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April, 2009
Includes: Research in patients, Translational research, New approach for immunology programs: the Dana Scholars, Update: Effects of heart surgery on the brain, 25th Anniversary: The Dana-Farber Cancer Institute, Special Case: Patient H.M., Special Focus: Deep Brain Stimulation, Support for science and math education
Our science grants reflect the Foundation's priorities: understanding the processes involved in brain and immune-related disorders; assessing the effects of experimental treatments; describing how the healthy brain and immune system work and how malfunctions lead to diseases; and adapting existing technologies and refining new techniques to improve diagnostic and treatment research and clinical practice. In 2008 we awarded almost $13 million in health and science research grants.
To draw talent into these fields, we favor new investigators with bold ideas and established investigators who wish to take a leap in a new direction or test a fledgling theory. We encourage experienced researchers to mentor newer colleagues.
We fund pilot studies to test new hypotheses about how the brain and the immune system function in health and disease. Many of our grants support small, promising studies on the first human patients, bridging the federal-funding gap between bench research and clinical trials. Scientists use the data they acquire in small studies to support their applications for federal and other funds to do extended research.
We give grants in brain and immuno-imaging, clinical neuroscience research, neuroimmunology, and human immunology. Application guidelines for each branch of research are available online. In 2008, investigators whose work we support have advanced treatments for several brain disorders, including the use of electrodes implanted in the brain (deep brain stimulation, or DBS) for intractable depression and Parkinson's disease. Other grants have explored connections between heart disease and depression, the potential of extended-release naltrexone to reduce heroin dependence, and the possibility that certain protein markers predict the risk of Alzheimer's disease. Others have refined techniques for imaging the brain and immune cells in action. Below are some highlights.
After a stroke, the speed and quality of care a patient receives can mean the difference between recovery and death or further injury and impairment. Under a 2005 grant, Stephan Mayer, M.D., and colleagues at New York-Presbyterian Hospital developed and tested a computerized brain monitoring system that alerts physicians, in real time, to impending problems in stroke patients being treated in intensive care units.
The system is intended to prevent further damage to brain tissue by monitoring several interrelated measures of brain oxygenation and metabolism and alerting doctors at the first signs of trouble. Using a probe inserted into the brain, the researchers discovered that two measures of adequate delivery of oxygen to brain tissues (oxygen tension and the ratio of lactate to pyruvate) can be influenced by manipulating blood pressure, temperature, and glucose. Dr. Mayer and his colleagues found a way to represent these measures together graphically and in real time so that doctors at the bedside can see what is happening and respond to it.
The system, called multimodality monitoring, tracks multiple parameters of brain physiology and function that can be affected by direct medical or surgical intervention. The researchers also plan to determine whether these measurements can predict stroke mortality and recovery.
The computer-based system, which the team continues to work on, is now used at the bedside in New York-Presbyterian's 18 neuro-ICU units to monitor oxygen levels in the brains of comatose patients who have had hemorrhagic strokes (bleeding in the brain from a ruptured blood vessel). The software signals when oxygen levels cross the line and become insufficient, leading to brain tissue damage. Then physicians can work immediately to restore the right oxygen balance, rather than waiting for a problem to cascade into further damage.
Through this work, the team has made several important discoveries:
Dr. Mayer's research on hypothermia in cardiac arrest patients has led New York City to require that such patients be taken only to hospitals that have the capacity of providing hypothermia treatment. Dr. Mayer presented some of his hypothermia findings at a September 2008 forum at the New York Academy of Sciences titled "Hypothermia—From Threat to Cure," co-sponsored by the Dana Foundation and the academy.
During two years of Dana-funded research, the team collected more than 2,500 hours of multimodal ICU data on 29 patients. Their report on the effects of insulin therapy was selected as one of the best scientific abstracts at the 2008 Society of Critical Care Medicine meeting.
The work has led to approval of a five-year National Institutes of Health (NIH) training grant for one of the investigators to study the effects of modulating hypothermia therapy on metabolism and brain oxygenation in stroke patients. It also has provided the necessary preliminary data for two additional NIH grants.
"This support has allowed us to address a significant unmet need in the clinical neurosciences, and has served as a building block toward the ultimate goal of developing a data management system that can be used in neurological intensive care units throughout the world," Dr. Mayer said.
Roughly one-third of the 1.6 million people in U.S. prisons (as of December 2007) report a history of heroin addiction. Continued addiction is considered a major contributor to the nation's high rate of re-incarceration, primarily due to arrests for stealing and causing harm in connection with buying heroin. Helping people kick addiction could prevent or reduce rates of incarceration and re-incarceration.
Some experts say the drug naltrexone is the perfect anti-addiction treatment; it completely blocks the effects of opiates, making relapse impossible. In addition, naltrexone produces no "high," unlike two other available drugs for treating heroin addiction, methadone and buphenorphene, which produce slight highs and are addictive themselves.
"Naltrexone completely blocks the actions of some drugs of abuse—the person won't get high," said Nora Volkow, M.D., director of the National Institute on Drug Abuse (NIDA) and a member of the Dana Alliance for Brain Initiatives. "It's a perfect example of how you can develop medications that interfere with the rewarding effects of drugs."
But in the more than 20 years since the U.S. Food and Drug Administration (FDA) approved the oral form of naltrexone for treating heroin addiction, the drug has had mixed success. The trouble is that the oral form of naltrexone is short acting. It must be taken daily or at least several times a week, and it requires recovering addicts to summon the willpower to remain heroin-free day after day.
In 2006, the FDA approved a long-acting (monthly) injectable form of naltrexone for treating alcohol addiction. Charles O'Brien, M.D., Ph.D., and colleagues at the University of Pennsylvania headed a consortium to investigate the feasibility of providing this new form of naltrexone to prevent heroin relapse among adult parolees and probationers in five cities.
Dana funding supported clinicians' efforts to work with the criminal justice system in the five sites during a yearlong pilot study to provide naltrexone as a therapeutic option. Adults on parole or probation with past histories of heroin addiction were invited to participate. Volunteers agreed to be tested to determine that they were heroin-free. Then they were given injections of naltrexone each month for six months, and they returned another six months later for final drug tests. The pilot study showed that the treatment sites could effectively work with their local criminal justice systems to offer the treatment without coercion. Sixty-five percent of the 30 participating adults completed their 6-month treatments, and more than three-quarters of these participants attended their 12-month follow-up appointments for tests showing they were still heroin-free.
In spring 2008, anticipating final approval of NIDA funding to expand the study, the researchers asked the Foundation for a bridge grant to continue the program into the fall. The Foundation agreed and, in October, NIDA awarded the team a $5 million grant to fully fund a large-scale study enrolling up to 400 more volunteers.
Today Alzheimer's disease is diagnosed on the basis of memory and related cognitive tests after other potential causes of its symptoms have been ruled out. These outward symptoms, however, develop decades after plaques of beta-amyloid peptide have begun to accumulate in the brain. Definitive diagnoses of Alzheimer's disease occur only after death, through autopsy of the brain and confirmation of the buildup of beta-amyloid.
Dana-sponsored researchers are using brain imaging and other tools to observe and measure beta-amyloid deposits in older adults to try to predict who is at risk for developing Alzheimer's. Such measures may help doctors foretell which adults with mild cognitive impairment are at risk of progressing to Alzheimer's disease, as well as gauge how well anti-Alzheimer's therapies are working. One day doctors may be able to prevent or even reverse the events leading to cognitive decline.
A promising radiologically labeled agent that appears to bind only to beta-amyloid in the brain and is visible through brain imaging was developed by researchers led by William Klunk, M.D., Ph.D., and Chester Mathis, Ph.D., of the University of Pittsburgh. Named Pittsburgh Compound-B (PIB), the fluorescent tracer temporarily "lights up" the beta-amyloid plaques so they are visible in positron emission tomography (PET) scans. Several Dana-funded studies suggest that PET imaging using PIB can provide a reliable and valid method for diagnosing Alzheimer's disease and for differentiating it from mild cognitive impairment that does not progress to Alzheimer's.
In 2004, a three-year Dana grant to Julie Price, Ph.D., at the University of Pittsburgh supported a study to see if PET-PIB testing reliably worked to identify and quantify levels of beta-amyloid. The researchers tested 34 adults. Some had been diagnosed with Alzheimer's, others had mild cognitive impairment, and a third group tested normal to determine whether using the PIB tracer could differentiate these three groups. Researchers found that it could. Their results have been reproduced at more than 25 PET imaging research centers studying more than 100 adults.
In 2005, a related three-year Dana grant funded further testing of the PET-PIB method by its developers at the University of Pittsburgh in collaboration with investigators led by Kirk Frey, M.D., Ph.D., at the University of Michigan and John Morris, M.D., at Washington University in St. Louis.
Researchers at the three institutions recruited healthy volunteers and adults with mild cognitive impairment. They collected baseline information on the presence and extent of brain beta-amyloid deposits in both groups. Researchers expect that some of the adults with mild cognitive impairment will develop Alzheimer's disease within a few years, and investigators will determine whether those who develop the disease experienced increased beta-amyloid buildup during that time. To date, the three institutions have imaged more than five dozen patients.
Consortium investigators reported in 2006 in the journal Neurology that PIB attaches in greater amounts to beta-amyloid in eight patients clinically diagnosed with Alzheimer's disease, compared with 41 same-aged adults with no clinical symptoms of the disease (with the exception of two of these asymptomatic adults, who also showed signs of beta-amyloid deposits). Under two grants from the National Institutes of Health, researchers will continue to follow these patients for at least five more years to determine whether they eventually develop Alzheimer's. These studies may help to validate PIB-PET testing as a reliable tool for diagnosing Alzheimer's early, when it might be most effectively treated.
In a related study, as reported in the journal Brain in March 2008, Drs. Klunk, Mathis, and colleagues confirmed that PIB binds directly to beta-amyloid deposits in the brains of people with Alzheimer's disease. They compared imaging results with autopsies of patients' brains.
Drs. Klunk and Mathis were awarded the 2008 Potamkin Prize for their development of PIB. The prize recognizes researchers who have made outstanding contributions to the study of Alzheimer's disease and related dementias.
Only one type of immune cell—the microglial cell—naturally resides in the brain and spinal cord to detect and respond to invaders or injury. Because the brain is isolated from the rest of the body by a film of cells called the blood-brain barrier, most infections and other harmful agents don't reach vulnerable central nervous system tissue.
When damage or infection is detected in the brain, microglial cells must react quickly, producing inflammation around the damaged tissue and summoning other immune cells to enter the brain or spinal cord to fight the invader. But sometimes microglial cells overreact and produce extensive inflammation that destroys surrounding healthy tissue. In other situations, called autoimmune diseases, immune cells are summoned to attack cells in the brain's own tissues that have been mistakenly identified as foreign invaders.
We are still in early stages of understanding how microglia operate. Scientists in labs worldwide are trying to tease out what is happening when these cells work as they should and why they sometimes go astray.
Microglia seem to cluster around the beta-amyloid deposits in the brain that are implicated in Alzheimer's disease (AD), but scientists aren't sure if their inflammatory actions are meant to clear the plaques away to help prevent further damage or are contributing to the destruction of tissue around plaques.
Joseph El Khoury, M.D., and colleagues at Massachusetts General Hospital used a 2006 Dana grant to explore how additional immune microglial cells are recruited into the brain from the spinal cord in mice—and what the cells do once they get there.
Dr. El Khoury found that the brains of mice with an Alzheimer's-like disease whose brains were genetically altered to lack the brain-cell receptor CCR2 (which appears to signal microglia to migrate to the brain from the spinal cord) accumulated fewer microglial cells than mice with intact CCR2 receptors. This relative lack of microglial cells recruited into the brain correlated with early and deadly accumulation of beta-amyloid around blood vessels in the brain, and the CCR2-deprived mice died far earlier than anticipated.
The researchers didn't expect to see such a dramatic and early response, Dr. El Khoury said. The study offers in vivo evidence that the brain's immune system plays a protective role—at least in early Alzheimer's disease—by mediating the clearance of beta-amyloid.
"Our data provide evidence . . . that the inflammatory response in AD is a 'double-edged sword,'" the authors wrote in their paper published in the Journal of Neuroscience in August 2008. They hypothesized that with increasing age, microglia become less effective in preventing the buildup of beta-amyloid that characterizes Alzheimer's disease, resulting in beta-amyloid accumulation in the brain. Too much beta-amyloid then stimulates the microglial cells to release toxic inflammatory agents, and this inflammation around amyloid plaques destroys nearby brain cells.
To further test this hypothesis, Dr. El Khoury and Changiz Guela, Ph.D., are using a new Dana grant to study human brain tissue obtained from autopsies of ten young, ten middle-aged, and ten older people. They will isolate microglia from the brain tissues and expose it to fluorescence-labeled beta-amyloid, to see if the actions of microglial cells change as a person ages.
If the results confirm that the role of microglial cells changes with age and leads to beta-amyloid buildup and deadly inflammation, the findings could eventually lead to new approaches to therapies for treating or preventing Alzheimer's disease.
Patients respond to cancer drugs in different ways, and physicians often try several drugs until they find the ones that work best for a specific patient. Since cancers grow quickly, time is of the essence in finding the most effective therapies.
A new imaging technique developed by Caius Radu, M.D., and colleagues at the University of California, Los Angeles, may provide a method for quickly predicting the effectiveness of a specific drug for a specific cancer patient.
Dr. Radu's team has devised a molecular probe whose molecules light up when viewed by positron emission tomography (PET) scanning. The probe attaches to the standard chemotherapy drug gemcitabine. In experiments with mice, the team watched as the probe—and the drug to which it was attached—was absorbed into one type of tumor, but not another.
"For the first time, we can watch a chemotherapy drug working inside the living body in real time," Dr. Radu says of the experiments.
The researchers plan to develop probes for several other widely used chemotherapy drugs to see if the method proves to be a clinically useful diagnostic test. They plan to start testing the probe's safety in healthy human volunteers this year. If this phase is successful, they will test the PET probe's utility in determining which cancer patients effectively respond to gemcitabine therapy.
"The beauty of this approach is that it is completely non-invasive and without side effects," Dr. Radu says. "If we are successful in transporting this test to a clinical setting, patients will be able to go home immediately."
Under a 2007 Dana grant, Dr. Radu's team also has begun to adapt their technique to studying autoimmune brain disease. They are focusing on an animal model of multiple sclerosis (MS).
Using the PET probe attached to immune T cells in mice with MS-like symptoms, the resesarchers are watching how immune T cells become activated in lymph tissues, migrate to the brain, and cross the blood-brain barrier to attack the myelin sheath that insulates nerve fibers. This research eventually may lead to finding out how to decrease immune T-cell activation in autoimmune multiple sclerosis and how to increase immune T-cell activation to fight melanoma, a cancer that often metastasizes to the brain.
Cancer starts as a series of premalignant changes in a particular tissue, a process that takes a long time to progress to a clinically evident tumor. Intervening at this premalignant stage is the aim of a Dana-supported research consortium composed of Olivera J. Finn, Ph.D., at the University of Pittsburgh, and Madhav Dhodapkar, M.D., formerly of Rockefeller University and now at Yale University.
The researchers have discovered that the human immune system recognizes alterations in premalignant forms of certain cancer cells and activates immune T cells and antibodies to prevent the premalignant cells from developing into cancer cells.
The Pittsburgh group studied people with lung cancer and others who were at a high risk of developing this cancer. The Rockefeller group studied people with multiple myeloma and people with monoclonal gammopathy of undetermined significance (MGUS), who have a high risk of developing multiple myeloma.
In both groups, many of the patients with the premalignant condition—but not the patients with cancer—were found to have spontaneous T-cell immunity to the specific tumor antigen that is present on the premalignant cells and on the cancerous cells. Patients' immune T cells "recognized" the antigen and reacted to it. This immune response is one of the strongest predictors of whether patients with MGUS will develop multiple myeloma—an even stronger predictor than genetic history, the researchers found.
But there was another surprise. "What we did not expect, and what we believe will lead to a new paradigm about cancer immunosurveillance, is that we found an even better immune response to these antigens in some healthy controls," said Dr. Finn.
That led the researchers to examine immune responses to another tumor antigen, MUC1, in a larger group of healthy adults. Their research showed that women who carried the specific immunity to MUC1 (anti-MUC1 antibodies) were less likely to develop ovarian cancer.
Other researchers, studying chronic inflammation and viral infections, recently showed that these immune processes alter the expression of some molecules in the same way that a malignant cancer transforms molecules. For instance, some viruses, such as varicella zoster (chicken pox virus) or human cytomegalovirus, cause overexpression and mislocalization of the molecule cyclin B1.
Based on this finding and their own results, the consortium researchers have revised their original hypothesis. They now propose that infections in childhood and adolescence generate immune memory for molecules in the body that are altered by the infection, such as cyclin B1 and MUC1. Dr. Finn said, "When later in life the immune system encounters abnormal expression of these molecules on tumor cells, they can serve as targets for tumor rejection. Normal tissue is never subject to the immune attack because expression of these molecules on normal cells is normal and therefore not visible to the immune system."
These findings support the use of MUC1 and cyclin B1 as potential preventive vaccines against multiple myeloma and lung cancer, respectively, in high-risk individuals. They also suggest that there must be other molecules of this kind. "By studying the immune system of healthy, tumor-resistant individuals, we might come up with a panel of antigens that can be used to evaluate cancer risk," Dr. Finn said.
This work has led to the filing of two patent applications and subsequent submission of two manuscripts for publication.
In her presidential address at the American Association of Immunologists conference in 2008, Dr. Finn said she is seeing "a new paradigm emerging in tumor immunology that may have a more general application to our understanding of immunosurveillance of not only cancer, but also viral and bacterial infections. . . . I am personally energized by this possibility and have fallen even deeper in love with tumor immunology for providing me with yet another window from which to peer into the endless intricacies of the immune system."
The Dana Foundation's human immunology program was begun more than five years ago to help advance patient-oriented research on immune-based diseases, including many affecting the brain.
As we do every several years with all our grant programs, we invited a respected scientist outside our fold to take a look at what we're doing. For immunology, we asked Professor Douglas T. Fearon, Sheila Joan Smith Professor of Immunology at University of Cambridge, to review our work. He wrote, "The projects that the Dana Foundation has supported appear to be of a uniformly high standard. I am also impressed by the breadth of subjects: they cover almost all aspects of human immunology, including infectious diseases, autoimmunity, allergy, and tumor immunology."
Patient-oriented research has a tough time competing against basic research because it is slower, and important variables (such as age and other health factors) are more difficult to control. Clinical and translational research are generally not a feature of immunology meetings, and it accounts for a small fraction of papers in major journals. Attracting and encouraging top new investigators to the field is therefore a major challenge, but it is an important need.
In 2008, the Foundation decided to concentrate our immunology efforts on helping to meet this need.
