Risk-Treatment Paradox: Penn Researchers Find Heart Attack Patients Not Always Receiving Lowest-Risk Care

Researchers Examine Bleeding Complications Associated with Two Cardiac Stent Placement Techniques

Newswise, December 29, 2015– More than 375,000 American each year experience a heart attack, during which blood flow to a part of the heart is impeded by blocked arteries. 

Physicians often treat patients with stents, which prop open the arteries to allow blood to flow again. 

They use two approaches to place stents: transradial, or entry of the catheter which delivers the stent through the wrist, or transfemoral, in which the catheter is placed through the groin. In a comparison of bleeding complications and mortality between the two approaches, researchers from the Perelman School of Medicine at the University of Pennsylvania found that those at risk for more bleeding were often treated with a riskier procedure – the transfemoral approach – a demonstration of the so-called risk-treatment paradox. 

The findings, from the largest study of its kind, are detailed in this week’s Journal of the American College of Cardiology: Cardiovascular Interventions.

The subject of the study, known as rescue percutaneous coronary intervention (PCI), is performed when a patient’s heart attack has not subsided after being treated with powerful clot-busting medications, an approach commonly used in developing countries and rural areas of the United States where access to catheterization labs are not immediately available. 

Researchers gathered data on 9,494 patients from the National Cardiovascular Registry’s CathPCI database and analyzed records for those who underwent rescue PCI between 2009 and 2013.

The findings revealed that transradial rescue PCI was only used in about 15 percent of the rescue PCI cases performed in the United States, and bleeding was reduced in these cases. 

The team also found that patients who were most prone to bleeding – as determined by a 33-category risk model which accessed clinical features such as age, body mass index, preexisting heart failure, and peripheral vascular disease – were more likely to be treated via transfemoral access, which is known to result in more significant post-procedure bleeding. 

Of the 1,348 transradial cases analyzed, only 93 patients experienced a bleeding complication. 

However in the 8,146 treated with transfemoral PCI, 967 had significant post-procedural bleeding, a five percent difference between the two groups.

“We were surprised to see how few of these rescue PCI cases were approached with transradial access, given the increase in bleeding one might expect when performing a procedure on a patient who recently received thrombolytic therapy,” said the study’s senior author, Jay Giri, MD, MPH, an assistant professor of Clinical Cardiovascular Medicine. 

“Even more interesting was the finding that among the group studied, patients at the highest risk for bleeding – those who would benefit most from transradial access – were least likely to receive that procedure. This counterintuitive finding is a demonstration of the ‘risk-treatment paradox,’ showing that doctors in these cases made treatment decisions based on what they are most comfortable with rather than what is best for the patient.”

The risk-treatment paradox describes a situation in which patients who are at the highest baseline risk for a condition are less likely to be treated aggressively for that condition. In the present case, the authors note that this finding may have been driven by decision-influencing factors such as physician training or experience.

Despite differences in bleeding rates, researchers found that there was no significant difference in mortality rates – a less than one percent variance. In addition, the team only evaluated cases where the patient was in stable condition following the clot-busting medication. 

Therefore, high-risk patients – those in need of assistive heart pumps – with a higher risk of death were not included in the analysis.

Giri added that until 2004, few transradial PCI procedures were performed in the United States, and little research was available to demonstrate its efficacy. 

“However, in recent years, both research and widespread education in the technique has led to exponential growth in its use,” he noted. “I would expect that over the next few years, transradial PCI will become the standard for heart attack patients, and these results help to further define best practices in its use.”

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. 

The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.

Study Uncovers Inherited Genetic Susceptibility Across 12 Cancer Types

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Newswise, December 29, 2015 — Researchers long have known that some portion of the risk of developing cancer is hereditary and that inherited genetic errors are very important in some tumors but much less so in others.

In a new analysis, researchers have shed light on these hereditary elements across 12 cancer types — showing a surprising inherited component to stomach cancer and providing some needed clarity on the consequences of certain types of mutations in well-known breast cancer susceptibility genes, BRCA1 and BRCA2.

The study, from Washington University School of Medicine in St. Louis, appears Dec. 22 in the journal Nature Communications.

The investigators analyzed genetic information from more than 4,000 cancer cases included in The Cancer Genome Atlas project, an initiative funded by the National Institutes of Health (NIH) to unravel the genetic basis of cancer.

