum dot. Much like trucks driving side-by-side down a multilane highway, the motor proteins likely became attached to different protofilaments along the microtubule (microtubules are made of 13 parallel protofilaments arranged into a hollow tube).As an individual protein encountered an obstacle (another motor protein, for example), the motion of the dot would pause until the force exerted by the other proteins attached to the dot caused it to become detached from the blocked protein. The greater the number of proteins pulling the dot along the microtubule, the greater the force acting on it and the more quickly it would become detached from blocked proteins (and thus, the briefer the pauses in its forward motion).In this way, motor proteins were able to cooperate to move cargo around roadblocks and to keep cargo attached to the microtubules despite heavy traffic, Tüzel says. "This is the first study to really look at the operation of the intracellular transportation system crowded conditions that are typical of living cells," he noted."It is important to understand how this system works and what can keep it from functioning properly because it is vital to the survival of all animal cells and motor proteins that make many fundamental biological processes, such as cell division, possible," he adds. "When the transport mechanism fails to work properly, it can lead to a variety of illnesses, including neurodegenerative diseases like Huntington's and Alzheimer's, and to cancer."

Source:WPI

Researchers find new culprit in castration-resistant prostate cancer

Scientists at Dana-Farber Cancer Institute have discovered a molecular switch that enables advanced prostate cancers to spread without stimulation by male hormones, which normally are needed to spur the cancer's growth. They say the finding could lead to a new treatment for prostate cancers that are no longer controlled by hormone-blocking drugs.
The researchers report in the Dec. 14 issue of Science that the molecular switch occurs in a protein, EZH2, which is increased in these tumors, termed castration-resistant prostate cancers (CRPC).
EZH2 is part of a protein complex that normally shuts off the expression of genes. But in CRPC cells, "It isn't working the way people had thought," said Myles Brown, MD, co-senior author of the report. Instead, EZH2 switches into a different mode, activating cell-growth genes -even in the absence of androgen hormones – that spur the dangerous growth and spread of these cancers.
As a result, the researchers suggest that drugs designed to stifle this unexpected function of EZH2 might be effective as a new treatment strategy for CRPC tumors.
Brown's co-senior author is X. Shirley Liu, PhD; together they lead Dana-Farber's Center for Functional Cancer Epigenetics.
Most prostate tumors are fueled by male hormones, or androgens, which interact with a molecule called the androgen receptor in cancer cells. When the receptor receives androgen signals, it transmits orders to the cell's nucleus to divide and grow. Surgical castration or administering drugs that halt androgen production can control cancers that have spread outside the prostate gland.
However, these cancers often escape their need for androgens after a few years of treatment and become resistant. Brown said the tumor cells reprogram the androgen receptors so that they activate cell-growth genes despite the absence of hormone stimulation.
EZH2 is known as an "epigenetic regulator," meaning that it regulates the activity of genes without changing their DNA structure. Previously it was found that EZH2 levels are dramatically increased in late-stage castration resistant prostate cancer, Brown said, but researchers thought the protein was acting primarily to turn off gene activity – which is its normal role.
Drugs aimed at blocking EZH2 activity are being tested in other cancers, where they are designed to block the protein's gene-suppressing role. However, they carry a risk of harmful side effects as a result. "But we found that isn't the important function of EZH2 in CRPC," Brown explained. "In these cancers, EZH2 works with the androgen receptor to turn on genes involved with cell growth." As a result, he proposes that inhibitors of EZH2 that avoid targeting its gene-repressor function might be a safe and effective strategy for use in castration-resistant prostate cancers.
Further, said Brown, the EZH2 protein itself is activated by a molecular signaling pathway known as PI3K, or PI3 kinase. Several PI3K inhibitors are in clinical trials at present, and Brown said that a combination of drugs to inhibit both that pathway and the EZH2 protein might be yet another way to attack the resistant prostate cancers.
Source:Dana-Farber Cancer Institute 

 