Instead of solely continuing to support consortium research, grants awarded in 2008 also went to several promising investigators selected as Dana Scholars. These are new faculty carrying out independent research, such as postdoctoral fellows making transitions to their first faculty positions as instructors or assistant professors. Scholars are initiating or engaged in immunology studies involving patients or patient tissues. [See the Grants section for specifics.]
Five Dana Scholar awards were made in late 2008. These new investigators are exploring the pathways that immune T cells use to attack hepatitis C virus, how lung inflammation occurs in asthma, how the immune system responds to therapeutic melanoma vaccines, how certain cells help limit HIV infection from progressing to AIDS, and why some people exposed to the tuberculosis bacterium develop tuberculosis while others do not. Support also enabled several research trainees to attend an immunology meeting. In 2009, immunology funding will focus solely on Dana Scholar awards.
Dana grants have helped fund a longitudinal study led by Guy McKhann, M.D., at Johns Hopkins University. Dr. McKhann's team is investigating heart surgery's possible effects on the brain, based on bedside reports that surgeries such as coronary artery bypass grafting cause cognitive decline. Some researchers theorized that this effect could be due to anesthesia, or that surgery using a pump to infuse the brain with oxygen, bypassing the heart, might induce tiny blood clots, which then travel to the brain and produce "mini-strokes."
But after the first decade of tracking bypass heart surgery patients and comparing them with several control groups, Hopkins researchers have concluded that neither of these theories is correct. The data indicate that underlying vascular disease, not heart surgery, is primarily responsible for long-term decline in cognitive functioning in people with coronary artery disease.
Also running counter to current thinking are the team's data suggesting the following:
During the next few years, the researchers will use statistical analyses to compare the effects of the two methods of bypass surgery (on the bypass pump or off the pump) on the brain. They will also continue to track the progress of vascular disease and brain performance in more than 400 patients.
What these researchers are learning may change how doctors and patients decide on treatment options. Doctors and patients can choose surgery without worrying that the procedure will add to the risk of long-term cognitive decline.
The research was published in the May 2008 Annals of Neurology, accompanied by a review that said, in part, "This study is extremely important because it is one of the few to include a nonsurgery comparison group with known cardiovascular disease. . . . In an age of adverse events that are uncovered often belatedly, it is comforting to reconsider the assumed cognitive deleterious effects from a common and efficacious treatment for heart disease." Dr. McKhann, who advises the Foundation on grant applications and writes a column for our Brain in the News print and online features, also wrote a review of this research for our online magazine, Cerebrum.
In 1983, the trustees of the Sidney Farber Cancer Institute renamed it the Dana-Farber Cancer Institute, following a series of grants the Foundation made to the institute, including a $10 million challenge grant in 1982. Charles A. Dana, Jr., said the award was meant "to focus the Foundation's support in cancer research and treatment in this single place," so the institute could build a permanent unrestricted endowment.
The Foundation had long supported the work of Sidney Farber, particularly by funding building projects for his cancer institute, including laboratories in 1962 and the Charles A. Dana Cancer Center, completed in 1976. The 1982 gift, which amounted to nearly 10 percent of the Dana Foundation's own endowment at the time, was intended to help the cancer institute raise enough funds for a permanent endowment, protecting its work from the vagaries of variable federal grant funding and donations.
Today, the Dana-Farber Cancer Institute employs about 4,000 people who support more than 200,000 patient visits a year. It is involved in some 600 clinical trials and remains internationally renowned for its blending of cutting-edge research and clinical care. The Foundation continues to support the institute with grants each year.
One of the most famous amnesiacs in neuroscience, Henry Gustav Molaison—known as Patient H.M.—died in 2008. In 1953, at age 27, H.M. underwent experimental surgical removal of parts of the medial temporal lobe (including the hippocampus and the amygdala) from both brain hemispheres to treat his severe epileptic seizures. He subsequently lost the ability to consolidate and store new memories, though he retained the ability to learn skills and to store information briefly.
A 1957 paper describing H.M.'s outcome by surgeon W.B. Scoville and Brenda Milner, Sc.D., of McGill University—later a Dana Alliance member—launched more than 100 subsequent studies of the biological basis of memory. The body of research on H.M. has established that there is a set of specific brain structures related to memory. [Dana podcast: Listen to H.M. speak, direct audio link]
Always willing to cooperate with researchers, H.M. said toward the end of his life that he wished to donate his brain to science upon his death; his legal conservator agreed. The Dana Foundation, along with the National Science Foundation, has funded a project to preserve this gift digitally to benefit science.
The night H.M. died, on December 2, 2008, his brain underwent nine hours in a magnetic resonance imaging (MRI) scanner, said Dana Alliance member and investigator Suzanne Corkin, Ph.D., of MIT, who had worked with Molaison for more than four decades.
Using novel computer-assisted neuroimaging techniques, researchers at the Brain Observatory of the University of California, San Diego, led by Jacopo Annese, Ph.D., will create a complete digital library of stained tissue slices that reveal microscopic anatomy far beyond the resolution of current MRI techniques. This will pinpoint the exact location and extent of H.M.'s surgically removed tissue and the conditions of the surrounding tissue.
The researchers will post the "digital map" of this special brain on the Web. Memory researchers will then be able to compare imaging studies of brain function with the H.M. brain tissue studies to validate and further explore the basis of memory in the brain.
The Web site will include information to help non-scientists understand how memory works in general, as well as to appreciate this particular case. This way, Mr. Molaison's contributions to neuroscience will continue.
In the new generation of surgical approaches to treating brain disorders, deep brain stimulation (DBS) stands out for its ability, through electrodes surgically implanted in precise locations in the brain, to change the activity in specific neural circuits. DBS surgery also enables neurosurgical researchers to record the activities of single brain cells and networks of cells to understand their functions in various cognitive activities.
The surgery involves implanting electrodes in target brain areas and connecting them through an insulated wire called an "extension" to a battery operated neurostimulator device placed under the skin near the collarbone. The neurostimulator does for neurons what a pacemaker does for the heart muscle: It disrupts the rhythm of the electrical impulses and changes the circuit. And unlike the removal of brain tissue, DBS surgery can be modified—the electrical current applied to a given area can be increased, decreased, reversed, or turned off altogether.
DBS is FDA-approved only for treating two motor diseases—Parkinson's disease and essential tremor—though the agency has given humanitarian device exemption approval for treating dystonia and obsessive-compulsive disorder. A small but growing number of researchers is investigating it as a potential treatment for highly intractable cases of thought and mood disorders, including depression. The number of people treated experimentally remains quite small, but several research groups have reported promising preliminary results. Why DBS works on mood disorder patients is still unclear.
"Ultimately, we're going to have to understand circuits to cure disease," said Mahlon DeLong, M.D., director of the Comprehensive Neuroscience Center at Emory University and a pioneer in using DBS for Parkinson's Disease. (Dr. DeLong, a Dana Alliance member, cowrote an essay on DBS for the 2008 Progress Report on Brain Research.)
The Dana Foundation supports scientists working to understand circuits, from lab research exploring the functions of specific brain circuits to clinical studies of the effectiveness of DBS in treating people with severe mood disorders and in restoring communication capabilities in patients emerging from a minimally conscious state. We sponsor forums and conferences for researchers, ethicists, and others to develop guidelines for the conduct of clinical research using this technology. In an effort to offset some of the hype created by overzealous reports and people desperate for a cure, we also sponsor public forums to talk about where the field is now.
Current research by Helen Mayberg, M.D., and her colleagues at Emory, who are using DBS to treat intractable depression, emanated from one of Dana's first imaging grants. Through a 1995 award, Dr. Mayberg used positron emission tomography (PET) and identified the brain's cingulate area as integral to severe depression.
"It has become apparent that we can dissect out the subcircuits involved in depression by looking at how the brain changes if you successfully treat depression with drugs or other therapies, so you can start to piece together the puzzle of what regions are most consistently affected," said Dr. Mayberg. "Over time, we have been developing the same kind of wiring diagram for depression that has been worked out for Parkinson's. Across our different studies, it became clear that certain things need to change in the brain in order for the depressed person to get well, which meshed with what other people were finding."
The first patients to receive DBS for depression were participating in a study at the University of Toronto led by Dr. Mayberg and her colleague, neurosurgeon Andres Lozano, M.D., Ph.D. Dr. Mayberg and her Emory coinvestigators received Dana support to expand the number of patients participating in these initial treatment studies.
In Toronto, patients with treatment-resistant depression received DBS implants and were followed for one year. The results from the first 20 patients show that DBS is relatively safe, and it provided significant improvement in most cases, as Drs. Mayberg, Lozano, and colleagues reported in Biological Psychiatry in September 2008.
At Emory, Dr. Mayberg and her colleagues are continuing the pilot research. To date, these investigators, using an experimental design that includes placebo periods and stimulation periods, have studied 13 people and plan to increase the sample size to 40 people. They also are using brain imaging to continue to try to characterize the brain processes involved in severe depression and to define how DBS affects these brain processes.
Based on their recent work to determine how DBS affects the brain's subcallosal cingulate gyrus and the anterior limb of the internal capsule, Dr. Mayberg and colleagues report that each area has distinct patterns of neural connections with areas of overlap in regions that are implicated in depression and in antidepressant response.
"DBS technology takes advantage of the fact that we can modulate specific circuits that are responsible for different kinds of behaviors," said Dr. Mayberg. "In the big picture, the idea that neural systems can be modulated by electricity introduces a whole new strategy for thinking about how to influence the brain in ways that we really hadn't conceptualized before."
According to Dr. Mayberg, a potential problem with DBS is that many members of the general public have come to view it as an established procedure—some people even e-mail Dr. Mayberg asking for it. Treating depression "is a tremendous application of this technique," she said during a forum in 2008 at the Dana Center in Washington, D.C. "But we are at a beginning, and we should act as such"—starting with the caveat that this deeply invasive treatment is not for all people who suffer depression, or even for a majority of them.
"There's no such thing as minor brain surgery," said Dr. Mayberg.
Parkinson's disease results from a loss of cells that transmit dopamine from one cell to another. As these cells die, brain signals fire improperly, and a person loses some control of body movements. Treatment with L-DOPA (an amino acid that can replenish dopamine supplies) works for a while, but eventually it leads to other movement problems in nearly 80 percent of patients.
DBS electrodes implanted in the subthalamic nucleus, which lies deep within the brain, block the uncontrolled synchronized signals that produce tremor and other symptoms in patients with Parkinson's disease. Surgeons can have difficulty determining exactly where to place the electrodes to block the abnormal neuronal signaling—and if they place the electrode improperly, the patient can experience serious side effects.
To improve the success of DBS for people with Parkinson's disease, neurosurgeon Peter Brown, M.D., F.R.C.P., and colleagues at the Institute of Neurology at University College, London, have been using two new techniques for determining more precisely where electrodes should be placed to produce the best results.
Through a grant awarded in 2004, the investigators found that electrical brain signaling activity of a particular frequency in the brain's subthalamic nucleus is characteristic of Parkinson's disease in both an animal model and in patients, and the location of neurons using that frequency for signaling shows precisely where to position the DBS electrodes for optimum benefit.
Dr. Brown's animal research also has demonstrated that excessive signaling by these neurons reduces the brain's capacity to code information and may contribute to Parkinson's motor symptoms. Contrary to conventional thinking, he found that the neurons' excessive signaling is produced by chronic, but not acute, disruption of dopamine used by the neurons to transmit their signals.
In September 2007, a group of leading DBS researchers joined with philosophers, ethicists, and patients in a consensus development meeting to draft guidelines for experimental use of DBS for disorders of mood, thought, and behavior. The Foundation cosponsored the conference, along with the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.
Clinical trials are currently exploring the use of DBS in treating depression, epilepsy, and obsessive-compulsive disorder. The September 2007 group identified 17 key points to be used as guidelines for protecting participants in clinical trials.
In 2008, those involved in drafting the guidelines reached a consensus about clinical trial designs and developed standards to protect human participants, given their potentially diminished capacity to provide valid informed consent. These guidelines will be published by the Archives of General Psychiatry in 2009.
As a complement to clinical trials of DBS, a consortium of translational research neurosurgeons at the University of California, Los Angeles, and the universities of Iowa and Toronto are receiving grant support from Dana to undertake a broad investigation of the neuronal underpinnings of memory and emotion, the use of implanted DBS electrodes, and the possibility that DBS recording of brain cells involved in the intent to move might eventually lead to a brain-computer interface facilitating movement in spinal-cord injured patients.
Andres Lozano, M.D., at Toronto; Matthew Howard, M.D., at Iowa; and Itzhak Fried, M.D., Ph.D., at UCLA are among the pioneers in assessing the effectiveness of DBS to treat intractable brain diseases such as depression, epilepsy, Parkinson's, and Alzheimer's disease. In 2007, they met in Los Angeles with cognitive neuroscientists to identify the most important questions that could be asked and answered through the direct recording of brain cell activity using implanted DBS electrodes.
While little currently is known about the brain basis of human cognition, improved technologies such as functional magnetic resonance imaging (fMRI), combined with direct recordings from single cells or groups of cells in humans, have made such exploration possible.
At their respective consortium centers, the neurosurgeons implant electrodes in the brains of patients with epilepsy a few weeks prior to their planned surgery, in which specific areas of brain tissue are removed to stop seizures that cannot be controlled by medication. By stimulating the implanted electrodes, the surgeons can pinpoint the originating focus and subsequent spread of the patient's seizures for surgical removal. But the surgeons need to spare any tissue that is vital to the patient's cognitive or motor functions. To identify these tissues, the surgeons have the patients perform specific cognitive and motor tasks while the implanted electrodes record activities of individual cells and networks of cells. These vital areas are then marked and spared during surgery.
This process, with the consent of the patient, also provides an opportunity for the neurosurgeons to identify cells and neural networks involved in specific cognitive functions.
The consortium chose three brain functions to explore during the next few years:
This memory study arose from a chance observation of a Toronto patient undergoing experimental DBS treatment for obesity. The patient had early Alzheimer's disease, and DBS appeared to improve his short-term memory.
Through this research, we hope to further scientific understanding of human cognition at the level of nerve networks within the brain. This "cells and circuits" approach is designed ultimately to reveal the neural basis for human cognition and lead to the development of new therapies for diseases that impair cognition, such as neurodegenerative diseases, autism, depression, and epilepsy.
Very few centers have the capacity to undertake such research. These are the first systematic studies of their kind. "This is a formidable team, arguably the only one in the world capable of pursuing this project," one peer reviewer wrote of the project when it was proposed. "The investigators are, quite simply, the best in the field. They have, individually and collectively, been responsible for some of the major technical advances with this approach, and they have completed some of the most remarkable work carried out with it. . . . The intellectual advances possible under this project, as well as the applications to brain disease, are quite apparent."
Many of the Dana Foundation's science education grants support collaborations with other organizations to enhance and augment the neuroscience curricula being taught in K–12 schools. Programs include producing print and online materials that contain current, credible information about the brain; publishing teacher's guides; holding workshops for teachers; and sponsoring talks by neuroscientists. Other grants support exchange among scientists at general conferences and at special single-subject workshops.
A grant in honor of Dana Alliance vice chairman James D. Watson, Ph.D., will enable New York City students in grades four and up to explore genetics and the scientific method at the new Harlem DNA Lab, a series of classrooms in the John S. Roberts Educational Complex in East Harlem. The state-of-the-art genome lab, which opened in September 2008, is a branch of the Dolan DNA Learning Center, itself part of Cold Spring Harbor Laboratory.
"Teaching our children—and the teachers who instruct them—about contemporary biology is not a luxury for the wealthiest school districts, but should be regarded as a must for our young people who will be entering the workforce in the next decade," said Cold Spring Harbor Laboratory president Bruce Stillman during the lab's opening ceremonies.
In 2008, the Dana Brain Science Educator Series, via a grant to the New York Hall of Science, gave 21 middle and high school teachers (Dana Fellows) the chance to learn more about the brain, to observe new ways to teach neuroscience in the classroom, and to develop grade-appropriate curriculum in neuroscience.
Drawing on the resources of the Dana Foundation and the Hall of Science, the Dana Fellows develop a set of content-rich lesson plans using inquiry-based methods. Fellows are expected to act as resources for colleagues and to encourage others to participate in similar professional development initiatives.
The 2008 Educator Series focused on brain damage and repair. Through lectures, panel discussions, a field trip, and an interactive lesson, the fellows explored current medications and cutting-edge treatments for such conditions as Alzheimer's disease, mental illness, and traumatic brain injury.
Brain scans are used to illustrate science stories, to serve as evidence in trials, and even to interpret people's political persuasions. But many scientists who use neuroimaging technology are concerned that these images are sometimes misinterpreted and misunderstood even by experts in other fields, let alone the press and the general public. For example, can a functional magnetic resonance imaging scan show that a person is lying? When we look at brain scans, does the left side of the picture correspond with the left side of the brain, or is it the right side?
Dana is supporting the Hastings Center's three-year roundtable project, started in 2008. The project brings together researchers, clinicians, philosophers, ethicists, and anthropologists to clarify the complexities of interpreting neuroimages and, ultimately, to explain them clearly to the public. After a series of interdisciplinary group meetings on topics such as neuroimaging technology's role in studies of addiction, aggression, and antisocial personality disorder, roundtable participants will produce background reports, a book of essays, and other materials, and they will share what they know at public symposia and briefings. Dana will participate in the sharing via our Web site and our continuing public events.
The Dana Center for Mathematics and Science Education provides education leaders in Texas and nationwide with validated knowledge about teaching and learning. It supports K–12 teachers and leaders working to implement high academic standards for all students.
In the late 1990s, the Dana Center in Austin helped coordinate new math and science standards for the State of Texas. Traveling to low-performing schools across the state, Dana Center staff listen to teachers and students and help them to reorganize and focus on learning ever-more-demanding science and math curricula. Partnering with the national education organization Achieve, Inc., the Dana Center directs the Urban Mathematics Leadership Network, which brings together district and state mathematics educators from across the country to share solutions to common pedagogical problems. In 2008, network educators meeting in Washington, D.C., concentrated on applying advances in what we know about learning to the practical problem of engaging students in more rigorous curricula. People representing 22 large urban districts serving nearly 4 million American schoolchildren shared information and took home new ideas.
These districts and their leaders charged the Dana Center with three new research and development projects:
Districts in the network have agreed to serve as laboratory sites for each of these tasks.
Through national and international seminars and its work with states, the Dana Center's goal remains to help school systems produce graduates with strong math knowledge and skills, as well as an understanding of how to apply those skills in learning, work, and life.
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subset: commoncrawl