“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” said senior author Li Ding, PhD, associate professor of medicine and assistant director of the McDonnell Genome Institute at Washington University. 

“But this is the first time on a large scale that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”

The new information has implications for improving the accuracy of existing genetic tests for cancer risk and eventually expanding the available tests to include a wider variety of tumors.

Past genomic studies of cancer compared sequencing data from patients’ healthy tissue and the same patients’ tumors. 

These studies uncovered mutations present in the tumors, helping researchers identify important genes that likely play roles in cancer. But this type of analysis can’t distinguish between inherited mutations present at birth and mutations acquired over the lifespan.

To help tease out cancer’s inherited components, the new study adds analysis of the sequencing data from the patients’ normal cells that contain the “germline” information. 

A patient’s germline is the genetic information inherited from both parents. This new layer of information gives a genetic baseline of a patient’s genes at birth and can reveal whether cancer-associated mutations were already present.

In all the cancer cases they analyzed, the investigators looked for rare germline mutations in genes known to be associated with cancer. 

If one copy of one of these genes from one parent is already mutated at birth, the second normal copy from the other parent often can compensate for the defect. 

But individuals with such mutations are more susceptible to a so-called “second hit.” As they age, they are at higher risk of developing mutations in the remaining normal copy of the gene.

“We looked for germline mutations in the tumor,” Ding said. “But it was not enough for the mutations simply to be present; they needed to be enriched in the tumor — present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”

In 114 genes known to be associated with cancer, they found rare germline mutations in all 12 cancer types, but in varying frequencies depending on the type. They focused on a type of mutation called a truncation because most truncated genes can’t function at all.

Of the ovarian cancer cases the investigators studied, 19 percent of them carried rare germline truncations. In contrast, only 4 percent of the acute myeloid leukemia cases in the analysis carried these truncations in the germline. 

They also found that 11 percent of the stomach cancer cases included such germline truncations, which was a surprise, according to the researchers, because that number is on par with the percentage for breast cancer.

“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Ding said. “This suggests we should pay attention to the potential involvement of these two genes in other cancer types.”

The BRCA1 and BRCA2 genes are important for DNA repair. While they are primarily associated with risk of breast cancer, this analysis supports the growing body of evidence that they have a broader impact.

“Of the patients with BRCA1 truncations in the germline, 90 percent have this BRCA1 truncation enriched in the tumor, regardless of cancer type,” Ding said.

Genetic testing of the BRCA1 and BRCA2 genes in women at risk of breast cancer can reveal extremely useful information for prevention. When, for example, the genes are shown to be normal, there is no elevated genetic risk of breast cancer. 

But if either of these genes is mutated in ways that are known to disable either gene, breast cancer risk is dramatically increased. In this situation, doctors and genetic counselors can help women navigate the options available for reducing that risk.

But mutations come in a number of varieties. Genetic testing also can reveal many that have unknown consequences for the function of these genes, so their influence on cancer risk can’t be predicted.

To help clarify this gray area in clinical practice, Ding and her colleagues Jeffrey Parvin, MD, PhD, professor and director of the division of computational biology and bioinformatics at The Ohio State University, and Feng Chen, PhD, associate professor of medicine at Washington University, investigated 68 germline non-truncation mutations of unknown significance in the BRCA1 gene. 

For each mutation, they tested how well the BRCA1 protein could perform one of its key DNA-repair functions. The researchers found that six of the mutations behaved like truncations, disabling the gene completely. 

These mutations also were enriched in the tumors, supporting a likely role in cancer.

“It is important to be able to show that these six mutations of unknown clinical significance are, in fact, loss-of-function mutations,” Ding said. 

“But I also want to emphasize the contrasting point. Many more show normal function, at least according to our analysis. Many of these types of mutations are neutral, and we would like to identify them so that health-care providers can better counsel their patients.”

Ding said more research is needed to confirm these results before they can be used to advise patients making health-care decisions.

“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”

Other key contributors to the study include Charles Lu, PhD; Mingchao Xie; Mike Wendl, PhD; Mike McLellan; Jiayin Wang, PhD; and Kim Johnson, PhD, from Washington University; and Mark Lerseison from Brown University.