Tea, Honey Help Combat Superbugs

Traditional remedies such as tea and honey help in the fight against resistant superbugs, say scientists. 
The more the drugs that are used, the more likely it is that any bacteria will build up a resistance to them, leading to what one expert called an "arms race" that he feared was being lost."I hate to say we're heading back towards the pre-antibiotics days when treating serious diseases was extremely problematic," the Telegraph quoted Professor Les Baillie, of Cardiff University, as telling the BBC. Professor Baillie is leading a team that is looking into whether old-fashioned cures such, as tea and honey, could be the next way to take on superbugs. 
Tea contains compounds called polyphenols that have health benefits including their ability to kill micro-organisms. 
Scientists from Prof Baillie's team have been looking at tea as a source of drugs to treat clostridium difficile - a bacterium that was responsible for at least 2,000 deaths and more than 24,000 infections last year. 
Rhidian Morgan-Jones, a Cardiff-based surgeon, said that there were real concerns about the future of medicine on a post-antibiotic age. 
"You're going back to the last century where before antibiotics all you had to do was lance boils, drain the puss and put people in bed and rest them. Some you cured and some you didn't," he said.
Source-ANI
 

 

Words have feelings

Emotion in voices helps capture the listener’s attention, but in the long run the words are not remembered as accurately

Does the emotion in our voice have a lasting effect? According to Annett Schirmer and colleagues from the National University of Singapore, emotion helps us recognize words quicker and more accurately straight away. In the longer term however, we do not remember emotionally intoned speech as accurately as neutral speech. When we do remember the words, they have acquired an emotional value; for example words spoken in a sad voice are remembered as more negative than words spoken in a neutral voice.

The study, looking at the role of emotion in word recognition memory, is published online in Springer's journal Cognitive, Affective & Behavioral Neuroscience.

In anger, sadness, exhilaration or fear, speech takes on an urgency that is lacking from its normal even-tempered form. It becomes louder or softer, more hurried or delayed, more melodic, erratic or monotonous. And this emotional speech immediately captures a listener's attention. Schirmer and colleagues' work looks at whether emotion has a lasting effect on word memory.

A total of 48 men and 48 women listened to sadly and neutrally spoken words and were later shown these words in a visual test, examining word recognition and attitudes to these words. The authors also measured brain activity to look for evidence of vocal emotional coding.

Their analyses showed that participants recognized words better when they had previously heard them in the neutral tone compared with the sad tone. In addition, words were remembered more negatively if they had previously been heard in a sad voice.

The researchers also looked at gender differences in word processing. They found that women were more sensitive to the emotional elements than men, and were more likely than men to recall the emotion of the speaker's voice. Current levels of the female sex hormone estrogen predicted these differences.

Schirmer and team conclude: "Emotional voices produce changes in long-term memory, as well as capturing the listener's attention. They influence how easily spoken words are later recognized and what emotions are assigned to them. Thus voices, like other emotional signals, affect listeners beyond the immediate present."

Reference:

Schirmer A et al (2012). Vocal emotions influence verbal memory: neural correlates and inter-individual differences. Cognitive, Affective & Behavioral Neuroscience; DOI 10.3758/s13415-012-0132-8

Battling Brittle Bones ... With Broccoli and Spinach?

Engineering Researchers at Rensselaer Polytechnic Institute Pinpoint the Origin of Bone Fractures

A new study from engineering researchers at Rensselaer Polytechnic Institute shows, for the first time, how the little-understood protein osteocalcin plays a significant role in the strength of our bones. The findings could lead to new strategies and therapeutics for fighting osteoporosis and lowering the risk of bone fracture.

Funded by the U.S. National Institutes of Health, the study details how fractures in healthy bones begin with the creation of incredibly tiny holes, each measuring only about 500 atoms in diameter, within the bone’s mineral structure. In the case of a slip, trip, or fall, the force of the impact on a bone physically deforms a pair of joined proteins, osteopontin and osteocalcin, and results in the formation of nanoscale holes. These holes, called dilatational bands, function as a natural defense mechanism, and help to prevent further damage to the surrounding bone. However, if the force of the impact is too great—or if the bone is lacking osteopontin, osteocalcin, or both—the bone will crack and fracture.