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Washington (CNN) - Senate Majority Leader Reid issued the following statement Tuesday night:
"The people of Massachusetts have spoken. We welcome Scott Brown to the Senate and will move to seat him as soon as the proper paperwork has been received. I want thank Senator Paul Kirk for his tremendous service over the last few months. His service to the people of Massachusetts in the place of his friend, Senator Ted Kennedy, was brief but honorable.
"While Senator-elect Brown's victory changes the political math in the Senate, we remain committed to strengthening our economy, creating good paying jobs and ensuring all Americans can access affordable health care. We hope that Scott Brown will join us in these efforts. There is much work to do to address the problems Democrats inherited last year, and we plan to move full speed ahead.
"Regardless of the size of their minority caucus, Senate Republicans have always had an obligation to join us in governing our nation through these difficult times. Today's election doesn't change that; In fact it is now more important than before for Republicans to work with us rather than against us if we are to find common ground that improves Americans' lives."
Pkm harry do not be so dam dum pass health caqe now


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MCKENZIE BRIDGE (AP) — It might be the most thrilling, most scenic trail in Oregon — perhaps even in the entire Northwest.
But the 26½-mile long McKenzie River National Recreation Trail, even with 1,600 feet of descent, is a grind of a ride.
The upper half is especially so because of all the lava rock mountain bikers must negotiate. In some spots, hikers are faster than riders.
Knowing this, I set out recently to ride the smoother, tamer lower 15 miles of the renowned trail. The last time I rode the entire McKenzie River Trail, it took me six hours. This time around, a three-hour ride sounded much more inviting.
The trail is located pretty much halfway between Bend and Eugene along state Highway 126. I had worked in Eugene the previous day, so I drove from there to meet up with some friends coming from Bend, Dustin Gouker and Jesse Cooke, at the McKenzie Bridge Ranger Station.
The plan was to do a shuttled ride from Trail Bridge Reservoir, the midpoint of the trail, down to the ranger station. That way, we could get the flavor of the trail without all that pesky lava rock.
The McKenzie River Trail is known for the clear, rushing water of the river, spectacular waterfalls and towering old-growth Douglas fir trees. But another reason mountain bikers drool over the trail is simply the nature of the path itself.
It starts out easy around the west side of Clear Lake and becomes extremely technical over the rugged lava rock near Sahalie and Koosah falls all the way to Trail Bridge Reservoir.
Then, just when you're totally cooked and can't go on, the trail turns into a smooth, easy ride along flowing singletrack all the way down to the ranger station. That section of trail was what we were seeking.
We hooked the bikes onto the rack on Dustin's car and drove up the highway from the ranger station to Trail Bridge Reservoir, where a father and son were crossing the highway with a stringer of trout.
Dustin parked on a gravel road near the reservoir, where we could access the trail.
The ride started with a challenging climb along some technical rock sections high above the water. We then surged down a fast descent, after which the trail took us hundreds of feet above the river again, past several cliffside corners where we had to ride slowly and with extra caution.
Most of the trail stays alongside the river, but some portions took us away from the water. One constant along the trail — and what makes it so different from any trail in Central Oregon — is the lush greenery of the Willamette National Forest. Bright green ferns, moss-covered Douglas firs and endless deciduous trees line the trail and provide a nearly constant canopy. On the day we rode, temperatures reached the 90s in Bend and Eugene, but it never felt warmer than 70 to me during the entire ride.
The mostly dust-free trail includes a few switchbacks, and on one of them Dustin took the turn a bit too fast and launched off the trail, down into a mess of green bushes on a steep hillside. I jumped off my bike and ran to help him, but the bushes were already keeping him from falling farther down toward the river.
His leg was stuck in his bike frame, and I lifted his bike as he worked to free himself. I got his bike up the slope and he made his way back up, injury-free except for a nasty scratch on his right leg ... and perhaps a bruised ego.
Crisis averted, we got back to the ride. The river provided cool air as we continued along the trail, which cuts through the Belknap Springs and Paradise campgrounds. At Paradise, we rode out to the highway and back down to the ranger station, where we had left my car.
We took several breaks along the way for food, water and photos, and we finished the 15 miles in about 2½ hours. (Bikers should be sure to take along extra food and water and a bicycle repair kit.)
Because we skipped the upper portion of the trail, which includes the waterfalls, we stopped on the drive back home to Bend to hike along the trail and check out Sahalie and Koosah falls, which were surging with bright whitewater in the middle of the green forest.
We were not entirely exhausted by the end of the ride and the short hike, and we probably could have ridden a few more miles.
But I don't mind waiting for a return trip until fall, when the autumn colors will give the McKenzie River Trail even more stunning scenery.
The original story can be found on The Bulletin's website: http://bit.ly/19kVDn7
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Much more impressive showing today, so here we are with your early-bird-gets-the-USMNT-to-the-next-round Roundup!
Favorites and Duds from Today's Commenting
It's always nice when a big story brings old-timers out of the woodwork, and Always Winning did not disappoint with this old-school home cooking in McKenna's Mariotti/Salisbury exposé.
Two favorites in the Douchey Picture post today: StuartScottsEye crafted a clever responsion joke, and FreemanMcNeil went longform for some well earned praise. Excellent stuff, gentlemen.
RMJ=H had a big day. This silly minuscule gimmick in the Cameroon Match-Fixing story thrives on some wonderfully endearing understatement, while this protracted "dialogue" made me giggle uncontrollably. How's about you crack an American craft beer, carve up the Comment of the Day between these two, and fire the grill.
Nikkolai at last returns to the Roundups with a delightful jab at Derrick Rose in the Carmelo-Bulls advertisement.
Amidst a veritable pile of shit in the Adam Richman Foodspin, Pleatherface doffed his chef's cap and penned this revolting challenge.
Total Fucking Duds
No stranger to this section of the Roundups, Jason returns with a vile hunk of word shit in the Serena Williams story.
That'll do it for me. Drop your favorites, omissions, or gripes down below. I'll see you tomorrow. #DontTread