This work was supported by the National Institutes of Health (NIH), including the National Cancer Institute (NCI), grants R01CA180006, R01CA178383, R01CA141090 and PO1CA101937; the National Human Genome Research Institute (NHGRI), grants U01HG006517, R01HG007069, U54HG003079 and T32 HG000045; the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), grant R01DK087960; the Department of Defense, grant PC130118; a Ministry of Education in Taiwan Fellowship, and CMB training grant GM 007067. The Cancer Genome Atlas (cancergenome.nih.gov) was the source of primary data.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MDM, Huang K, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, Miller CA, Kanchi KL, Eldred JM, Larson DE, Welch JS, You M, Ozenberger BA, Govindan R, Walter MJ, Ellis MJ, Mardis ER, Graubert TA, Dipersio JF, Ley TJ, Wilson RK, Goodfellow PJ, Raphael BJ, Chen F, Johnson KJ, Parvin JD, Ding L. Patterns and functional implications of rare germline variants across 12 cancer types. Nature Communications. Dec. 22, 2015.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. 

The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC Health

Fifty-Two From Twelve Million: Scientists Find the Genes That Set Into Motion Age-Related Macular Degeneration

Research Findings Could Lead to Diagnostics and Treatment for the Eye Disease

Newswise, December 29, 2015 — In one of the latest examples of precision medicine, teams of geneticists from nine countries, involving more than 100 scientists, analyzed the genes of more than 33,000 individuals in the hope of finding genetic variations responsible for age-related macular degeneration (AMD), the leading cause of vision loss among people age 50 or older.

Their research, involving complex computational analysis of more than 12 million genetic variations across the human genome, identified 52 variations associated with the disease.

By identifying these genetic variations, spread across 34 gene regions, scientists are a step closer to developing diagnostics that identify which patients are at high risk for acquiring the disease and formulating therapeutics either to prevent or treat the disease caused by these genetic variations.

Leading the coordination of the massive, multi-national research effort conducted by the International AMD Genomics Consortium was Case Western Reserve University School of Medicine’s Jonathan L. Haines, PhD, whose team also helped guide the complex computational analysis of the data from those study participants with advanced AMD and those without AMD.

Their findings appear in the December 15 edition of Nature Genetics.

“The enormity and complexity of studying the genetics behind AMD required a large-scale computational analysis study of the disease that could only be performed by bringing together the world’s leading researchers,” said Haines. Haines is the chair of Epidemiology and Biostatics and the Mary W. Sheldon, MD, Professor of Genomic Sciences, as well as the director of the Institute for Computational Biology—a joint venture between Case Western Reserve University, University Hospitals Case Medical Center and Cleveland Clinic.

As part of their research, consortium investigators chose to study both common and rare genetic variations. Genetic variations are the DNA sequence differences between individuals. Genetic variations affect physical traits such as eye color or susceptibility to specific diseases. 

Because of the millions of genetic variations present in the genome, it took genetic computational analysis from multiple centers to pinpoint the variations specific to AMD.

Using sophisticated computer programs, scientists were able to sort and synthesize more than 12 million genetic variations culled from the study’s more than 33,000 individual participants.

Moreover, they applied another dynamic big data science technique -- computational pathway analysis -- whereby statistically significant variations are grouped together based on the genes they are associated with and the biological pathways those genes affect.

Computational pathway analysis reveals how these gene variation groupings may affect biological events leading to AMD.

The combined computational analysis of the entire consortium identified, for the first time, a genetic variant specific to one subtype of AMD. The group identified one genetic variant located near the MMP9 gene region that is implicated only in the particularly damaging wet form of AMD.

AMD comes in dry and wet forms. Both damage vision by destroying cells in the macula, the small center of the retina in the back of the eye. It’s the macula’s job to focus images coming through the eye, which are then converted to electrical signals and sent through the optic nerve to the brain.

Localized inflammation in the retina triggers the development of drusen, which are fatty, lipid-rich deposits that accumulate in the eye as a natural part of the aging process. 

Enough inflammation and drusen accumulation will destroy photoreceptors in the back of the eye that receive the electrical signals from the retina, causing vision loss.

Dry AMD causes loss of cells in the macula and progresses more slowly. The wet form progresses rapidly and causes an abnormal growth of blood vessels within the macula.

These blood vessels impair vision by leaking fluid into the eye and are the result of uncontrolled vascular endothelial growth factor (VEGF) spurring development of new blood vessels.