The multi-university study, led by Deepak Vashishth, head of the Department of Biomedical Engineering at Rensselaer, is the first to give evidence of fracture at the level of bone’s nanostructure. Partnering with Rensselaer on the study were Villanova University, the Hospital for Special Surgery in New York, and Yale University.

“This study is important because it implicates, for the first time, the role of osteocalcin in giving bone the ability to resist fracture,” Vashishth said. “Since osteocalcin is always the point of fracture, we believe that strengthening it could lead to a strengthening of the overall bone.”

Long known but little understood, the protein osteocalin has been produced by and present in animal bones since before the dawn of humanity. Recently, abnormalities in ostoecalcin production have been associated with type 2 diabetes as well as problems in reproductive health. Vashishth’s new study, however, is the first to explain the structural and mechanical importance of osteocalcin in bone.

Now that osteocalcin is known to participate in bone fracture, new strategies for strengthening the bond between osteocalin and osteopontin can be investigated, Vashishth said. Augmenting the body’s natural supply of osteocalcin, for example, could be one possible strategy for treating osteoporosis and other conditions leading to increased fracture risk, he said. Osteocalin must be in its carboxylated form to get absorbed into bone, and the protein is carboxylated by vitamin K. Vashishth said future studies could investigate the relation between vitamin K intake, osteocalcin, and bone strength.

“Currently, all of the advice for treating osteoporosis is related to calcium. We believe there’s more to the story than just calcium, and the results of this new study raise an important question about vitamin K. Leafy green vegetables are the best source of vitamin K—wouldn’t it be great if eating spinach and broccoli was not only healthy, but also good for your bones? We plan to investigate this link in future,” Vashisth said.

Results of the new study, titled “Dilatational band formation in bone,” were recently published online by Proceedings of the National Academy of Sciences, and will appear in an upcoming print edition of the journal. The study may be viewed online at: http://www.pnas.org/content/early/2012/10/31/1201513109.full.pdf

At Rensselaer, this research was conducted in the laboratories of the Center for Biotechnology and Interdisciplinary Studies.

Along with Vashisth, co-authors of the paper are Rensselaer BME graduate students Atharva Poundarik and, Tamim Diab, BME post-doctoral fellows Grazyna Sroga, and Ani Ural (currently a faculty member at Villanova University), Adele Boskey of the Musculoskeletal Integrity Program at the Hospital for Special Surgery in New York, and Caren Gundberg of the Department of Orthopedics and Rehabilitation at Yale University.

Source:RPI

What causes hot flushes during menopause?

Hot flushes are not 'in the head,' but new research suggests they may start there; a UA research team has identified a region in the brain that may trigger the uncomfortable surges of heat most women experience in the first few years of menopause

		Picture: Through her studies, Dr. Naomi Rance has worked out the neuroanatomy of KNDy neurons and discovered how they participate in important life functions such as reproduction and body temperature regulation.