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|Event Date :
|Sunday, June 16, 2019
|Registration Dates :
|Saturday, March 2, 2019 ~ Sunday, June 9, 2019
MUSE enterprise/Las Conchas
All category:
# Kids
# Juvenille
# Adult
# Master1
# Master2
Registration Dates:
Super promo registration: March 02 - April 06
Weight Category ¥4,000
Weight Category & Open Weight ¥6,000
Kids fees: Under 15 year old Category ¥3,000
Early registration: April 07 - April 26
Weight Category ¥5,000
Weight Category & Open Weight ¥7,000
Kids fees: Under 15 year old Category ¥4,000
Regular registration days: April 27 - May 16
Weight Category ¥6,000
Weight Category & Open Weight ¥8,000
Kids fees: Under 15 year old Category ¥5,000
Last minutes registration: May 17 - June 06
Weight Category ¥7,000
Weight Category & Open Weight ¥9,000
Kids fees: Under 15 year old Category ¥6,000
- Registration deadline: june/06/2019
- Athlete correction deadline: june/09/2019
Refund Deadline: june/10/2019
(we only refund those athletes with no opponents in their division)
- Registration checkday: june/09/2019
- Organizer´s correction day: june/10/2019
- Schedule release date: june/13/2019
- Brackets release date: june/13/2019
Final Check Date (Important):
June 09 is the last day to check the registration. All athletes and instructors must check the fighters list.
Those without oponents in your division must contact us for change of division
The brackets will be generated following the list of registered fighters and the awards will be given only for those registered and on the brackets, so the check is obligatory for everyone
Final Date for checking and correction:
* June 09 is the last day to check your registration. All athletes, coaches, and instructors are required to check the fighters list for any possible changes needed.
* If you have no opponent in your division, please contact us for a change of division or you will automatically receive a medal. No refunds will be made if you failed to contact us.
* Fighters' list is official and it will be used to generate the brackets. Please be sure to check your details in the fighters' list before the final deadline. Further, awards will only be given to those who are listed in the brackets so please check accordingly.
Changes to your registration:
- Email your changes to email@example.com
- Please be sure to include the following
> Fighter's name
> Tournament Name
> Necessary Corrections
- Make sure the subject on the email is "Corrections"
Refund Policy:
The registration fee is non-refundable and non-transferable.
Exemption: Athletes who are alone in their bracket are eligible to receive a full refund of the registration fee if they contact firstname.lastname@example.com and request to withdraw their name from the competition prior to the end of the appointed event registration check day.
Conduct at the winnner´s podium:
We ask your understanding and cooperation in fallowing these standard in the upcoming tournament:
*** All competitors must be in proper uniform (full Gi for Gi competitions or rash guard and shorts for NO-GI competitions).
*** Banners are not permitted at the podium
*** Athletes who place in 1st, 2nd and 3rd in their division will receive a medal at the event. All the medals should be picked up at the event's podium.
Rules and Requirements for joining the event:
* Any athlete who has proven to be a black belt in judo,has fought MMA professionally, has an amateur MMA record or has proven experience in wrestling, Olimpic wrestling or greco-Roman wrestling, can not participate in any league as a white belt. Proven experience in the U.S. consists of having competed at the collegiate level or highter and in other countries,having competed in nationwide events.
* Matches may start 30 minutes in advance. Athletes should be in the warm up area at least 40 minutes prior to the time assigned for his or her division on the schedule.
* It is mandatory to have an official government photo ID at all times.
* The official weight measurements of this event is in KILOGRAMS.
* All athletes must be affiliated with a black belt. Your head black belt can be in a different location/country, what's important is you and the team that you are representing is properly recognized by the head instructor.
* We reserve the right to check your affiliation. Failure to provide any means to contact your head instructor will not be accepted into the event.
* All athletes must bring a valid ID on the event day. We reserve the right to randomly check IDs for verification purposes
* Athletes who place in 1st, 2nd and 3rd in their division will receive a medal at the event. All the medals should be picked up at the event's podium.
* Any false information provided during registration such as, but not limited to, DOB, may lead to immediate disqualification. Such actions are subject to suspension or even banishment from future Muse Enterprise/Las Conchas. events.
* If you are alone in your bracket you can contact email@example.com till the day before registration check day and request a change on your registration. ASJJF does not guarantee that the division you want to be moved to will have another competitor at the day of the event.
* Muse Enterprise/Las Conchas. reserves the right to close registration when we reach full capacity, or on the day of the appointed event registration deadline, whichever comes first.
* It is the responsibility of the athlete to be knowledgeable of the rules and guidelines pertaining to the sport (as outlined in the ASJJF Rules Book).
* We strongly suggest that athlete registration is finalized before making any travel arrangements.
* Before each fight, athletes will be asked to show their valid form of photo identification(ID) to the officials. Make sure you have it on hand.
*This tournament is organized by the MUSE enterprise/Las Conchas.
|Gifu Memorial Center Judo-Jyo
|Address :
|Gifu ken Gifu city
- We will not accept registrations after the registration end date
- The registration deadline can be closed before the registration end date if the number of fighters exceed the total number allowed
- * The money must arrive until the day specified otherwise the registration will be cancelled (The registration is considered completed only after the registration fee payment)
- Registration fee refund: only if there are no opponents in your category. There will be no refund in case of: disqualification, weight disqualification, you came late or not coming to the event