The consortium’s big-data solution paid off when they found genetic variations in the region near the MMP9 gene that exclusively affect the wet form of AMD. What MMP9 does is trigger VEGF to produce blood vessel growth in the eye. 

The finding suggests an explanation for why anti-VEGF therapy is not as effective in many AMD patients whose genetic make-up with the MMP9 gene variation makes them more susceptible to the disease’s progression. MMP9-induced VEGF production might overwhelm the anti-VEGF therapy’s effect.

“Almost every study up until now has only looked at common variations that are pervasive in the population,” said a lead author Jessica N. Cooke Bailey, PhD, a post-doctoral fellow in the School of Medicine’s Department of Epidemiology and Biostatics. 

“Our robust big data techniques allowed us to look for the rare variations that occur, for example, in one in 1,000 individuals. In the genetics world, those really rare genetic variations are important because those significantly increase the risk of a disease such as AMD in individuals who have them.”

Additionally, the consortium’s study located 10 variations pointing to genes involved in maintaining the extracellular matrix within the eye. 

The matrix is made up of nonliving material among cells that provides structural support in the eye. Seven of these 10 variations affecting the extracellular matrix point to a wet AMD subtype with no early-stage symptoms and with rapid progression.

“The possible connection between AMD and these extracellular matrix genes may allow for predictive genetic tests and more effective therapies for people with this type of AMD," Cooke Bailey said.

As for future research, next steps will be functional mechanistic studies to determine why and how key gene variations activate to cause AMD.

“More than 10 million Americans are affected by AMD,” Cooke Bailey says.

 “More than 2 million individuals over the age of 50 have the advanced disease. AMD also adds billions of dollars to health care costs. With more people entering their senior years, the AMD-affected population will only continue to grow, which makes this research particularly crucial.”

The study was funded in part by NEI Intramural Research Program and by NEI grants EY023164, EY012118, EY022310, T32 EY023194, P30-EY005722, EY0022005, EY016862, and EY022310. The study also was supported by NIH National Human Genome Research Institute grants HG006513, HG007022, and 1U01HG006389; National Institute on Aging grants AG019085; and National Center for Advancing Translational Sciences grant UL1TR000427. Dr. Cooke Bailey is supported in part by a PhARMA Informatics Postdoctoral Fellowship.

Study Reveals Environment, Behavior Contribute to Some 80 Percent of Cancers

“Substantial contribution of extrinsic risk factors to cancer development” publishes December 16 in Nature

Newswise, December 29, 2015– A team of researchers from Stony Brook University, led by Yusuf Hannun, MD, the Joel Strum Kenny Professor in Cancer Research and Director of the Stony Brook University Cancer Center, have found quantitative evidence proving that extrinsic risk factors, such as environmental exposures and behaviors weigh heavily on the development of a vast majority (approximately 70 to 90 percent) of cancers. 

The finding, reported in the December 16 online issue of Nature, in a paper titled “Substantial contribution of extrinsic risk factors to cancer development,” may be important for strategizing cancer prevention, research and public health.

Inspired by a January 2015 research paper in Science, which concluded that the majority of the variation in cancer risk among tissues is due to “bad luck,” the Stony Brook team used the same data to assess what leads to the risk of developing cancer. 

The interdisciplinary team of researchers from the Departments of Applied Mathematics and Statistics, Medicine, Pathology and Biochemistry, concluded the opposite – that most cancers are the result of external risk factors.

“Cancer is caused by mutations in the DNA of cells, which leads to uncontrolled cell growth instead of orderly growth. But the development of cancer is a complex issue, and we as a scientific community need to have solid analytical models to investigate what intrinsic and extrinsic factors cause certain forms of cancer,” said Dr. Hannun, senior author of the paper.

“Many scientists argued against the ‘bad luck’ or ‘random mutation’ theory of cancer but provided no alternative analysis to quantify the contribution of external risk factors,” explained Song Wu, PhD, lead author of the paper, and Assistant Professor in the Department of Applied Mathematics and Statistics, Stony Brook University. 

“Our paper provides an alternative analysis by applying four distinct analytic approaches.”

They developed four distinct approaches to assess cancer risk. With these four approaches, they discovered collectively and individually that most cancers are attributed largely to external risk factors, with only 10-to-30 percent attributed to random mutations, or intrinsic factors.

