White Blood Cells Found in Controlling Red Blood Cell Levels

BRONX, N.Y., March 18, 2013- Researchers at Albert Einstein College of Medicine of Yeshiva University and the Icahn School of Medicine at Mount Sinai have found that macrophages – white blood cells that play a key role in the immune response – also help to both produce and eliminate the body's red blood cells (RBCs). The findings could lead to novel therapies for diseases or conditions in which the red blood cell production is thrown out of balance. The study, conducted in mice, is published today in the online edition of the journal Nature Medicine. "Our findings offer intriguing new insights into how the body maintains a healthy balance of red blood cells," said study leader Paul Frenette, M.D., professor of medicine and of cell biology and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein. "We've shown that macrophages in the bone marrow and the spleen nurture the production of new red blood cells at the same time that they clear aging red blood cells from the circulation. This understanding may ultimately help us to devise new therapies for conditions that lead to abnormal RBC counts, such as hemolytic anemia, polycythemia vera, and acute blood loss, plus aid recovery from chemotherapy and bone marrow transplantation." Einstein has filed a joint patent application with Mount Sinai related to this research, which is currently available for licensing and further commercialization. Previous studies, all done in the laboratory, had suggested that macrophages in the bone marrow act as nurse cells for erythroblasts, which are RBC precursors. But just how these "erythroblastic islands" (macrophages surrounded by erythroblasts) function in living animals was unclear. A few years ago, Andrew Chow, a Mount Sinai M.D./Ph.D. student in the laboratories of Drs. Frenette, and Miriam Merad, M.D., Ph.D., professor of oncological sciences and immunology at Mount Sinai found that bone marrow macrophages express a cell surface molecule called sialoadhesin, or CD169 – a target that could be used for selectively eliminating macrophages from bone marrow. Doing so would help pinpoint the role of macrophages in erythroblastic islands in vivo. That's what Drs. Frenette and Merad did in the current study involving mice. They found that selectively eliminating CD169-positive macrophages in mice reduces the number of bone marrow erythroblasts – evidence that these macrophages are indeed vital for the survival of erythroblasts, which develop into RBCs. "What was surprising is that we couldn't see any significant anemia afterward," said Dr. Frenette. The researchers then analyzed the lifespan of the red blood cells and found that they were circulating for a longer time than usual. "After we depleted the macrophages in the bone marrow, we discovered that we had also depleted CD169-positive macrophages present in the spleen and liver. It turns out that the macrophages in these two organs are quite important in removing old red blood cells from the peripheral circulation. Taken together, the findings show that these macrophages have a dual role, both producing and clearing red blood cells," he said. The researchers also examined the role of macrophages in polycythemia vera, a genetic disease in which the bone marrow produces too many RBCs, typically leading to breathing difficulties, dizziness, excessive blood clotting and other symptoms. Using a mouse model of polycythemia vera, they found that depleting CD169-positive macrophages in bone marrow normalizes the RBC count. "This points to a new way to control polycythemia vera," said Dr. Frenette. "Right now, the standard of care is phlebotomy [periodic blood removal], which is cumbersome." The title of the paper is "CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress." The first author of the paper is Dr. Andrew Chow. Other co-authors of the study include Matthew Huggins, Daniel Lucas, Ph.D., Jalal Ahmed, B.S., Sandra Pinho, Ph.D., Yuya Kunisaki, M.D., Ph.D., and Aviv Bergman, Ph.D., of Einstein, and Daigo Hashimoto, M.D., Ph.D., Clara Noizat and Marylene Leboeuf of Mount Sinai, New York, NY. The study was done in collaboration with Nico van Rooijen at Vrije Universiteit, Amsterdam, The Netherlands; Masato Tanaka at RIKEN Research Center for Allergy and Immunology, Yokohama, Japan, and Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; and Zhizhuang Joe Zhao, Ph.D., at University of Oklahoma Health Sciences Center, Oklahoma City, OK. The study was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL097700, R01HL069438, and R01HL116340); the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056638); and the National Cancer Institute (R01CA112100), all part of the National Institutes of Health. Albert Einstein College of Medicine Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. In 2012, Einstein received over $160 million in awards from the NIH for major research centers at Einstein in diabetes, cancer, liver disease, and AIDS, as well as other areas. Through its affiliation with Montefiore Medical Center, the University Hospital for Einstein, and six other hospital systems, the College of Medicine runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States.

UK surgeons perform first 'warm liver' transplant

 London, Mar 16 - In a medical advance that can hugely benefit transplant surgeries of vital organs, surgeons in Britain have successfully performed two liver transplants using a device that can keep organs ÒwarmÓ and less prone to damages outside the body.

A group of scientists from Oxford University have invented a machine which preserves human livers outside the body for up to 24 hours making 'warm liver' transplants a reality.

Two liver tranplants were carried out last month at King's College Hospital in London and both the patients are recovering well, surgeons and Oxford scientists told here yesterday.
ÒI was impressed to see how quickly each liver started to function following the transplant. This technology has the potential to be hugely significant and could save lives,Ó said Dr Wayel Jassem, the transplant surgeon who performed both operations.

The new advance is set to revolutionise organ transplants as it offers the potential to increase the number of viable organs available to patients and also gives enough time to doctors to organise surgery.
ÒIt provides an environment where the donor liver hardly knows it has left the body. Instead of cooling it to slow its metabolism we keep it functioning at normal temperature and with oxygen and nutrition,Ó said Professor Peter Friend of the Nuffield Department of Surgical Sciences at Oxford University.

After being removed from the donor, the liver is placed in the machine and tubes are connected to the main blood vessels.

Oxygenated blood and nutrients are pumped through the liver which continues to function and produce bile.
The Oxford inventors say their machine allows the liver to recover from damage it has sustained and enables medical staff to test the viability of the organ to see whether it is likely to work before being transplanted into the patient.

ÒIn experiments we have shown we can preserve a liver and monitor its function outside the body for periods up to 24 hours. By contrast livers kept on ice have to be transplanted with 10-12 hours at most,Ó Prof Coussios explained.

At present many donor livers are rejected for transplantation because they are damaged.
Some have been deprived of oxygen while others contain too much fat and do not survive the cooling process.

But the team stresses that it is too early to draw any firm conclusions as to the benefits of Òwarm liverÓ transplantation.

A further eight patients will receive livers using the new technique at King's College Hospital and after this initial safety trial, a broader study across three European countries is planned.
It may be several years before liver specialists can tell whether the technique has proven benefits.
The same concept is also being tested on heart and lung transplants.

Mindfulness can improve self-knowledge

 Washington, Mar 16 - Mindfulness may help you learn more about your own personality, according to a new study. The study published in the journal Perspectives on Psychological Science, explores one potential strategy for improving self-knowledge: mindfulness.

Mindfulness a technique often recognised for its positive effects on mental health involves paying attention to your current experience (eg, thoughts, feelings) and observing it in a non-judgmental manner.
Recent research has highlighted the fact that people have many blind spots when it comes to understanding their patterns of thinking, feeling, and behaving.

Despite our intuition that we know ourselves the best, other people have a more accurate view of some traits (eg, intellect) than we do.

In some cases, blind spots in self-knowledge can have negative consequences, such as poor decision-making, poor academic achievement, emotional and interpersonal problems, and lower life satisfaction.
In the new study, psychological scientist Erika Carlson of Washington University in St Louis said that two components of mindfulness, attention and nonjudgmental observation, can overcome the major barriers to knowing ourselves.

She argued that the motivation to see ourselves in a desirable way is one of the main obstacles to self-knowledge.
For instance, people may overestimate their virtuous qualities to ward off negative feelings or boost self-esteem.

However, non-judgmental observation of one’s thoughts, feelings, and behaviour, might reduce emotional reactivity such as feelings of inadequacy or low self-esteem that typically interferes with people seeing the truth about themselves.