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Every day across the world in our coffee houses, we are engaged in the business of coffee. Whether it's serving a strong macchiato for a regular guest's morning hit, or a making a round of creamy cappuccinos for the office next door – coffee is our hero. We also see ourselves in the business of people, and it is this humanitarian focus that runs deep in our DNA as long as we are serving coffee.
The Oxford Dictionary defines the adjective 'humanitarian' as being concerned with or seeking to promote human welfare. All the coffee lovers out there will probably agree that providing their daily coffee/s is already a humanitarian act that exponentially benefits their welfare.
However, not only does having a humanitarian focus mean treating each other and our guests with value and respect, we believe that we can also have a positive impact on the communities through which we serve and source our coffee. This is far from a unique pursuit, and it is invigorating to see how businesses internationally are now incorporating a form of corporate social responsibility into their business processes and profits.
Like any other business, we have often felt overwhelmed with the staggering requests for charity partnership, sponsorship or donation that continually arrive in our mail and inboxes. "Where do we start? How can choose which cause to support?"
For this reason, With Heart™* was established four years ago to provide a more concerted structure to our global humanitarian strategy. Our approach is not to give away money to the cause who shouts the loudest, but instead to partner with not-for profit and charitable organisations who share a sustainable strategy in tackling society's issues today.
Today, Gloria Jean's™ coffee houses across the globe are listening to what their local community care about most and support causes that touch their heart.
In Australia, the With Heart Local campaign has empowered local coffee houses across the country to support their chosen charity for the past two months. This campaign alone has created inspiring waves of passion and dedication in the communities. Even in difficult economic climates, significant funds over and above the previous year have been raised.
For example, in Bangladesh the team organised a campaign at short notice to donate a portion of their sales to support families affected by the recent tragedy where an eight-storey commercial building collapsed in Savar, Bangladesh.
Following that, we recently filmed a mini-documentary in Delhi with one of our long-standing charity partners Opportunity International and their microfinance partner, Shikhar.
Check out the link here for a one-minute condensed version, which outlines why we believe in microfinance.
As you can see, the humanitarian efforts that a business can engage in ranges from short impromptu disaster relief support, to localised campaigns, to long term partnership support for sustainable solutions. Whatever the approach, the very heart of it will always be a shared belief that together, we can actually make a difference in real peoples' lives.
With Heart® is a Gloria Jean's Coffees™ international foundation
Image taken by Lauren Horton in association with Compassion Australia.