First, the researchers examined extrinsic risks by tissue cell turnover. In a data-driven approach, they re-examined the quantitative relationship between observed lifetime risk of cancer (ie, for lung, pancreatic, colorectal and other tissues) and division of the normal tissue stem cells in those groups reported in the Science paper. 

If intrinsic risk factors played a major role, the tissue with the similar stem cell divisions would show similar observed lifetime cancer risk. They found this pattern to be a rare one, and thus determined intrinsic factors played a vital role in only about 10 percent of cancers. 

These results are supported by strong epidemiologic evidence; for example studies showing that immigrants moving from countries with lower cancer incidence to countries with higher rates of cancer incidence acquire the higher risk in their new country.

The researchers also mathematically surveyed and analyzed recent studies on mutational signatures in cancer, which are regarded as “fingerprints” left on cancer genomes by different mutagenic processes. 

Some 30 distinct signatures among various cancers were identified. They analyzed the signatures and categorized them as having intrinsic or extrinsic origins. 

They found that while a few forms of cancer had a greater than 50 percent of intrinsic mutations, the majority of cancers, such as colorectal, lung, bladder and thyroid cancers had large proportions of mutations likely caused by extrinsic factors.

The team also analyzed the SEER (Surveillance, Epidemiologic and End Results Program) data, which showed that many cancers have been increasing in incidence and in mortality, suggesting that external factors contribute heavily to these cancers.

Lastly, they used computational modeling to dissect the contribution of the intrinsic processes in the development of cancer, based on known gene mutations in cancer and the likelihood that they arise from intrinsic mutation rates. 

They found that when three or more mutations are required for cancer onset (which is a currently accepted parameter), intrinsic factors are far from sufficient to account for the observed risks, indicating small percentages of intrinsic cancer risks in many cancers.

The four methods involved both data- and model-driven quantitative analyses, with and without using the stem cell estimations. The idea behind the overall approach was to assess cancer risk by multiple methods and not by a single type of analysis.

Dr. Hannun concluded that their overall approach “provides a new framework to quantify the lifetime cancer risks from both intrinsic and extrinsic factors, which will have important consequences for strategizing cancer prevention, research and public health.”

Co-authors of the paper include: Scott Powers of the Department of Pathology at Stony Brook University, and Wei Zhu, of the Department of Applied Mathematics and Statistics at Stony Brook University. 

All of the authors are collaborating investigators at the Stony Brook University Cancer Center.

About Stony Brook University
Part of the State University of New York system, Stony Brook University encompasses 200 buildings on 1,450 acres. Since welcoming its first incoming class in 1957, the University has grown tremendously, now with more than 25,000 students and 2,500 faculty. 

Its membership in the prestigious Association of American Universities (AAU) places Stony Brook among the top 62 research institutions in North America. U.S. News & World Report ranks Stony Brook among the top 100 universities in the nation and top 40 public universities, and Kiplinger names it one of the 35 best values in public colleges. 

One of four University Center campuses in the SUNY system, Stony Brook co-manages Brookhaven National Laboratory, putting it in an elite group of universities that run federal research and development laboratories. A global ranking by U.S. News & World Report places Stony Brook in the top 1 percent of institutions worldwide. 

It is one of only 10 universities nationwide recognized by the National Science Foundation for combining research with undergraduate education. As the largest single-site employer on Long Island, Stony Brook is a driving force of the regional economy, with an annual economic impact of $4.65 billion, generating nearly 60,000 jobs, and accounts for nearly 4 percent of all economic activity in Nassau and Suffolk counties, and roughly 7.5 percent of total jobs in Suffolk County.

Improving Brain’s Garbage Disposal May Slow Alzheimer’s and Other Neurodegenerative Diseases

Drug that enhances removal of toxic brain proteins improves cognition in mice

Newswise, December 29, 2015--A drug that boosts activity in the brain’s “garbage disposal” system can decrease levels of toxic proteins associated with Alzheimer’s disease and other neurodegenerative disorders and improve cognition in mice, a new study by neuroscientists at Columbia University Medical Center (CUMC) has found. 

The study was published today in the online edition of Nature Medicine.

“We have shown for the first time that it’s possible to use a drug to activate this disposal system in neurons and effectively slow down disease,” said study leader Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute. 

“This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.” 

The drug used was rolipram, which causes nausea and thus is not a good drug for use in humans, but similar drugs do not incur nausea as a side effect and could go into clinical trials very quickly. 

To remain healthy, brain cells must continually clear out old, worn, or damaged proteins, a task performed by a small molecular cylinder called the proteasome. 

The proteasome acts as a kind of garbage disposal, grinding up the old proteins so they can be recycled into new ones. In neurodegenerative diseases, proteins tagged for destruction accumulate in the brain’s neurons, suggesting that the cell’s proteasomes are impaired.

Using a mouse model of neurodegeneration, the researchers first discovered that tau--a toxic protein that accumulates in Alzheimer’s and other brain degenerative diseases--sticks to the proteasome and slows down the protein disposal process.

Administering rolipram activated the proteasome and restored protein disposal to normal levels. The drug also improved the memory of diseased mice to levels seen in healthy mice.

Rolipram has been tested before in mice and was shown to improve memory, but the mechanism for how this occurred was unclear. The new research shows that by inhibiting of the PDE-4 enzyme, rolipram produces a physical change in the proteasome that increases its activity.

“We still don’t know exactly where the activation is happening, but what’s new is that we can modify the proteasome to increase its activity. There could be many other ways to do this,” said the study’s first author, Natura Myeku, PhD, an associate research scientist in pathology and cell biology at CUMC.

Drugs that target proteasomes in this way should work for any disease caused by the accumulation of abnormal proteins, including Alzheimer’s, Huntington’s, Parkinson’s and frontotemperoral dementia.

“Treatments that speed up these cell disposal mechanisms should, in theory, only degrade abnormal proteins. We don’t need to know what the toxic form of the protein is,” Dr Duff said. 

“In Alzheimer’s disease, there are at least four different types: amyloid, tau, alpha-synuclein, and TDP43. A well-functioning proteasome can clear out everything at once.”

“This exciting research from Dr. Duff’s team advances our basic understanding of the proteasome system, provides a way to repair the system when it breaks, and alleviates symptoms of neurodegenerative disorders,” said Rod Corriveau, PhD, program director at the National Institute of Health’s National Institute of Neurological Disorders and Stroke, which provided funding for the study.

The study is titled, “26S proteasome dysfunction and cognitive impairment caused by aggregated tau accumulation can be attenuated by PKA-mediated phosphorylation of proteasomes.” 

The other contributors are: Catherine L. Clelland (CUMC), Sheina Emrani (CUMC), Nikolay V. Kukushkin (Harvard Medical School, Boston, MA), Li Liu (CUMC), Yvette H. Figueroa (CUMC), and Wai Haung Yu (CUMC).

The study was supported by grants from the National Institute of Neurological Disorders and Stroke (NS074593), the CurePSP Foundation, the National Institute of General Medical Sciences (GM051923), the Fidelity Biosciences Research Initiative, and the Multiple Myeloma Research Foundation.

The researchers declare no financial or other conflicts of interest.

The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases and to discover ways to prevent and cure these diseases. 

It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system, and with the Departments of Pathology & Cell Biology and of Neurology to allow the seamless integration of genetic analysis, molecular and cellular studies, and clinical investigation to explore all phases of diseases of the nervous system. For more information, visit The Taub Institute at www.cumc.columbia.edu/dept/taub/.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. 

The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. 

For more information, visit www.cumc.columbia.edu or www.columbiadoctors.org

What to Do When a Loved One Is Suddenly Hospitalized

Loyola social worker offers coping tips

Newswise, December 23, 2015 — According to the Centers for Disease Control and Prevention, each year approximately 2.1 million patients in the Emergency Department are transferred to an intensive care unit. When that happens, relatives are also impacted and need a support system, according to Loyola University Health System (LUHS) licensed clinical social worker Kelly McElligott.

“Families are totally unprepared for a sudden injury and overwhelmed when it is a very serious injury,” says McElligott. “Families need a roadmap to guide them through their worst moments, and that is my job as a hospital social worker.”

McElligott works in Loyola’s Burn Center, the largest burn center in Illinois and nationally renowned for treating the most complex wounds. “Our average length of stay is about three weeks but we have many patients who are with us for several months, due to the severity of their condition,” says McElligott.

“The patients and their families have at their disposal a multidisciplinary team of physical therapists, dietitians, psychologists, chaplains and social workers. We all work together with the traditional care team of surgeons, physicians and nurses.” Loyola pioneered the integrated care model that is emulated by hospitals internationally.

Here are McElligott’s top tips for adults who find a loved one suddenly in the hospital:

Take care of yourself. “If you do not take care of yourself, you cannot take care of someone else,” says McElligott. “Many family members, especially parents, feel they need to be at the hospital 24/7 with their loved one,” she says. “Everyone needs to take time to eat, sleep, exercise and be with other people in the outside world.”

When one member is in the hospital, it is important for the whole family to continue to move forward. “Life does not stop because someone is in the hospital. Other family members need attention and support also,” she says.

“Mom and Dad need to be role models more than ever at this time. The hospital team can help support and guide them. And they can feel strengthened and confident to continue to guide their families.”

Accept help from your community. “Friends, relatives, colleagues and others will offer assistance and it is critical to accept help,” says McElligott.

“For example, coming home to a clean house and a meal in the refrigerator is very convenient and also comforting.” Online programs can be useful helpmates, such as those that coordinate meal organization, task and errand running, and communication with family.

“Many times, key family members are reluctant to ask or receive help. Usually there are outgoing neighbors or colleagues who will serve as primary contacts to relieve the burden,” says McElligott.

“People feel better when they have something to do; let them help and everyone will benefit.”

Ask a lot of questions. “Nurses, physicians, social workers and all medical staff are here to answer questions and offer resources,” says McElligott. “No individual could know what to expect when a severe injury occurs. That’s what medical professionals are for.”

Use a notepad or laptop and take notes when meeting with your health team. “Write down questions or concerns as they come to you and share them with your care team,” she says. “As they say in school, there are no bad questions, so do not feel shy or embarrassed. The more you know, the less you will fear.”

Talk to others about your experience. “Reach out to people for support by sharing your experience or what you have witnessed,” says McElligott. “Often, this will help reduce anxiety and build confidence.”

Sharing your story is often difficult and emotional at first, but becomes easier over time. “Talking helps define the event or injury, remove the emotion and perceived stigma, and can help identify next steps to move forward,” she said. “Getting feedback from others also can be reassuring and supportive.”

Use peer support. “Others who have walked the path you are on offer invaluable support, insight and understanding,” says McElligott. For example, Loyola offers a bi-monthly burn support group for patients and their families. “Speakers are brought in to share specific expertise but the greatest benefit comes through the informal talking among families,” she says.

Former burn patients are frequent visitors to the hospital floor and visit with patients and their families. “There are amazing stories of patients and family members who are very withdrawn and depressed who respond positively to our former burn patient volunteers,” she says. “They are able to see that life does go on, there are others who survived much worse injury and are still laughing, socializing and enjoying life.”

McElligott says it is a privilege to meet patients and their families during one of the worst times of their lives, and to guide them through the recovery process. 

“People are very resilient,” she says. “The transformations that happen once the shock wears off are amazing.”

UAB Studying Impact of Ketogenic Diet on Cognition in Older Adults with HIV

Newswise, December 23, 2015– Poor cognitive function is a serious problem in the aging HIV-positive population, where it has been estimated that up to 59 percent of HIV-positive adults demonstrate at least mild cognitive impairment.

University of Alabama at Birmingham School of Nursing Assistant Professor Shannon Morrison, Ph.D., is exploring multiple effects of a ketogenic diet — a high-fat, low-carbohydrate diet with adequate protein — in medically stable, older persons living with HIV who have mild to moderate neurocognitive impairment.

The study, following previous encouraging research, is supported by a one-year, $60,000 grant from the UAB Center for Clinical and Translational Science.

“In the studies that have been conducted so far, the ketogenic diet has shown some promising results in improving cognition in other neurocognitive disorders,” Morrison said. 

“We’re hoping to see if the same or similar results will occur to the older, cognitively impaired HIV population. I am just thrilled at this opportunity and am preparing to begin recruitment in early January.”

A person consumes fewer than 50 total grams of carbohydrates per day on a ketogenic diet. When the amount of carbohydrates, or sugars, the body has to process for fuel is limited, it will start to break down fat and, as a byproduct of that fat metabolism, produce the ketones for which the ketogenic diet is named.

“What a ketogenic diet does is change the energy source the body uses for fuel for its activities,” Morrison said. 

“If you are not taking in much sugar, your body will start breaking down fat for energy, and a byproduct of the fat metabolism is ketone bodies. The body, including the brain, is then able to efficiently utilize ketone bodies for energy.”

This randomized control trial, “The Effect of a Ketogenic Diet on HIV-Associated Neurocognitive Impairment,” will compare the effects of a 12-week ketogenic diet versus a patient-choice diet on cognitive function and cardiovascular risks in 20 older persons with stable HIV disease. 

This study is a part of the National Center for Advancing Translational Sciences of the National Institutes of Health.

For this pilot study, half the participants will be randomly assigned to the ketogenic diet group and half to the patient-choice diet group. 

Baseline data will be collected as the starting point to look for changes that may be linked to improved cognitive function similar to what has been seen in people with other neurological disorders, including Alzheimer’s disease, Parkinson’s disease and epilepsy, who ate a ketogenic diet. 

In addition, five members of the ketogenic group will undergo functional magnetic resonance imaging after 12 weeks to examine changes in neural activity associated with consumption of a ketogenic diet.

“The ketogenic diet has shown to decrease systemic inflammation in Alzheimer’s and Parkinson’s diseases, as well as after a cerebral vascular injury and traumatic brain injury in patients,” Morrison said. 

“We hope that the ketogenic diet will reduce systemic inflammation that may reduce heart and diabetes risks as well as improve cognitive performance in HIV-positive individuals.”

Throughout the 12-week trial, those in the ketogenic diet group will be provided meals and snacks. The meals will be matched for energy content to maintain current energy balance and will consist of less than 50 grams of carbohydrates per day with the participants’ daily carb intake coming primarily from non-starchy, fresh vegetables.

Morrison hopes the results of this study will lead to a larger clinical trial down the road and ultimately to solutions that will help improve neurocognitive performance in older HIV-positive patients.

“We hope to find ways to help these individuals function more independently without adding more medication for them to take but rather through an improved diet,” she said.

Is There An Objective Measurement to Identify Individuals at Risk of Developing Depression?

New Study Suggests a Potential Biomarker in the Brain

December 23, 2015--A network of interacting brain regions known as the default mode network (DMN) was found to have stronger connections in adults and children with a high risk of depression compared to those with a low risk.

These findings suggest that increased DMN connectivity is a potential precursor, or biomarker, indicating a risk of developing major depressive disorder (MDD).

The study was published online today in Neuropsychopharmacology.

Researchers at Columbia University Medical Center (CUMC) and New York State Psychiatric Institute (NYSPI) used magnetic resonance imaging to compare people at high risk for depression to those at low risk based on their family history of depression.

This approach allowed researchers to look for differences in the brain that are not a consequence of the depression itself, since the disorder had not yet manifested in most of the individuals.

The DMN brain system is more active when people are focused on internal thinking, such as ruminative thoughts.

Increased DMN connections have previously been seen in individuals with MDD, may relate to ruminative symptoms, and typically normalize with antidepressant treatment. The study reveals that the process of increasing DMN connections may occur before the onset of depression.

“These findings suggest that looking at activity in the DMN may offer an objective method of identifying people who are at risk of developing major depression,” said lead author Myrna Weissman, PhD, the Diane Goldman Kemper Family Professor of Epidemiology (in Psychiatry) at CUMC and Chief of the Division of Epidemiology at NYSPI.

“This may represent a another way toward advancing prevention and early intervention for this major public health issue.”

“If this insight proves correct,” said Jonathan Posner, MD, lead author and Associate Professor of Clinical Psychiatry at CUMC, ”behavioral interventions that improve the functioning of the DMN, such as meditation and mindfulness, could be used to address a brain-based problem (increased DMN connections), before it leads to a depressive illness.”

The article, entitled “Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression,” was published online as an accepted article preview in Neuropsychopharmacology; doi: 10.1038/npp.2015.342. The authors are Jonathan Posner, Jiook Cha, Zhishun Wang, Ardesheer Talati, Virginia Warner, Andrew Gerber and Myrna Weissman at the College of Physicians and Surgeons, Columbia University, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA; and Bradley S Peterson at the Institute for the Developing Mind, Children’s Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

This study was supported in part by NIMH grants R01-MH036197 and K23-MH091249 and the Sackler Institute for Psychobiology

Dr Posner has received research support from Shire Pharmaceuticals. The remaining authors have no competing interests to report.