Hot flushes affect millions of people, and not just women. Yet, it is still unclear what causes the episodes of temperature discomfort, often accompanied by profuse sweating.
Now a team of researchers around Dr. Naomi Rance, a professor in the department of pathology at the UA College of Medicine, has come closer to understanding the mechanism of hot flushes, a necessary step for potential treatment options down the road. This research was published recently in theProceedings of the National Academy of Sciences.
The team identified a group of brain cells known as KNDy neurons as a likely control switch of hot flushes. KNDy neurons (pronounced "candy") are located in the hypothalamus, a portion of the brain controlling vital functions that also serves as the switchboard between the central nervous system and hormone signals.
"Although the KNDy neurons are a very small population of cells, our research reveals that they play extremely important roles in how the body controls its energy resources, reproduction and temperature," said Melinda Mittelman-Smith, who led the study as part of her doctoral thesis. "They are true multitaskers."
By studying KNDy neurons in rats, the research team created an animal model of menopause to elucidate the biological mechanisms of temperature control in response to withdrawal of the hormone estrogen, the main trigger of the changes that go along with menopause.
They discovered that tail skin temperature was consistently lower in rats whose KNDy neurons were inactivated, suggesting the neurons control a process known as vasodilation, or widening of the blood vessels to increase blood flow through the skin.
"The hallmark of hot flushes is vasodilation," explained Rance, who also is a neuropathologist at The University of Arizona Medical Center. "When you flush, your skin gets hot and you can see the redness of the skin. It is an attempt of the body to get rid of heat, just like sweating. Except that if you were to measure core temperature at that point, you would find it is not even elevated."
Although the results are not yet directly applicable in helping individuals affected by hot flushes, they mark a necessary first step, Rance said.
"Obviously we can't do these studies in women, and only if we understand the mechanism is there a chance of developing therapies. All that is known so far is that dwindling estrogen levels have something to do with it but anything after that is a black box."
"Right now the only effective way of treating flushes is estrogen-replacement therapy. If we could figure out what is causing those flushes, we could try to develop a better, more targeted therapy."
Rance said hot flushes usually last for four or five years and occur in up to 80 percent of women but also in men undergoing certain hormone treatments for prostate cancer.
"For some people it's not too bad, but it can be very severe in other individuals; they loose sleep et cetera. So the question I have been asking myself is, 'How come we haven't figured this out?'"

		Picture:An important switchboard between the brain and the body's hormonal system, the hypothalamus (red) is where the KNDy neurons -- the potential triggers of hot flushes -- reside.

Together with her coworkers, Rance has studied KNDy neurons and their functions for two decades.
"KNDy neurons respond to circulating estrogens," Mittelman-Smith explained. "When these hormones are at very low levels, as is the case in menopause, these neurons go haywire if you will. They grow very large and manufacture several times more neurotransmitter than they did with estrogens present."
"Because the neurons talk to known thermoregulatory centers of the brain, we think this increased signaling activity may inappropriately tell the body, 'I'm hot, release heat.' This triggers heat loss mechanisms like sweating and opening up of blood vessels in the skin."
Analogous to women going through menopause, the tail skin temperature goes up in rats after removal of the ovaries, where estrogen is produced.
"Rats regulate heat dissipation with their tail because the rest is covered by fur," Rance explained. "In rats without ovaries, the lack of estrogen causes vasodilation, which we can measure as increased tail skin temperature."
"Once we knew that estrogen really does control tail skin temperature in a rat, we wanted to know what role, if any, the KNDy neurons play in this."
When Rance and her team compared the tail skin temperatures of rats with intact KNDy neurons to those with inactivated KNDy neurons, they discovered that while tail skin temperatures still followed the same ups and downs over the course of the day and night cycle, they were lower in the absence of KNDy activity.
"They have lower levels of vasodilation," Rance said. "It is very consistent. Their tail skin temperature is lower than rats with normal KNDy neurons and stays low. It doesn't matter if they have estrogen or not; it doesn't matter if it's night or if it's day."
"The rats didn't seem unhappy at all," she added. "You'd think they'd be curling up and shivering, but no. There was no difference in the core temperature, so they weren't internally cold. We did all the activity measurements and found them to be completely normal. We couldn't tell a difference other than lower vasodilatation."
Rance said she is not surprised that the same neuronal switches that are important for reproduction also control thermoregulation.
"Being able to regulate body temperature is very important for the species and also for reproduction because it is important for a pregnant woman to avoid extreme hyperthermia. Hot flushes are a symptom of hyperactivity of these neurons."
The researchers caution that while KNDy neurons are critical for normal thermoregulation, they are by no means the sole center for managing body temperature.
"These animals would be in much more trouble if that were the case," Mittelman-Smith said. "In fact, I don't view KNDy neurons as a thermoregulatory center at all, but rather a group of cells that has the ability to influence thermoregulatory centers."
Rance added: "I wouldn't say we solved the problem, but we have a good clue about what could be causing the flushes."
Source:University of Arizona