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Tony Winner Jennifer Holliday to Headline The Iridium's Valentine's Day Party, 2/14
Tony and Grammy Award-winning singer and actress Jennifer Holliday will play The Iridium, February 14, 2013. Best known for her iconic performance of "And I Am Telling You I'm Not Going" from Dreamgirls, Jennifer will headline The Iridium's annual Valentine's Day celebrations, which feature a special dinner menu and sets at 7 p.m. and 9 p.m. Cost: $60.00.
Over Thirty years ago, Jennifer Holliday's show-stopping, heart-wrenching performance of the torch ballad "And I'm Telling You, I'm Not Going" in the smash hit Broadway musical, Dreamgirls, made her a household name and introduced her big soulful voice to the world. Her portrayal of Effie "Melody" White, a role which she co-created, not only brought theatergoers to their feet for 8 performances a week, but also garnered her a Tony Award for Best Actress in a Musical and her first Grammy Award for Best R&B Female Vocalist.
Born and raised in Houston, Texas, Holliday went straight from the Pleasant Grove Baptist Church Choir to the Broadway stage in the Big Apple. One Sunday, while singing in the church choir, she was discovered by dancer Jamie Patterson who was touring in the national company of A Chorus Line. Jamie not only set up an audition for Jennifer in New York for the show Your Arms Are Too Short To Box With God, but he also bought her an airline ticket and made arrangements for her to stay with his aunt. During the audition with the show's creator and director, Vinnette Carroll, Jennifer sang her favorite hymn, "God Will Take Care Of You." And that He did. She was hired for the show that same day.
Jennifer toured with Your Arms Are Too Short To Box With God for five months and then made her Broadway debut with the show as Jennifer-Yvette Holliday.
While on Broadway, Jennifer's talent was noticed by the renowned Broadway director and choreographer Michael Bennett, the creator of A Chorus Line. He invited her to participate in an untitled project that he was producing. Even though Jennifer was still performing in Your Arms Are Too Short To Box With God, Bennett's project sounded too good to pass up. The project turned out to be Dreamgirls. At this early stage of the workshop process however the role of Effie was not fully developed and even the signature song "And I'm Telling You..." had not been written yet. During workshops for the show, Jennifer began shaping and changing the storyline of Effie's character to be what she felt would be a more truth portrayal. And around this time Bennett suggested that it would be better if Jennifer dropped the hyphen and go by Jennifer Holliday, which she did.
Dreamgirls had previews in Boston opened on Broadway on December 21, 1981 at the Imperial Theatre...and the rest is history. The show ran for five years and won universal acclaim. Holliday's other theater credits include Sing Mahalia Sing: The Mahalia Jackson Story, Downhearted Blues: The Bessie Smith Story, Harlem Suite (with Aretha Franklin), Chicago (starring as "Mama Morton"), Grease (starring as "Teen Angel") and Black Nativity (starring as the "Angel of God"). Jennifer also reprised her role as Effie to sold-out crowds in 2007.
Music lovers around the country and Jennifer's die-hard fans, both old and new, are hoping that her latest "Rediscovery" will inspire and encourage her to record again. It has been 20 years since she recorded a main-stream solo project. Holliday's recording career has been moderately successful with the release of five albums beginning in 1983. Her second album, "Say You Love Me," won her a second Grammy for her rendition of Duke Ellington's classic, "Come Sunday."
Miss Holliday has enjoyed a parallel career as a recording artist. "And I'm Telling You, I'm Not Going" remains her biggest chart-topping success to date. The song was #1 on the R&B Charts for four consecutive weeks and a Top 40 hit on the Pop Charts. From 1985 to 1992 she enjoyed five Top 10 singles on the R&B and Dance Charts such as "I'm On Your Side" and "No Frills Love." Over the years Jennifer has worked with and recorded with many other major artists including Barbra Streisand, Luther Vandross, David Foster,Paul Simon, Michael Jackson, Marvin Hamlisch and Foreigner on a special version of "I Want To Know What Love Is",just to name a few of her collaborations.
Jennifer - the actress - paved a new path in her career when TV producer David E. Kelley saw her on the Rosie O'Donnell show and gave her a call about making a guest appearance on "Ally McBeal," the Fox TV series that starred Calista Flockhart. The response to her version of Randy Newman's "Short People" was so overwhelming that Kelley wrote her character, Lisa Knowles, into the series as a regular. As the outspoken, quirky choir director and lead soloist at McBeal's church, Jennifer's character appeared on the series for five seasons. Over the years, she has also appeared on other TV series such as "Touched By An Angel," "Hang Time," "Happily Ever After," "The Love Boat" and "Ellen."
Holliday continues to perform all over the world with leading symphonies such as the Boston Pops, The National Symphony Orchestra,The San Diego Symphony and The Cincinnati Pops Symphony. She's performed at The White House for four U.S. Presidents (Reagan, G.H.W.Bush ,Clinton and Bush). In 2000 she received an Honorary Doctorate of Music from the Berklee College of Music for her work on behalf of mental health awareness, depression and suicide prevention. Jennifer continues to believe that music has a healing power and she also strongly believes that her music and her story are her gift to her audiences.
Lately, Jennifer has been finishing work on two CD projects - her first full-length CDs in 20 years. She's tweaking an album of Classic Jazz Standards entitled "Love Me By Name" that will feature evergreen love songs.
In May 2012, Jennifer got the break of a life-time and a second wind for her career when she performed for the 11th American Idol Season Finale with teen sensation Jessica Sanchez. Once again, Jennifer performed her hit song "And I'm Telling You!" as a duet with Jessica and together they both made history while over 15 Million people witnessed before their eyes a new star being born in Little Jessica and the rebirth of a broadway icon for Jennifer Holliday,"The Original Dream Girl"!