Lack of information is another barrier to self-knowledge in some situations, people might not have the information they would need to accurately assess themselves.

For instance, we have a hard time observing much of our nonverbal behaviour, so we may not know that we’re grimacing or fidgeting during a serious conversation.

Mindfulness could also help in this domain, as research has shown that mindfulness training is associated with greater bodily awareness.

New cancer diagnostic technique developed

Washington, Mar 16 - Researchers have devised a new molecular sensor that can detect high levels of lactate - a telltale sign of cancer - in individual cells.

Cancer cells break down sugars and produce the metabolic acid lactate at a much higher rate than normal cells. This phenomenon signals that cancer is present, via diagnostics such as PET scans, and possibly offers an avenue for novel cancer therapies.

Now, a team of Chilean researchers at The Centro de Estudios Cientificos (CECs), with the collaboration of Carnegie’s Wolf Frommer, has devised a molecular sensor that can detect levels of lactate in individual cells in real time.

Prior to this advance, no other measurement method could non-invasively detect lactate in real time at the single-cell level.
The work, published in the journal PLOS ONE, is a boon to understanding how different types of cells go awry when cancer hits.

ÒOver the last decade, the Frommer lab at Carnegie has pioneered the use of Forster Resonance Energy Transfer, or FRET, sensors to measure the concentration and flow of sugars in individual cells with a simple fluorescent colour change,Ó said Alejandro San Martin, lead author of the study.

ÒUsing the same underlying physical principle and inspired by the sugar sensors, we have now invented a new type of sensor based on a transcriptional factor. A molecule that normally helps bacteria to adapt to its environment has now been tricked into measuring lactate for us,Ó Martin said.

ÒStandard methods to measure lactate are based on reactions among enzymes, which require a large number of cells in complex cell mixtures,Ó said Felipe Barros, leader of the project.

ÒThis makes it difficult or even impossible to see how different types of cells are acting when cancerous. Our new technique lets us measure the metabolism of individual cells, giving us a new window for understanding how different cancers operate,Ó Barros said in a statement.

Researchers turned the sensor on in three cell types: normal brain cells, tumour brain cells, and human embryonic cells. The sensor was able to quantify even very low concentrations of lactate, providing an unprecedented sensitivity and range of detection.

The researchers found that the tumour cells produced lactate 3-5 times faster than the non-tumour cells.
ÒThe high rate of lactate production in the cancer cell is the hallmark of cancer metabolism,Ó said Frommer.

New Drugs May Improve Quality of Life for People with Parkinson's Disease

SAN DIEGO, March 15, 2013 - Three studies released today present possible positive news for people with Parkinson's disease. The studies, which will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 16 to 23, 2013, report on treatments for blood pressure problems, the wearing-off that can occur when people have taken the main drug for Parkinson's for a long time, and for people early in the disease whose symptoms are not well-controlled by their main drugs. "All of these treatments are promising news for people with Parkinson's disease, which is the second most common neurodegenerative disease after Alzheimer's disease," said Robert A. Hauser, MD, MBA, of the University of South Florida in Tampa and a Fellow of the American Academy of Neurology, who was an author of all three studies. The first study dealt with the rapid drop in blood pressure that people with Parkinson's can experience when standing up, which can lead to dizziness, fainting and falls. The problem, which affects about 18 percent of people with the disease, occurs because the autonomic nervous system fails to respond to changes in posture by releasing enough of the chemical norepinephrine. In the study, 225 people were randomized to receive either eight weeks of stable dose treatment with a placebo or the drug droxidopa, which converts to norepinephrine. After one week of stable treatment, those who received the drug had a clinically meaningful, two-fold decrease in the symptoms of dizziness and lightheadedness, when compared to placebo. They also had fewer falls, or 0.38 falls per patient per week, compared to 1.73 for those receiving a placebo on average over the entire 10-week study duration. The second study looked at treatment with a new drug for "wearing-off" that occurs with people who have been taking levodopa for several years. As each dose wears off, people experience longer periods of time where the motor symptoms do not respond to levodopa. For the study, 420 people who were experiencing an average of six hours of "off" time per day received a placebo or one of four dosages of the drug tozadenant in addition to their levodopa for 12 weeks. People receiving two of the dosages of the drug had slightly more than an hour less off time per day at the end of 12 weeks than they had at the start of the study. They also did not have more troublesome involuntary movements during their "on" time, called dyskinesia, that can occur. The third study looked at 321 people with early Parkinson's disease whose symptoms were not well-controlled by a dopamine agonist drug. For the 18-week study, the participants took either the drug rasagiline or a placebo in addition to their dopamine agonist. At the end of the study, those taking rasagiline had improved by 2.4 points on a Parkinson's disease rating scale. In addition, rasagiline was well tolerated with adverse events similar to placebo. The blood pressure study was supported by Chelsea Therapeutics. The "wearing-off" study was supported by Biotie Therapies, Inc., The early Parkinson's disease study was supported by Teva Pharmaceuticals. Learn more about Parkinson's disease at http://www.aan.com/patients. The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson's disease and epilepsy.

Boeing Provides Details on 787 Battery Improvements

EVERETT, Wash., March 15, 2013 - Boeing (NYSE: BA) announced today that a comprehensive set of improvements that will add several layers of additional safety features to the lithium-ion batteries on 787 commercial jetliners are in production and could be ready for initial installation within the next few weeks. New enclosures for 787 batteries also are being built and will be installed in airplanes in the weeks ahead. These improvements, which continue to undergo extensive certification testing, will allow operators to resume commercial flights with their 787s as soon as testing is complete and the U.S. Federal Aviation Administration (FAA) and other international regulators grant their final approval. The improvements include enhanced production and operating processes, improved battery design features and a new battery enclosure. "As soon as our testing is complete and we obtain regulatory approvals, we will be positioned to help our customers implement these changes and begin the process of getting their 787s back in the air," said Boeing Commercial Airplanes President and CEO Ray Conner. "Passengers can be assured that we have completed a thorough review of the battery system and made numerous improvements that we believe will make it a safer, more reliable battery system." Battery system changes include changes to the battery itself, the battery charging unit and the battery installation. Earlier this week the FAA approved Boeing's certification plan, which lays out the discrete testing to be done to demonstrate that the battery improvements address the conditions laid out in the Airworthiness Directive that has suspended 787 commercial operations. Development Team Created Solution The enhancements to the battery system address causal factors identified by the Boeing technical team as possible causes of battery failure. The technical team's findings also were verified by an independent group of lithium-ion battery experts from a number of industries, universities and national laboratories. "We've come up with a comprehensive set of solutions that result in a safer battery system," said Mike Sinnett, vice president and chief project engineer, 787 program, Boeing Commercial Airplanes. "We have found a number of ways to improve the battery system and we don't let safety improvements go once they are identified. We incorporate them into our processes and products." Enhanced Production Controls and Operating Processes The first layer of improvements is taking place during the manufacture of the batteries in Japan. Boeing teamed with Thales, the provider of the integrated power conversion system, and battery maker GS Yuasa to develop and institute enhanced production standards and tests to further reduce any possibility for variation in the production of the individual cells as well as the overall battery. "We've all developed a better understanding of the sensitivities of this technology to variations during the manufacturing process," said Sinnett. "And we all feel the need to increase monitoring of this process on an ongoing basis." Four new or revised tests have been added to screen cell production, which now includes 10 distinct tests. Each cell will go through more rigorous testing in the month following its manufacture including a 14-day test during which readings of discharge rates are being taken every hour. This new procedure started in early February and the first cells through the process are already complete. There are more than a dozen production acceptance tests that must be completed for each battery. Boeing, Thales and GS Yuasa have also decided to narrow the acceptable level of charge for the battery, both by lowering the highest charge allowed and raising the lower level allowed for discharge. Two pieces of equipment in the battery system – the battery monitoring unit and the charger are being redesigned to the narrower definition. The battery charger will also be adapted to soften the charging cycle to put less stress on the battery during charging. Improved Battery Design Features Changes inside the battery will help to reduce the chances of a battery fault developing and help to further isolate any fault that does occur so that it won't cause issues with other parts of the battery. To better insulate each of the cells in the battery from one another and from the battery box, two kinds of insulation will be added. An electrical insulator is being wrapped around each battery cell to electrically isolate cells from each other and from the battery case, even in the event of a failure. Electrical and thermal insulation installed above, below and between the cells will help keep the heat of the cells from impacting each other. Wire sleeving and the wiring inside the battery will be upgraded to be more resistant to heat and chafing and new fasteners will attach the metallic bars that connect the eight cells of the battery. These fasteners include a locking mechanism. Finally, a set of changes is being made to the battery case that contains the battery cells and the battery management unit. Small holes at the bottom will allow moisture to drain away from the battery and larger holes on the sides will allow a failed battery to vent with less impact to other parts of the battery. New Battery Enclosure The battery case will sit in a new enclosure made of stainless steel. This enclosure will isolate the battery from the rest of the equipment in the electronic equipment bays. It also will ensure there can be no fire inside the enclosure, thus adding another layer of protection to the battery system. The enclosure features a direct vent to carry battery vapors outside the airplane. New titanium fixtures are being installed in the electronics equipment bays to ensure the housing is properly supported. "Our first lines of improvements, the manufacturing tests and operations improvements, significantly reduce the likelihood of a battery failure. The second line of improvements, changes to the battery, helps stop an event and minimize the effect of a failure within the battery if it does occur. And the third line of improvements, the addition of the new enclosure, isolates the battery so that even if all the cells vent, there is no fire in the enclosure and there is no significant impact to the airplane," said Sinnett. Testing Status Testing to gain FAA approval of the battery enhancements has already started, with the FAA's permission. During engineering testing, which occurs prior to certification testing, the team demonstrated that the new housing could safely contain a battery failure that included the failure of all eight cells within the battery. The "ultimate" load is the equivalent of 1.5 times the maximum force ever expected to be encountered during a battery failure. The housing easily withstood this pressure and did not fail until the pressure was more than three times the ultimate load. Through another test, the team demonstrated that fire cannot occur within the new enclosure. Its design eliminates oxygen, making the containment unit self-inerting. Inerting is a step above fire detection and extinguishing as it prevents a fire from ever occurring. The design also vents all vapors by venting directly outside of the airplane rather than into the equipment bay. "We put this new design through a rigorous set of tests. We tried to find a way to introduce a fire in the containment but it just wouldn't happen. Even when we introduced a flammable gas in the presence of an ignition source, the absence of oxygen meant there was no fire. "We drew from the new industry standard, DO311, established by RTCA, to establish our testing plan," said Sinnett. "These standards weren't available when we set the testing plan for the baseline battery and they helped us ensure the new design is robust and safe. We intend to show, during certification, that the 787 battery meets all objectives of DO-311 and only deviates from specific requirements where the 787-unique items are not covered by the standards." RTCA is a not-for-profit organization that serves as a federal advisory committee in establishing guidelines for the aviation industry. Working towards Resuming Flights "We are following all of the necessary protocols to get our new design fully approved and properly installed so that we can help our customers start flying as soon as possible. We're simultaneously moving out on an effort to resume deliveries but completing our certification work and getting the delivered fleet flying again is our first priority," said Conner. "Our customers and their passengers have been incredibly patient as we have worked through this process and we thank them very sincerely for their continued support and confidence in the 787. "The more-electric architecture of the 787 brings real value not just to the airlines but to our industry. By reducing fuel use, we are reducing our environmental footprint. This battery technology is an important part of the more-electric architecture, which is helping us to cut fuel use by more than 10 billion gallons of fuel over the life of this program. "New technologies require extra attention and hard work, but the benefits are real."