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ESA engineers explore nano-world with new X-ray instrument
ESA engineers examining candidate materials for future space missions have a new instrument for extremely superficial studies: performing nano-scale analysis of ultra-thin slices of a material's outermost skin.
The X-ray Photoelectron Spectrometer (XPS) was custom-built to ESA specifications by VG Scienta in the UK and delivered to the Materials and Electrical Components Laboratories at ESA's ESTEC technical centre in Noordwijk, the Netherlands this month.
The XPS, as a surface science tool, will allow engineers to analyse test material surface structure and composition to a depth of just two to four nanometres – a nanometre being a billionth of a metre, or, typically, a few dozen individual atoms.
"Nobel-prize-winning chemist Wolfgang Pauli had a saying: 'God made solids but the devil made surfaces," explained Christopher Semprimoschnig, head of the Materials Space Evaluation and Radiation Effects Section of ESA's Materials and Components Technology Division.
"The bulk of a material has a regular structure but the surface where the material meets outside space is irregular.
"This new instrument is very important because we're interested in how test materials react with space radiation, and any changes to surface chemistry can substantially alter the material's overall behaviour.
"In addition, we'll be able to identify and analyse ultra-thin layers of condensed materials on surfaces. For the very important task of verifying if something is really clean then this will be the instrument of choice.
"If we are searching for life on Mars then we wouldn't want to send our own biological contamination there."
The XPS will be useful in preparing a range of ESA missions, including LISA Pathfinder, which will flight-test technologies for the future detection of gravitational waves predicted by Albert Einstein.
"LISA Pathfinder is based around a block of gold–platinum alloy free-floating within the spacecraft, and measuring external forces deflecting it to prevent it from deviating," Christopher added.
"Any surface contamination, down to the atomic scale, could lead to control problems."
The spectrometer's ability to reveal how outer surfaces will be materially changed by different properties of space will be crucial for the Europa Jupiter System Mission, proposed to send a spacecraft into the radiation-drenched orbit of Jupiter.
The XPS is the operational opposite of the better-known electron microscope and associated energy-dispersive X-ray spectroscopy. While an electron microscope shoots electrons into a sample and records the X-rays emitted, the XPS probes samples with high-energy X-rays that kicks out electrons with a varying range of energies, detected by the instrument's hemispherical electron analyser.
"The kinetic energy of these electrons is a function of their binding energy – the difference in energy between the ionised and neutral atoms – and depends on the chemical structure of the substances analysed," said Christopher.
"This means we learn the precise nature of the surface chemical bonds, which is a substantial step forward."
To maximise accuracy, the XPS is an ultra-high vacuum instrument, with pumps creating a vacuum that is a thousand times purer than previous instruments, typically allowing up to 10 000 seconds to analyse a sample before the few remaining atoms in the chamber can contaminate it.
In addition, the instrument is equipped with a focused ion gun that will help to examine depth concentration profiles of samples up to a few tens of microns.
The XPS will be used for 'nano-analysis' in conjunction with other instruments, most notably the Atomic Force Microscope (AFM) that employs a nanometer-wide tip like a stylus across a record player to reveal surface topography down to the atomic scale, measuring roughly a single atom per second.


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IE is there a way to use the split level and try and keep the files in one directory together, BUT have that directory span to the next package if the directory contents size is greater than the package (or remaining) size rather than stop processing and throwing a warning?
Basically I like the idea of fill but wish to keep files with it's siblings as much as possible while sacrificing space, becuase I have directories with content larger than 4.38GiB that I want to keep together and span.
So in a perl script for example you could iteerate through the path list until you gather over the package size, move back one copy to a package, then start gathering next package from current path.
I'm not aware of another program which does this, if you are, that would help.


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The three time Challenge Tour winner was tied for the overnight lead alongside Welshman Stuart Manley after opening with a 65 but took advantage of the benign early morning conditions on the second day after teeing off at the 10th hole.The 29 year old birdied the par four 12th hole before three consecutive birdies from the 14th were followed by another gained shot at the par three 18th, where he sank a 35 foot putt from the fringe at the back of the green.
He followed that with another birdie at the first before a run of six pars and a birdie at the eighth hole to move to 14 under par as he completed the first two rounds without a single bogey and sat on 14 under at the top of the leaderboard."The key today was to follow yesterday's round with a good start today and I did that," said Dinwiddie, who had just 25 putts for each of the first two rounds. "I played the 10th well but didn't quite make the putt. I made a great putt for par at the 11th which was key to keeping the momentum and then I birdied the 12th which got it started.
"The putt at the 18th is certainly not one you'd expect to make. All in all though, my goal was to shoot seven under again today and the start helped that."Obviously you have to putt well too. I read the greens well on the first day and did it again today. I just need to keep more of that for the weekend."
Another Englishman was the closest player to Dinwiddie in the clubhouse after Chris Paisley carded a second successive four under par round of 68.The 26 year old got off to a positive start when he birdied the tenth, his opening hole, before another birdie at the 12th. He followed that up with a bogey, however, before a birdie at the 15th and a bogey at the 16th meant he reached the turn in one under par.
An eagle at the second hole, after his second shot with a hybrid dropped to within 15 foot before holing the putt, and a birdie at the fifth meant he was in the clubhouse on eight under par."I got off to a really good start over three tricky opening holes which was nice," said Paisley. "I made a good save then, on the 14th, for par. It wasn't great for a few holes then but I played really solid on my back nine and it could have been a few shots lower but overall I'm happy with that round.
"The course is set up really well. It's a bit different from the last few years. There's a bit more rough which I think is good. I've been playing well recently so I feel good."Obviously there's a long way to go and Robert is playing well so I have a lot of work to do to catch up but I've still got 36 holes to try and do that."
James Busby (68), Matt Haines (69) and Francis McGuirk (71) were all in the clubhouse on seven under par while American Brooks Koepka added a six under par round of 66 to his level par opening round and was a shot further back.Manley, meanwhile, birdied the 12th hole, his third, before a bogey at the at the 13th was followed by an eagle at the 14th to move him to within five shots of the lead.
|Player name
|PAISLEY, Chris
|MCGUIRK, Francis
|KOFSTAD, Espen
|DOUGHERTY, Nick
|NIXON, Matthew
|BUSBY, James


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German police officers swoop on Deutsche Bank offices in tax evasion probe
FRANKFURT, Germany Deutsche Bank (DB) says its co-chief executive Juergen Fitschen and chief finance officer Stefan Krause are under investigation as part of a tax evasion probe linked to the bank's emissions trading business.
The bank said Wednesday Fitschen and Krause are being investigated because they signed off on the company's 2009 tax declaration. The bank says any errors in the declaration were corrected later in a timely way, adding that prosecutors say the changes were made too late.
HSBC bankers dodge personal accountability
Report: Deutsche Bank drops unethical traders
Prosecutors said 500 police officers swooped Wednesday on Deutsche Bank AG offices and private properties in Frankfurt, Berlin and Duesseldorf.
Fitschen took over as co-CEO along with Anshu Jain earlier this year; in 2009, he was the head of the company's regional businesses.
The Frankfurt prosecutors' office says 25 employees of the bank are suspected of serious tax evasion, money laundering and attempted obstruction of justice. Arrest warrants have been issued against five, but those do not include Fitschen and Krause, a prosecutor's spokesman said.
Deutsche Bank said the investigation began in spring 2010 and focuses on "a limited number of individuals" under suspicion of fraud connected with value-added tax in the trading of carbon emission certificates.
It said it was cooperating with the investigation. The bank also faces lawsuits over alleged participation by former employees in rigging benchmark interest rates such as Libor along with other major banks, and has said it has put aside money for potential penalties in the matter.
Carbon trading schemes cap the emissions of businesses and set limits for countries. Businesses must buy carbon permits if they exceed their limit, or can sell the right to emit carbon if their emissions are lower. The idea is to limit the emission of greenhouse gases such as carbon dioxide that are believed to cause global warming.


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Alejandro Ingelmo Shoes Spring 2013
Alejandro Ingelmo's Futuristic Shoes Take Us to Infinity and Beyond
Alejandro Ingelmo's Futuristic Shoes Take Us to Infinity and Beyond
For the ultimate respite from stormy conditions today, draw your attention to Alejandro Ingelmo's enticing, space-age Spring '13 footwear collection. If you're not familiar with the designer, Alejandro has a knack for melding his Cuban roots with the streets of his current hometown of NYC. The results? Modern, sexy designs that have earned him a spot as one of the top 10 candidates of the CFDA Vogue Fashion Fund in '08 and nominations for the Swarovski Award for Accessory Design in '09 and '11. His latest collection highlights provocative lace-up sandals and sexy high heels made out of modern finishes like iridescent metallic and holographic python prints. High heels aren't your thing? Alejandro also created some chic leather and suede kitten heels perfect for office and beyond. Unfortunately, we will have to wait until Spring to get our hands on a pair but for now, check out our three favorite styles below and check out the complete collection in the slideshow. Which one is your top pick?
- How amazing would this stunning black and metallic sandal look with all your little black dresses? We love the futuristic cutout details.
- Want legs for days? These strappy suede nude lace-up pumps should do the trick. Pair with a fit-and-flare minidress and you're set.
- We love the idea of pairing these gorgeous iridescent python print pumps with cropped skinny jeans and a blazer for a boy-meets-girl look.


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We decided to stop the development of the non-Unicode nnBackup. The current nnBackup stable build (nnBackup 2.28) will be the last build in this non-Unicode branch (some bug-fixing updates are possible though!).
Now we are into active development of the new-generation Unicode-aware nnBackup (ver 3.0) which will be backward compatible with it's predecessor (all nnBackup 2.0 command line options will be supported in the forthcoming nnBackup 3.0). Note, please: the new nnBackup 3.0 will not work on Win95/98/ME. So, if you still use one of these operating systems you should stick with nnBackup 2.28.
The upgrade to the nnBackup 3.0 wil be free for all of the registered nnBackup 2.0 users. We are contemplating some nnBackup registration price hike (of EUR5-10) to coincide with the forthcoming 3.0 release, so you may consider buying a license right now, before the price was changed. Once again: no worries for existing customers, updates are still free!
The first public nnBackup 3.0 beta will be announced shortly.


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WASHINGTON _ The National Biodiesel Board (NBB) on Thursday welcomed a proposed rule from the EPA establishing this year's Advanced Biofuels requirements under the Renewable Fuel Standard (RFS).
"We want to thank the EPA and the entire Obama Administration for standing strong behind these important standards for Advanced Biofuels," said Anne Steckel, NBB's vice president of federal affairs. "The U.S. biodiesel industry is poised and ready to help meet these requirements, and that will mean reduced greenhouse gas emissions, a better economy and more domestic fuel choices for consumers."
"With plants across the country and more than a billion gallons of production last year, the U.S. biodiesel industry is already the leading producer of Advanced Biofuels in the country, accounting for more than 80 percent of required production to date," Steckel added. "The industry is adding new feedstocks and building capacity every year, and this policy will only help us continue that growth."
Biodiesel is the first and only domestic fuel produced on a commercial scale nationwide to meet the EPA's standards as an Advanced Biofuel - meaning it reduces greenhouse gas emissions by more than 50 percent compared with petroleum diesel. According to the EPA, biodiesel reduces greenhouse gas emissions by 57 percent to 86 percent, depending on the feedstock used to produce it. The industry has exceeded the RFS production requirements for two consecutive years, and in 2012 it produced nearly 1.1 billion gallons of fuel, with plants in nearly every state in the country supporting more than 64,000 jobs.
Under the RFS, the Biomass-based Diesel requirement is a subset of the overall Advanced Biofuel requirement. For 2013, the EPA's proposal calls for an overall Advanced Biofuel requirement of 2.75 billion gallons. Within that total, the Biomass-based Diesel requirement - which has already been finalized and was not a part of today's announcement - is 1.28 billion gallons. Refiners have the option of using biodiesel or other EPA-designated Advanced Biofuels to help fill the remaining overall Advanced Biofuel pool, and many experts are predicting that biodiesel will play an increasing role in doing so this year.
Biodiesel is made from an increasingly diverse mix of feedstocks including recycled cooking oil, soybean oil and animal fats. There are more than 200 EPA-registered production plants nationwide.
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Middlesbrough v Hastings United
This is proper FA Cup third round fare. Hastings are the lowest ranked team left in the competition, some 153 places below their hosts this weekend, are in the third round for the first time in the club's history and have a ready made tabloid headline for a dogged performance in the 'Battle of Hastings'. If there isn't a feature on their left back having to do his post delivery round before training on Football Focus I'll be shocked. Boro are enjoying a fine season, fourth in the Championship, and are odds on favourites to progress but have suffered a mysterious bout of hamstring injuries to the first team squad. Hope springs eternal for the minnows.
Romance rating: 8/10


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The Cheetah Animated Infographic
The Cheetah infographic introduces to you nature's speed machine from Jacob O'Neal (jacobneal.com). Learn about how each body part is important to the Cheetah and why you don't want to be on this mammal's menu.
Did you know that cheetahs can accelerate from 0 to 60 MPH faster than a Ferrari? The amazing cheetah is the perfect example of natural specialization. They're made for speed. Such a beautiful animal deserves a closer look!
This is definitely a cool infographic design! I really like this use of the animated GIF image file format. Seriously! I REALLY like this design. Animated GIFs have been used and abused for decades, but the use of animation here is done in a way that is very visually appealing. It actually adds to the value of the content, and catches your attention.
One issue with animated GIF image file infographics is social sharing. Not all social media and photo sharing services can support the animated format, so you also need a static JPG image as a backup for anyone that want to share with those service.
Thanks to Chris for sending in the link!


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WASHINGTON — Liver trouble killed a giant panda cub that died suddenly last month less, than a week after its surprise birth at the National Zoo, the institute's chief veterinarian said Thursday.
Suzan Murray said the cub's cause of death was liver necrosis, or the death of liver cells. Murray said at a news conference the cub's lungs were also underdeveloped and likely didn't provide enough oxygen to the liver.
The cub's underdeveloped lungs may have been caused by being born prematurely, Murray said. Zoo scientists are trying to learn more about how common the liver and lung defects are in newborn pandas that don't survive.
The cub, a female, was born Sept. 16.
Zoo officials and panda fans were devastated by its death less than a week later. The birth was a surprise because it hadn't been clear whether Mei Xiang was still fertile.
Don Moore, the zoo's associate director for animal sciences, said panda mother Mei Xiang has been showing less mothering behavior and has stopped cradling a toy in recent days.
In addition, after spending nearly four weeks in her den, she has stopped staying inside and is sleeping out in the panda yard. As a result, zoo keepers on Wednesday cleared out the nest she had built.
The zoo has a five-year agreement with China to keep its two pandas, Mei Xiang and Tian Tain, through 2015. Murray will travel to China this month as the zoo begins planning for the future. They will discuss whether to keep both pandas in Washington or to swap one or both out for the next breeding season.
A decision should be made in November, Moore said.


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Follow us on Twitter: Elite_Systems
IMPORTANT: To 'Save' the game go 'Back' to the Main Menu before quitting the App.
Jet S more...
Follow us on Twitter: Elite_Systems
IMPORTANT: To 'Save' the game go 'Back' to the Main Menu before quitting the App.
Jet Set Willy for the ZX Spectrum (an 8-bit personal home computer released in the UK in 1982 by Sinclair Research Ltd, which sold in excess of 5 million units worldwide) is one of THE defining games of the 1980s.
Jet Set Willy: ZX Spectrum is offered as an in-app purchase from within the ZX Spectrum: Elite Collection app. (The in-app is priced at £1.49/€1.59/US$1.99 and include 5 more ZX Spectrum games).
Jet Set Willy: ZX Spectrum is also available in this stand-alone form. It does not include any other ZX Spectrum games but it does include an infinite-lives version.
Jet Set Willy: ZX Spectrum is the 100% original ZX Spectrum game, as written by Matthew Smith in 1984 and is brought to you - as an officially licenced product - utilizing our ZX Spectrum: Elite Collection technology.
- portrait and landscape play / display modes
- iDaptive (user-definable, game-specific joystick, keypad & canvas) Controls
- 'auto save', on exiting the game
- authentic 'Spectrum' sound
Jet Set Willy was published in 1984 by Software Projects. The game is a sequel to Manic Miner (1983), and is the second game in the immensely popular Miner Willy Series. The Plot: A tired Miner Willy has to tidy up all the items left around his house after a huge party. With this done his housekeeper Maria will allow him access to his bedroom. Willy's mansion was bought with the wealth obtained from his adventures in Manic Miner but much of it remains unexplored and it appears to be full of strange creatures, possibly a result of the previous (missing) owner's experiments. Willy must explore the enormous mansion and its grounds (including a beach and a yacht) to fully tidy up the house so he can get some much-needed sleep. Game-play: Willy moves from room to room in his mansion collecting objects. Unlike the screen-by-screen style of its prequel, the player can explore the mansion at will and tackle the screens in the order of their choosing. Willy is controlled using only left, right and jump. He can climb stairs by walking into them (jumping through them to avoid them) and climb swinging ropes by pushing left or right depending on what direction the rope is swinging in. The play area itself consists of 60 flick-screen making-up the mansion and its grounds and containing hazards (static killer objects), patrolling monsters (killer guardians which move along predetermined paths), various platforms and collectable objects. The collectable items glow to distinguish them from other items in the room. Willy loses a life if he touches an enemy or falls too far, and he is returned to the point at which he entered the room. This may lead to a game-ending situation in which Willy repeatedly falls from a height, losing all lives in succession. Bugs: As originally released, the game could not be completed due to several bugs. Although actually four completely unrelated issues, they became known collectively as "The Attic Bug". After the player entered the room The Attic, various rooms would undergo corruption on all subsequent game plays, including all monsters disappearing from The Chapel, and other screens triggering instant death. Initially Software Projects attempted to pass off this bug off as an intentional feature to make the game more difficult, claiming that the rooms in question were filled with poison gas. However, they later rescinded this claim and issued a set of POKEs to correct the flaws.
Matthew Smith (born 1966) is a British computer game programmer. He is best known for his games Manic Miner and Jet Set Willy for the ZX Spectrum, released in 1983 and 1984 respectively. Matthew created this game when he was 18 ...
About Elite®: Elite Systems Ltd was incorporated in England in 1984.


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Subscribe To Weekend Box Office: Resident Evil: Retribution Tops Finding Nemo 3D Updates
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How many Resident Evil movies does it take before audiences get bored? No one's quite sure, but after this weekend's disappointing debut of Resident Evil: Retribution, we may be closing in on an answer.
The fifth film in the RE franchise opened at first place, but that was little consolation given the sharp drop it saw from the previous entry. At $21 million it fell short of Resident Evil: Afterlife's $26 million debut and came in fourth place overall in the franchise. While it technically topped the original Resident Evil's $17 million debut, the increased ticket prices mean fewer people bought tickets making it the least popular RE opening of all time.
There was also bad news for Disney's 3D re-release of Finding Nemo. There were hopes its solid popularity among audiences and its status as one of Pixar's highest grossing films, might help it get the same launch as The Lion King when it re-opened in 3D last year to the tune of $30 million. Not so. Audiences handed over little more than half that amount, sending Nemo home with just $17 million and second place this weekend.
Despite only opening in 200 theaters, Richard Gere's much discussed and critically accliamed Arbitrage only missed the top ten by two spots and less than half a million dollars. That was a far better turn out than new comer Last Ounce of Courage which, despite opening in almost 1,500 venues, only banked $1.7 million this weekend. The movie, which comes from conservative studio Rocky Mountain Pictures (best known for bank rolling 2016 Obama's America and Expelled: No Intelligence Allowed) has a direct-to-video feel to it and the lack of marketing suggests the studio might have felt the same way. The result? A number 15 opening and destined for a quick trip out of theaters.
Meanwhile Paul Thomas Anderson's award-season-buzzey drama The Master opened on just five screens but saw nearly $750,000 in sales. While it's snobby art house feel might keep the bigger audiences away when it releases wide, its well known cast, including Amy Adams, Philip Seymour Hoffman and Joaquin Phoenix, may help it hit number one when it expands.
For the full weekend top ten, check out the chart below: