sid_melo blogreen: 05/23/14

sexta-feira, 23 de maio de 2014

Going beyond the surface: New tech could take light-based cancer treatment deep inside the body

May 15 / 2014

University at Buffalo

Photodynamic therapy (PDT) is an effective treatment for easily accessible tumors such as oral and skin cancer. But the procedure, which uses lasers to activate special drugs called photosensitizing agents, isn't adept at fighting cancer deep inside the body. Thankfully, that's changing due to new technology that could bring PDT into areas of the body which were previously inaccessible. The new tech involves using near-infrared beams of light that, upon penetrating deep into the body, are converted into visible light that activates the drug and destroys the tumor.

The laser irradiated area (the white square) shows live cancer cells (green) as well as dead cancer cells (red) as a result of the irradiation.

Photodynamic therapy (PDT) is an effective treatment for easily accessible tumors such as oral and skin cancer.

But the procedure, which uses lasers to activate special drugs called photosensitizing agents, isn't adept at fighting cancer deep inside the body. Thankfully, that's changing due to new technology that could bring PDT into areas of the body which were previously inaccessible.

Described May 11 in the journal Nature Photonics, the approach involves using near-infrared beams of light that, upon penetrating deep into the body, are converted into visible light that activates the drug and destroys the tumor.

"We expect this will vastly expand the applications for an effective cancer phototherapy that's already in use," said co-author Tymish Ohulchanskyy, PhD, University at Buffalo research associate professor and deputy director for photomedicine at the university's Institute for Lasers, Photonics and Biophotonics (ILPB).

Doctors have used PDT to treat cancer for decades. Cancer cells absorb the drug, which is delivered to the tumor via the bloodstream or locally. Visible light is then applied to the site, which causes the drug to react with oxygen and create a burst of free radicals that kill the tumor.

Unfortunately, visible light does not penetrate tissue well. Conversely, near-infrared light penetrates tissue well but doesn't activate the drugs efficiently.

To solve this problem, some researchers are developing drugs that absorb near-infrared light. This method is limited, however, because stable and efficient near-infrared absorbing photosenzitizers are notoriously difficult to synthesize.

The UB-led team took a different approach, which uses the tumor's natural environment to tune the light into the necessary wavelengths.

For example, the near-infrared laser beam interacts with the natural protein collagen, which is found in connective tissues. The interaction changes the near-infrared light to visible light, a process known as second harmonic generation. Likewise, natural proteins and lipids within the cells interact with near-infrared laser light and change it to visible light through another process called four-wave mixing.

Thus, visible light can be generated in tumors deep inside the body, and it can be absorbed by the drug. This activates the drug, which then destroys the tumor.

The procedure has numerous advantages, said the study's leader, Paras Prasad, PhD, SUNY Distinguished Professor in chemistry, physics, electrical engineering, and medicine at UB, and the ILPB's executive director.

"There are no long-term side effects for PDT, it's less invasive than surgery, and we can very precisely target cancer cells," he said. "With our approach, PDT is enriched to provide another tool that doctors can use to alleviate the pain of millions of people suffering from cancer."

UB has applied for a patent to protect the team's discovery, and the university's Office of Science, Technology Transfer and Economic Outreach (UB STOR) is discussing potential license agreements with companies interested in commercializing it.

Story Source:

The above story is based on materials provided by University at Buffalo. The original article was written by Cory Nealon. Note: Materials may be edited for content and length.

Journal Reference:

A. V. Kachynski, A. Pliss, A. N. Kuzmin, T. Y. Ohulchanskyy, A. Baev, J. Qu, P. N. Prasad. Photodynamic therapy by in situ nonlinear photon conversion. Nature Photonics, 2014; DOI: 10.1038/nphoton.2014.90

Dramatic Improvements in nanogenerator power efficiency for wearable, implantable electronics

Click to enlarge

This is a photograph of large-area PZT thin film nanogenerator (3.5 cm × 3.5 cm) on a curved glass tube and 105 commercial LEDs operated by self-powered flexible piezoelectric energy harvester.

The energy efficiency of KAIST's piezoelectric nanogenerator has increased by almost 40 times, one step closer toward the commercialization of flexible energy harvesters that can supply power infinitely to wearable, implantable electronic devices.

Nanogenerators are innovative self-powered energy harvesters that convert kinetic energy created from vibrational and mechanical sources into electrical power, removing the need of external circuits or batteries for electronic devices. This innovation is vital in realizing sustainable energy generation in isolated, inaccessible, or indoor environments and even in the human body.

Nanogenerators, a flexible and lightweight energy harvester on a plastic substrate, can scavenge energy from the extremely tiny movements of natural resources and human body such as wind, water flow, heartbeats, and diaphragm and respiration activities to generate electrical signals. The generators are not only self-powered, flexible devices but also can provide permanent power sources to implantable biomedical devices, including cardiac pacemakers and deep brain stimulators.

However, poor energy efficiency and a complex fabrication process have posed challenges to the commercialization of nanogenerators. Keon Jae Lee, Associate Professor of Materials Science and Engineering at KAIST, and his colleagues have recently proposed a solution by developing a robust technique to transfer a high-quality piezoelectric thin film from bulk sapphire substrates to plastic substrates using laser lift-off (LLO).

Applying the inorganic-based laser lift-off (LLO) process, the research team produced a large-area PZT thin film nanogenerators on flexible substrates (2 cm x 2 cm).

"We were able to convert a high-output performance of ~250 V from the slight mechanical deformation of a single thin plastic substrate. Such output power is just enough to turn on 100 LED lights," Keon Jae Lee explained.

The self-powered nanogenerators can also work with finger and foot motions. For example, under the irregular and slight bending motions of a human finger, the measured current signals had a high electric power of ~8.7 μA. In addition, the piezoelectric nanogenerator has world-record power conversion efficiency, almost 40 times higher than previously reported similar research results, solving the drawbacks related to the fabrication complexity and low energy efficiency.

Lee further commented, "Building on this concept, it is highly expected that tiny mechanical motions, including human body movements of muscle contraction and relaxation, can be readily converted into electrical energy and, furthermore, acted as eternal power sources."

The research team is currently studying a method to build three-dimensional stacking of flexible piezoelectric thin films to enhance output power, as well as conducting a clinical experiment with a flexible nanogenerator.

Video: http://www.youtube.com/watch?v=G_Fny7Xb9ig

Story Source:

The above story is based on materials provided by The Korea Advanced Institute of Science and Technology (KAIST). Note: Materials may be edited for content and length.

Journal Reference:

Kwi-Il Park, Jung Hwan Son, Geon-Tae Hwang, Chang Kyu Jeong, Jungho Ryu, Min Koo, Insung Choi, Seung Hyun Lee, Myunghwan Byun, Zhong Lin Wang, Keon Jae Lee. Highly-Efficient, Flexible Piezoelectric PZT Thin Film Nanogenerator on Plastic Substrates. Advanced Materials, 2014; 26 (16): 2514 DOI: 10.1002/adma.201305659

Massive online open classrooms not yet meeting high expectations, new study finds

The rollout of MOOCs, or massive open online courses, three years ago by some of the country's leading universities triggered predictions that bricks-and-mortar campuses would soon be obsolete and that learning would be forever changed.

Well, maybe -- but not any time soon, according to one of the first comprehensive studies of MOOCs from the perspective of institutions, released on May 15 by researchers at Teachers College, Columbia University. The study is based on 83 interviews with faculty members, administrators, researchers, and other actors in the MOOC space from 62 institutions, mostly in the U.S. It includes 13 case studies to illustrate how MOOCs are successfully being used to address institutional goals.

The study finds that a primary goal for institutions offering MOOCs is to extend institutional reach and access to education. "MOOCs are providing educational opportunities to millions of individuals across the world," write Fiona M. Hollands (Ph.D. '03) and Devayani Tirthali (Ed.D. '13, Ed.M. '12), respectively of the College's Center for Benefit-Cost Studies of Education and the Institute for Learning Technologies, in their report, "MOOCs: Expectations and Reality." However, to date, "most MOOC participants are already well-educated and employed." Consequently, "the evidence suggests that MOOCs currently are falling far short of 'democratizing' education and may, for now, be doing more to increase gaps in access to education than to diminish them."

Using MOOCs to "build and maintain brand" is another frequently mentioned institutional goal, but while MOOCs often generate media attention, "isolating and measuring impact of any new initiative on brand is a difficult exercise," the report suggests. Indeed, increasing access to online offerings and enhancing brand may be contradictory goals, because the former can be seen as diminishing the selectiveness of the offering institution.

Hollands and Tirthali report that it is still too early to know whether MOOCs can live up to the hype of providing a cost-effective means for producing better educational outcomes on a mass scale. Cost analyses of MOOC production and delivery at four different institutions found that costs ranged from $39,000 to $325,000 per MOOC. "MOOCs have, so far, proved to be a significant drain on time and money for institutions," Hollands and Tirthali write. That picture could change as institutions reuse MOOC materials, share them with each other, develop common courses, replace on-campus courses with MOOCs, and save on faculty teaching time and facilities costs. Revenue streams from MOOCs have been slow in materializing. Unless costs of MOOC production can be recovered through fees, Hollands and Tirthali speculate that "free, non-credit bearing MOOCs are likely to remain available only from the wealthiest institutions that can subsidize the costs from other sources of funds."

As for improving learning outcomes, MOOCs, on the whole, cannot yet make that claim. "While interviewees provided many examples of how MOOCs have been used to change instruction, for the most part, actual impact on educational outcomes has not been documented in any rigorous fashion," the report asserts.

However, two cases highlighted in the report provide examples of positive effects on student performance as a result of adopting MOOC-inspired strategies such as frequent assessment and automatic feedback, or of integrating MOOCs into flipped on-campus courses.

Hollands and Tirthali conclude that "while the potential for MOOCs to contribute significantly to the development of personalized and adaptive learning is high, the reality is far from being achieved." To get there, "a great deal of coordination and collaboration among content experts, instructors, researchers, instructional designers, and programmers will be necessary."

Hollands and Tirthali make several recommendations to institutions for increasing the value of MOOCs to improve access and educational outcomes, and to reduce the costs of higher education. These include:

• Identifying multiple channels of communication to advertise MOOCs to less connected audiences, and providing more instructional scaffolding to serve less educated participants • Assessing the impact of MOOC pedagogy on educational outcomes by conducting pre- and post-assessment of participant skills and knowledge • Developing metrics to assess gains in cognitive and non-cognitive skills that can be applied outside the MOOC environment • Finding ways to confer economic value on MOOC completion, such as providing employer-recognized credentials • Using MOOCs to substitute standardized courses across multiple campuses, or for continuing professional development and certification • Working towards standardization of data formats across online learning platforms in order to facilitate research • Establishing an accreditation system to evaluate MOOCs and other non-degree-based learning experiences to allow learners to accumulate a portfolio of credentials.

The report can be found online at: http://cbcse.org/wordpress/wp-content/uploads/2014/05/MOOCs_Expectations_and_Reality.pdf

Story Source:

The above story is based on materials provided by Columbia University, Teachers College. Note: Materials may be edited for content and length.

New imaging technology: Phase contrast x-ray

The researchers have succeeded in advancing an emerging imaging technique for breast investigations: the X-ray phase-contrast mammography. The new developments enable distinguishing between the different types of microcalcifications observed in breast tissue and help assigning them to malignant lesions. The study has just been published in Nature Communications.

One of the advantages of the phase contrast technique is its ability to provide images of high contrast. In the future, this technique can aid physicians to determine in a non-invasive way where premalignant and malignant breast lesions are most likely located. One goal of breast cancer screening is to detect (groups of) microcalcifications in the breast, because these may be associated with early stages of breast cancer since they often occur in connection with cancer cell death. Mammographic screening does not allow definite conclusions regarding the underlining conditions that cause calcifications. Only tissue biopsies that are examined under the microscope by pathologists can determine which lesions have caused the calcareous deposits.

Clinical equipment could be used for phase contrast imaging

At the PSI, the use of phase contrast for medical X-ray imaging has been investigated for several years. X-ray radiation as used in conventional mammography was long considered not suitable for phase contrast procedures because of its incoherence and mixture of multiple wavelengths. "The fact that we have now managed to use these X-ray sources for the phase contrast method in order to develop a new and improved imaging method is a considerable step towards application in daily clinical practice," says Marco Stampanoni, Professor at the Institute for Biomedical Engineering at ETH Zurich and Head of the X-ray Tomography Group at the PSI. He received an ERC Consolidator Grant in 2012 to advance the clinical use of X-ray phase contrast.

In X-ray phase contrast, the extent in which tissue absorbs x-rays is not the only quantity that is being measured but also how tissue deflects radiation laterally (refraction) and consequently how it influences the sequence of oscillation peaks and valleys of X-ray waves -- the so-called phase. Depending on the tissue type, the overall scattering also varies. To be able to measure the phase shift, researchers use three very fine grids. The first one is located directly at the source. It ensures that the object is illuminated with the required coherence. Another grid is placed behind the object and generates an interference signal that is analyzed by a third grid downstream. Using suitable algorithms, the re-searchers calculate the absorption, phase and scattering properties of the object from the interference signal. This information can be used to generate sharp and high-contrast images that show very detailed soft tissue properties. A discovery by Zhentian Wang, PostDoc in Prof. Stampanoni's team, initiated this development: "During my trials with the phase contrast method, I noticed that there are microcalcifications with different absorption and scattering signals. That indicated that the new method might identify different types of calcifications," he says. Wang subsequently reviewed through medical literature and found studies that showed that a certain type of calcification is more frequently associated with breast cancer precursors. "I was persuaded that my observation could be very interesting for breast cancer diagnosis, since it could distinguish between the different types of microcalcifications," says the researcher.

Clinically relevant

The relevance of the new method was also confirmed by the physicians who participated in the study: "We are hopeful that the new technique, in comparison to standard mammography, will help to better indicate where a biopsy must be carried out in the breast," says Rahel Kubik, Head of the Institute of Radiology at the Kantonsspital Baden. "Still, it is not ready for clinical use as it needs to be validated in a larger number of cases," says the radiologist. "But it is very encouraging that the new method enables a distinction between the different well-known microscopic types of calcifications," confirms Gad Singer, Head of the Institute of Pathology at the Kantonsspital Baden.

Whether the technology will make it to clinical use also depends on the radiation dose. "The aim will be to significantly improve quality, resolution and diagnosis with the same radiation dose as for a standard mammography so that breasts can be better examined" says Nik Hauser, Head of Gynaecology and of the Interdisciplinary Breast Center at the Kantonsspital Baden. "If we can significantly improve imaging, this would enable better assessments of tumor extent prior to surgery. Then the new method will quickly become important," he is convinced. The foundation for a new imaging device has been laid, says Hauser. "We are optimistic that we soon will be able to present further results." To date, the re-searchers have worked with a prototype. They examined breast tissue samples, but no patients have been involved yet. "One of our next aims will be to develop a device for clinical use," says Marco Stampanoni.

Benign prostatic hyperplasia

Prostate gland enlargement is a common condition as men get older. Also called benign prostatic hyperplasia (BPH) and prostatic hypertrophy, prostate gland enlargement can cause bothersome urinary symptoms. Untreated prostate gland enlargement can block the flow of urine out of the bladder and can cause bladder, urinary tract or kidney problems.

There are several effective treatments for prostate gland enlargement. In deciding the best option for you, you and your doctor will consider your particular symptoms, the size of your prostate, other health problems you may have and your preferences. Your choices may also depend on what treatments are available in your area. Treatments for prostate gland enlargement include medications, lifestyle changes and surgery.

Symptoms

Prostate gland enlargement varies in severity among men and tends to gradually worsen over time. Prostate gland enlargement symptoms include:

Weak urine stream
Difficulty starting urination
Stopping and starting while urinating
Dribbling at the end of urination
Frequent or urgent need to urinate
Increased frequency of urination at night (nocturia)
Straining while urinating
Not being able to completely empty the bladder
Urinary tract infection
Formation of stones in the bladder
Reduced kidney function

The size of your prostate doesn't necessarily mean your symptoms will be worse. Some men with only slightly enlarged prostates have significant symptoms. On the other hand, some men with very enlarged prostates have only minor urinary symptoms.

Only about half the men with prostate gland enlargement have symptoms that become noticeable or bothersome enough for them to seek medical treatment. In some men, symptoms eventually stabilize and may even improve over time.

When to see a doctor

If you're having urinary problems, see your doctor to check whether your symptoms are caused by an enlarged prostate and find out what tests or treatment you may need. If you're unable to pass urine at all, seek immediate medical attention.

If you don't find urinary symptoms too bothersome and they don't pose a health threat, you may not need treatment. But you should still have your symptoms checked out by a doctor to make sure they aren't caused by another problem such as prostate cancer.

Despite economic blows, infant health has improved among US poor

Despite worsening economic conditions for those at the bottom, infant health has steadily improved among the most disadvantaged Americans, according to a review published in Science by Princeton University's Woodrow Wilson School of Public and International Affairs.

The researchers cite programs and policies like Medicaid, the Supplemental Feeding Program for Women, Infants, and Children (WIC) and the Food Stamp program -- now known as Supplemental Nutrition Assistance Program (SNAP) -- as the driving forces behind such marked improvements.

"We've long known that the health of infants is vulnerable, especially for those born to disadvantaged mothers," said co-author Janet Currie, the Henry Putnam Professor of Economics and Public Affairs and director of the Wilson School's Center for Health and Wellbeing. "However, we now know better how to protect infants from these shocks. Our review shows how current policies have helped to counteract the effects of growing income inequality."

Past research suggests that health at birth is an important predictor of long-term outcomes related to education, employment and income. And for babies born to poor mothers, the risks are amplified. Disadvantaged mothers are more likely to have worse underlying health, poor nutrition, limited access to care and more exposure to harmful pollutants and other stressors. These four health obstacles significantly affect a baby's birth weight -- a strong determinant of infant health.

In an extensive review of health literature, Currie and co-author Anna Aizer, an associate professor of economics and public policy at Brown University, evaluated these aforementioned obstacles, showing how programs and policies have helped to interrupt the cycle.

Nutrition and Health

Disadvantaged mothers have poorer health than their advantaged peers. They are more likely to smoke, drink alcohol and use illicit drugs. They typically have worse underlying health, and are more likely to have preexisting conditions such as diabetes and hypertension. Likewise, they are more susceptible to diseases, such as influenza. All of these health factors significantly increase the likelihood of delivering low-birth-weight babies.

But programs like Medicaid, WIC and SNAP are helping, the researchers write. Mothers living in counties where WIC is offered are now less likely to have low-birth-weight babies. The same is true for those receiving SNAP. One study showed that access to food stamps in early childhood led to a significant reduction in obesity, high blood pressure and diabetes later in life. These mothers also became more economically independent later.

In that same vein, the Nurse Family Partnership Program (NFP), which provides guidance to pregnant women and new mothers, has helped poor children by reducing their chances of being injured or involved with criminal activity. Past research shows that this program benefits the poorest of mothers, with especially large effects for those with lower levels of intelligence and mental health.

"WIC is up for congressional reauthorization in the next fiscal year, and NFP, which the Obama administration originally hoped to greatly expand, has grown very little relative to the need," said Currie. "While there may be other programs that could be effective, it's important to take an evidence-based approach to policy recommendations. These studies provide valuable insights for policy makers and can inform future decisions."

Pollution, Violence and Stress

Poor women are more likely to be affected by outside forces like pollution, violence and stress, which all affect infant health.

Because of lower housing costs, poor mothers tend to live near and be exposed to sources of pollution -- which has been shown to have particularly negative effects on infants in the womb. But a study of electronic toll-collection devices (E-ZPass) in New Jersey, which greatly reduced auto emissions in the vicinity of toll plazas, showed significant reductions in low birth weight and prematurity among babies born in those areas. Likewise, levels of pollution have declined greatly overall since the introduction of the Clean Air Acts in the 1970s.

Poor women also are more likely to be abused by their partners, and their exposure to stress worsens physical and mental health. Such exposure affects infant health in negative ways as children suffer from physical diseases, trauma and even lower IQs due to stress in utero.

Thankfully, local, county-level policing policies have been effective in reducing intimate partner violence. Because of these reductions, fewer women have been medically treated for assault. While this policy targets women, Currie and Aizer writes, it has the added benefit of helping newborn health.

Family Planning

Another big area of concern is access to care and family planning. Poor women are more likely to have unplanned pregnancies and pregnancies that are closer together, the researchers write. However, recent work shows how Medicaid expansions of coverage for family-planning services have helped lower birth rates and multiple pregnancies. While such policies haven't improved infant health, per say, they've benefited mothers while influencing children's longer-term outcomes.

Future Research

Overall, poor mothers benefit from programs and policies both before giving birth and after. But often women only become eligible for these programs after the baby is born, creating a potential time gap in services.

"Given the research on the importance of prenatal conditions, such policies are potentially missing a major window of opportunity," said Currie.

Early-education programs have especially been shown to improve long-term outcomes for low-income children. Intervening early -- before a child is three years old -- can have long-lasting effects on IQ.

Despite Currie and Aizer's overall conclusion that infant health has improved, unanswered questions remain -- providing fodder for future work. The researchers write that it would be helpful to know, for example, how exposure to diseases like the flu compares with exposure to pollution, but the science isn't there yet.

"Looking backward, we can ask, how much of the recent gain in infant health is due to the various aspects we have discussed? Which public policies and programs have had the most impacts on infant health while also counteracting the negative effects of growing income inequality? Which are the most cost-effective?

"Looking forward, we can ask, what are the most promising strategies for continuing to improve infant health, and how much will this improvement reduce inequality in years to come?"

Story Source:

The above story is based on materials provided by Princeton University, Woodrow Wilson School of Public and International Affairs. The original article was written by B. Rose Huber. Note: Materials may be edited for content and length.

Journal Reference:

Anna Aizer And Janet Currie. The intergenerational transmission of inequality: Maternal disadvantage and health at birth. Science, May 2014 DOI: 10.1126/science.1251872

Key mechanism in metabolic pathway that fuels cancers identified

May 22 / 2014

UT Southwestern Medical Center

A significant step in cracking the code of an atypical metabolic pathway that allows certain cancerous tumors to thrive has been cracked, providing a possible roadmap for defeating such cancers. "With this finding, we have learned there are particular enzymes that work together to enable the reverse pathway to function, much like the tiny gears that turn in opposite directions to power a mechanical clock," commented the lead author.

Ralph DeBerardinis, M.D., Ph.D.

In a breakthrough discovery at the Children's Medical Center Research Institute at UT Southwestern (CRI), a research team led by Ralph DeBerardinis, M.D., Ph.D., has taken a significant step in cracking the code of an atypical metabolic pathway that allows certain cancerous tumors to thrive, providing a possible roadmap for defeating such cancers.

Published in Cell Reports, andfollowing up on Dr. DeBerardinis' landmark finding in 2011, this most recent discovery identifies the triggering mechanism that plays a key role in causing a series of energy-generating chemical reactions known as the Krebs cycle to run in reverse.

"With this finding, we have learned there are particular enzymes that work together to enable the reverse pathway to function, much like the tiny gears that turn in opposite directions to power a mechanical clock," said Dr. DeBerardinis, director of CRI's Genetic and Metabolic Disease Program and associate professor in the Department of Pediatrics and the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center.

The identification of the mechanism could provide a future target for drugs that would attack tumors relying upon the reverse pathway for sustenance and growth. Tumors of this type, often found in the brain, lungs and kidneys, tend to be difficult for oncologists to treat because cells using the atypical pathway seem to resist existing treatments like chemotherapy.

"Prior to this discovery, we didn't have enough information about how to tap into the reverse metabolic pathway without disrupting the pathways that were operating in the typical, forward manner," said Dr. DeBerardinis, senior author of the study. "We now believe there is a specific enzyme critical to the reverse pathway that can be deleted without impairing normal function. If we can eliminate that enzyme, we may be able to starve tumors of their supply of building blocks for growth."

Story Source:

The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

Andrew R. Mullen, Zeping Hu, Xiaolei Shi, Lei Jiang, Lindsey K. Boroughs, Zoltan Kovacs, Richard Boriack, Dinesh Rakheja, Lucas B. Sullivan, W. Marston Linehan, Navdeep S. Chandel, Ralph J. DeBerardinis. Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.04.037

'I can' mentality goes long way after childbirth

May 22 / 2014

Michigan State University

The way a woman feels about tackling everyday physical activities, including exercise, may be a predictor of how much weight she'll retain years after childbirth says a professor. A study followed 56 women during pregnancy and measured their physical activity levels, along with barriers to exercise and the ability to overcome them. Six years later, the research team followed up with more than half of the participants and found that the women who considered themselves less able to take on these barriers had retained more of their pregnancy weight. Top barriers identified in the study included time, motivation and childcare issues.

The way a woman feels about tackling everyday physical activities, including exercise, may be a predictor of how much weight she'll retain years after childbirth says a Michigan State University professor.

James Pivarnik, a professor of kinesiology and epidemiology at MSU, co-led a study that followed 56 women during pregnancy and measured their physical activity levels, along with barriers to exercise and the ability to overcome them.

Six years later, the research team followed up with more than half of the participants and found that the women who considered themselves less able to take on these barriers had retained more of their pregnancy weight. Top barriers identified in the study included time, motivation and childcare issues.

The research could help health professionals better understand what these real and perceived obstacles are and help women deal with negative perceptions while incorporating physical activity into their daily lives.

"The women who had difficulty believing they could overcome barriers that often occur in daily life or just thought they weren't cut out for physical activity overall retained 11 to 13 more pounds of pregnancy weight later on," Pivarnik said.

In contrast, the study revealed that those who showed higher levels of self-confidence had four to five times more physical activity during pregnancy and performed almost three times more activity six years later.

"We know that it's beneficial for a woman to be active in some way during and after pregnancy so she can regain her fitness and help with weight loss," Pivarnik said. "But what can affect this is whether women think they can or can't do it."

Exercise physiologist and co-author Patricia Bauer helped lead the study, in addition to support from MSU professors Deborah Feltz and Nigel Paneth, and Christopher Womack with James Madison University.

The study can be found in a recent print edition of the American Journal of Lifestyle Medicine and was funded by the National Institutes of Health.

Story Source:

The above story is based on materials provided by Michigan State University. Note: Materials may be edited for content and length.

Journal Reference:

P. W. Bauer, J. M. Pivarnik, D. L. Feltz, N. Paneth, C. J. Womack. Relationship of Past-Pregnancy Physical Activity and Self-efficacy With Current Physical Activity and Postpartum Weight Retention. American Journal of Lifestyle Medicine, 2013; 8 (1): 68 DOI: 10.1177/1559827613498061

Gene behind unhealthy adipose tissue identified

May 22 / 2014

Karolinska Institutet

A gene driving the development of pernicious adipose tissue in humans has been identified by researchers for the first time. The findings imply that the gene may constitute a risk factor promoting the development of insulin resistance and type 2 diabetes. "Our findings represent an important step forward in the understanding of how adipose tissue links to the development of metabolic disease," comments one of the principal investigators.

Dr. Peter Arner, Ph.D., is a Professor of Medicine at Karolinska Institutet in Stockholm, Sweden.

Researchers at Karolinska Institutet in Sweden have for the first time identified a gene driving the development of pernicious adipose tissue in humans. The findings imply, which are published in the scientific journal Cell Metabolism, that the gene may constitute a risk factor promoting the development of insulin resistance and type 2 diabetes.

Adipose tissue can expand in two ways: by increasing the size and/or the number of the fat cells. It is well established that subjects with few but large fat cells, so-called hypertrophy, display an increased risk of developing type 2-diabetes. In the current study, researchers identified a gene, EBF1, which according to these new findings drive the development of the unhealthy adipose tissue. This gene encodes a protein that controls a set of other genes, a so-called transcription factor, and regulates the formation of new fat cells as well as their metabolic function.

The investigators compared adipose tissue from subjects with small or large fat cells and found that EBF1 was closely linked to hypertrophy. Individuals with large fat cells had markedly lower EBF1 expression in their adipose tissue, displayed altered lipid mobilisation and were insulin resistant. Insulin resistance -- a condition characterised by reduced cellular response to the hormone insulin that is released when the blood glucose levels rise after a meal -- is an important causal factor underlying the increased risk of diabetes in individuals with hypertrophic adipose tissue. Insulin resistance leads to increased circulating levels of glucose and lipids in the blood.

In collaboration with Professor Mark C. Horowitz at Yale School of Medicine, U.S. the researchers also investigated genetically modified mice expressing lower levels of the murine variant of the human EBF1-gene. It turned out that these mice developed adipose hypertrophy and displayed increased lipid mobilisation from fat cells. When the mice were put on high-fat diet they became insulin resistant.

"Our findings represent an important step forward in the understanding of how adipose tissue links to the development of metabolic disease," comments Professor Peter Arner, one of the principal investigators at Karolinska Institutet along with Hui Gao, Niklas Mejhert and Mikael Rydén. "This is the first time someone has identified a gene which may cause malfunctioning adipose tissue in (hu)man. In the future, it might be possible to develop drugs that improve EBF1 function in adipose tissue, which could be used to treat type 2-diabetes."

Story Source:

The above story is based on materials provided by Karolinska Institutet. Note: Materials may be edited for content and length.

Journal Reference:

Hui Gao, Niklas Mejhert, Jackie A. Fretz, Erik Arner, Silvia Lorente-Cebrián, Anna Ehrlund, Karin Dahlman-Wright, Xiaowei Gong, Staffan Strömblad, Iyadh Douagi, Jurga Laurencikiene, Ingrid Dahlman, Carsten O. Daub, Mikael Rydén, Mark C. Horowitz, Peter Arner. Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue. Cell Metabolism, 2014; DOI: 10.1016/j.cmet.2014.03.032

HIV-positive children more likely to develop drug resistance

May 22 / 2014

Tulane University

74 percent of HIV-positive children in a study developed resistance to at least one form of drug treatment. The researchers followed almost 450 children enrolled in the Pediatric HIV/AIDS Cohort Study, one of the largest studies of HIV-positive children in the United States. "The problem with drug resistance is that once you develop it, it never goes away," said the principal investigator. "Some patients with very resistant virus have no effective treatment options. Resistant virus is the major reason for death among youth with perinatal HIV."

Study principal investigator Dr. Russell Van Dyke, professor of pediatric infectious diseases at Tulane University School of Medicine.

Children born with HIV are far more likely to develop resistance to antiretroviral drugs than adults, according to a new Tulane University School of Medicine study.

Researchers following almost 450 children enrolled in the Pediatric HIV/AIDS Cohort Study, one of the largest studies of HIV-positive children in the United States, found that 74 percent had developed resistance to at least one form of drug treatment and 30 percent were resistant to at least two classes of HIV treatment drugs. In comparison, nearly 36 percent of adults with HIV have resistance to one form of drug treatment and only 12 percent have resistance to at least two classes.

The study, which tracks patients at 14 sites across the country, followed participants from 7 to 16 years of age at enrollment.

"The problem with drug resistance is that once you develop it, it never goes away," said principal investigator Dr. Russell Van Dyke, professor of pediatric infectious diseases. "Some patients with very resistant virus have no effective treatment options. Resistant virus is the major reason for death among youth with perinatal HIV."

Fortunately, most adolescents with resistant HIV remain sensitive to newer agents from all classes, allowing salvage therapy. Just one child in the study had resistance to all HIV drugs and only 18 percent had resistance to one drug from each of the three primary classes of HIV medications.

The study emphasizes the importance of drug adherence for children and adolescents with HIV who typically take multiple medications daily to manage the disease. Once daily, single-pill HIV medications for adults are not yet available for children, Van Dyke said.

"The best way to prevent resistance from developing is to take your medicine and suppress your viral load," Van Dyke said. "You develop resistance when you take some of your medications but not all. Then you've got virus that is replicating in the face of taking your medication. Lack of adherence is the major reason resistance develops."

The study abstract was presented recently at the Conference on Retroviruses and Opportunistic Infections, and is available for viewing online at: http://croiconference.org/sites/all/abstracts/897.pdf

Story Source:

The above story is based on materials provided by Tulane University. The original article was written by Keith Brannon. Note: Materials may be edited for content and length.

Misguided DNA-repair proteins caught in the act

Accumulation of DNA damage can cause aggressive forms of cancer and accelerated aging, so the body's DNA repair mechanisms are normally key to good health. However, in some diseases the DNA repair machinery can become harmful. Scientists led by a group of researchers at The Scripps Research Institute (TSRI) in La Jolla, CA, have discovered some of the key proteins involved in one type of DNA repair gone awry.

The focus of the new study, published in the May 22, 2014 edition of the journal Cell Reports, is a protein called Ring1b. The TSRI researchers found that Ring1b promotes fusion between telomeres -- repetitive sequences of DNA that act as bumpers on the ends of chromosomes and protect important genetic information. The scientists also showed inhibiting this protein can significantly reduce the burden on cells affected by such telomere dysfunction.

"We are very far from therapy, but I think a lot of the factors we've identified could play key roles in processing dysfunctional telomeres, a key event in tumorigenesis [cancer initiation]," said Eros Lazzerini Denchi, assistant professor at TSRI who led the study.

The Trouble with Telomeres

Humans are born with long telomeres, but these become shorter every time a cell in the body divides. With age, telomeres become very short, especially in tissues that have high proliferation rate.

That's when the problems start. When telomeres become too short, they lose their telomere protective cap and become recognized by the DNA repair machinery proteins. This can lead to the fusion of chromosomes "end-to-end" into a string-like formation.

Joined chromosomes represent an abnormal genomic arrangement that is extremely unstable in dividing cells. Upon cell division, joined chromosomes can rupture, creating new break points that can further re-engage aberrant DNA repair. These cycles of fusion and breakage cause a rampant level of mutations that are fertile ground for cancer.

"You basically scramble the genome, and then you have lots of chances to select very nasty mutations," said Lazzerini Denchi.

Setting a DNA Trap

To understand how to prevent these deleterious fusions, Lazzerini Denchi and his colleagues wanted to identify all the repair factors involved.

The researchers decided to set a trap. Using genetically engineered cells, the researchers were able to remove a telomere binding protein called TRF2. Without TRF2, telomeres are unprotected and DNA repair proteins are recruited to chromosome ends, where they promote chromosome fusions.

The researchers then trapped and isolated all the proteins they found bound to the telomeres. "It was like a fishing expedition, and the bait in our case was the telomeric DNA sequence," said Lazzerini Denchi.

Cristina Bartocci, a postdoctoral fellow in Lazzerini Denchi's lab at the time and first author of the new study, spent more than two years perfecting a technique to identify proteins that flocked to the telomeres. "It was a pretty challenging experiment to perform," she said.

The researchers then separated the proteins from the DNA sequences and sent the proteins to TSRI Professor John Yates's laboratory for mass spectrometry analysis. This analysis revealed 24 known repair proteins and 100 additional proteins whose role in dysfunctional telomeres had not been previously described.

The team then refined their search and took a closer look at the role of the repair factor protein called Ring1b. For the first time, the scientists were able to link Ring1b to the chromosome fusion process. Bartocci said the role of Ring1b in dysfunctional telomere repair was "pretty striking."

"If you don't have Ring1b, the process of fusing the chromosomes is not very efficient," said Lazzerini Denchi.

In addition to Ring1b, the team has found nearly 100 factors that might be related to errors in DNA damage repair. The next step in this research is to further refine the long list of DNA repair factors and study other proteins that could affect human health.

Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.

Journal Reference:

Cristina Bartocci, Jolene K. Diedrich, Iliana Ouzounov, Julia Li, Andrea Piunti, Diego Pasini, John R. Yates, Eros Lazzerini Denchi. Isolation of Chromatin from Dysfunctional Telomeres Reveals an Important Role for Ring1b in NHEJ-Mediated Chromosome Fusions. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.04.002

Protective proteins reduce damage to blood vessels

May 21 / 2014

Biotechnology and Biological Sciences Research Council

Proteins found in our blood can reduce damage caused to blood vessels as we age, and in conditions such as atherosclerosis and arthritis, new research finds. Calcification is a major risk factor for heart attack and stroke. Blood vessels can harden as calcium phosphate (CaP) crystals, normally found in bones and teeth, build up in soft tissue as we age or as a result of illness. This can lead to complications in patients with atherosclerosis, a major cause of death whereby arteries thicken and are at risk of becoming blocked.

Calcium phosphate crystals (needle-shaped, indicated by arrows) being engulfed by a human vascular smooth muscle cell (SMC).

Researchers have uncovered how proteins found in our blood can reduce damage caused to blood vessels as we age, and in conditions such as atherosclerosis and arthritis.

Calcification is a major risk factor for heart attack and stroke. Blood vessels can harden as calcium phosphate (CaP) crystals, normally found in bones and teeth, build up in soft tissue as we age or as a result of illness. This can lead to complications in patients with atherosclerosis, a major cause of death in the UK whereby arteries thicken and are at risk of becoming blocked.

However a team of scientists at the BBSRC-funded Babraham Institute has discovered how CaP damages vessels, and how proteins normally found in our circulation can help prevent this process.

In the study funded by the British Heart Foundation, researchers found that small CaP crystals were being consumed by blood vessel cells, resulting in abnormally high levels of calcium ions, which can prove toxic.

They discovered that two proteins in the blood, fetuin-A and albumin, can slow down the uptake of CaP crystals by blood vessel cells, reducing the release of calcium ions and protecting against damage.

Dr Diane Proudfoot, who led the study, explained: "Small changes in calcium levels within a cell controls many aspects of normal cell function. However, when calcium levels become excessive, the cell can die. By delaying the uptake of these crystals and reducing the release of calcium ions, proteins fetuin-A and albumin can help to keep calcium ions at a safe level."

The research, published today in the journal PLOS ONE, offers potential to develop treatments to prevent and reduce the damaging effects of CaP crystals.

Dr Proudfoot added: "Interestingly, lower levels of these proteins have been observed in patients with chronic kidney disease who can suffer a higher level of mortality due to cardiovascular disease. In the future, there is potential to use fetuin-A that has been artificially created or extracted from blood as a treatment for patients with low levels of this protein."

Professor Melanie Welham, BBSRC Executive Director for Science, said: "BBSRC-funded science helps us to explore the biological processes that underpin our health. This research provides important insights into healthy aging and may lead to therapeutic strategies to prevent the problems associated with calcification in aging and several diseases."

Story Source:

The above story is based on materials provided by Biotechnology and Biological Sciences Research Council. Note: Materials may be edited for content and length.

Journal Reference:

Yana Dautova, Diana Kozlova, Jeremy N. Skepper, Matthias Epple, Martin D. Bootman, Diane Proudfoot. Fetuin-A and Albumin Alter Cytotoxic Effects of Calcium Phosphate Nanoparticles on Human Vascular Smooth Muscle Cells. PLoS ONE, 2014; 9 (5): e97565 DOI: 10.1371/journal.pone.0097565

Some pancreatic cancer treatments may be going after wrong targets

May 22 / 2014

University of Michigan Health System

New research represents a significant change in the understanding of how pancreatic cancer grows – and how it might be defeated. Unlike other types of cancer, pancreatic cancer produces a lot of scar tissue and inflammation. For years, researchers believed that this scar tissue, called desmoplasia, helped the tumor grow, and they’ve designed treatments to attack this. But new research finds that when you eliminate desmoplasia, tumors grow even more quickly and aggressively. In the study, mice in which the desmoplasia was eliminated developed tumors earlier and died sooner.

New research represents a significant change in the understanding of how pancreatic cancer grows – and how it might be defeated.

Unlike other types of cancer, pancreatic cancer produces a lot of scar tissue and inflammation. For years, researchers believed that this scar tissue, called desmoplasia, helped the tumor grow, and they’ve designed treatments to attack this.

But new research led by Andrew D. Rhim, M.D., from the University of Michigan Comprehensive Cancer Center, finds that when you eliminate desmoplasia, tumors grow even more quickly and aggressively. In the study, mice in which the desmoplasia was eliminated developed tumors earlier and died sooner.

“This flies in the face of 10 years of research,” says Rhim, assistant professor of gastroenterology at the U-M Medical School. “It turns out that desmoplasia is a lot more complex than previously thought. Components of this complex scar tissue may be the body’s natural defense against this cancer, acting as a barrier or fence to constrain cancer cells from growing and spreading. Researchers who have been trying to target desmoplasia to kill tumors may need to reevaluate their approach.”

Several drugs targeting desmoplasia are in clinical trials and one was recently stopped early because of poor results. “Our study explains why this didn’t work,” Rhim says.

The researchers were able to arrive at this surprising conclusion by using a better mouse model. Previous models have used mice with compromised immune systems injected with human pancreatic cancer cells, producing tumors that don’t closely resemble human pancreatic cancer. The current model utilizes mice that are genetically engineered to express the two most common genetic mutations seen in pancreatic cancer. The mice developed cancer spontaneously, and the cancer closely resembled human pancreatic cancer.

Results of the study appear in Cancer Cell. The work represents a collaboration among teams at the University of Pennsylvania, Columbia University, Johns Hopkins University, Memorial Sloan Kettering Cancer Center and Mayo Clinic.

Using genetically engineered mice, the researchers blocked desmoplasia by knocking down the signaling pathway that produces it. They discovered that desmoplasia prevents the formation of blood vessels that fuel the tumor. When it’s suppressed, the blood vessels multiply, giving the cancer cells the fuel to grow. The researchers next wondered: What if you then target blood vessels with treatment?

What they found in this study was that a drug designed to attack blood vessels, called an angiogenesis inhibitor, significantly improved overall survival in the mice who had desmoplasia blocked. Angiogenesis inhibitors already exist on the market with approval from the U.S. Food and Drug Administration.

Another key finding of the study is that eliminating desmoplasia created tumors that resembled undifferentiated pancreatic cancer in humans. Undifferentiated tumors lack desmoplasia, have abundant blood vessels and grow and spread quickly. About 10 percent of pancreatic cancers in patients are undifferentiated.

This suggests that angiogenesis inhibitors may be effective in patients with undifferentiated tumors.

This study suggests that patients with highly aggressive, undifferentiated pancreatic cancer may be good candidates for treatment with an angiogenesis inhibitor, a drug that is already approved by the U.S. Food and Drug Administration for other cancers. Researchers are moving toward developing a clinical trial. Plans for such an approach are currently underway.

Story Source:

The above story is based on materials provided by University of Michigan Health System. Note: Materials may be edited for content and length.

Journal Reference:

Andrew D. Rhim, Paul E. Oberstein, Dafydd H. Thomas, Emily T. Mirek, Carmine F. Palermo, Stephen A. Sastra, Erin N. Dekleva, Tyler Saunders, Claudia P. Becerra, Ian W. Tattersall, C. Benedikt Westphalen, Jan Kitajewski, Maite G. Fernandez-Barrena, Martin E. Fernandez-Zapico, Christine Iacobuzio-Donahue, Kenneth P. Olive, Ben Z. Stanger. Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma. Cancer Cell, 2014; DOI: 10.1016/j.ccr.2014.04.021

Pathology of Sanfilippo A syndrome: Research provides more insight

May 22 / 2014

International Union of Crystallography

Sanfilippo A syndrome is a rare genetic lysosomal storage disease inherited from the parents of the patient. Lysosomes are the body's vehicle for breaking down many of its by-products such as proteins, nucleic acids, carbohydrates, lipids and cellular debris. New research advances the knowledge of the structural features of sulfamidase in the context of this illness, and will greatly facilitate the discovery of suitable compounds and drugs to assist in managing the disease and its debilitating effects.

Sanfilippo A syndrome or Mucopolysaccharidosis IIIA (MPS-IIIA) is a rare genetic lysosomal storage disease inherited from the parents of the patient. Lysosomes are the body's vehicle for breaking down many of its by-products such as proteins, nucleic acids, carbohydrates, lipids and cellular debris. The spherical vesicles are known to contain 50 different enzymes which are all active around an acidic environment of about pH 5.

Whilst each lysosomal disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic, which is when the enzyme sulfamidase is present in too small an amount or is missing completely in the cell. When this occurs, substances usually broken down by the cell as unwanted matter accumulate in the cell, leading to severe problems.

Affected children of the disease show developmental delay, behavioural abnormalities such as hyperactivity, and signs of neurodegeneration such as progressive loss of cognitive and motor functions, cerebral convulsions and spastic quadriplegia.

About 80% of the genetic alterations in sulfamidase represent replacement of single amino acids that result in functional inactive enzyme mutants. However the molecular understanding of the effects of these mutations has been confined by a lack of structural data for this enzyme.

A group of scientists from Germany and Spain have been successful in resolving the crystal structure of sulfamidase which provides convincing evidence for the molecular consequences of these amino acid replacements and is fundamental for the development of successful structure-based drug design for this devastating neurodegenerative disorder.

Key features for the successful development of novel therapeutic molecules comprise their specific activity to increase residual enzymatic activity of sulfamidase mutants and their ability to pass the blood brain barrier.

The knowledge of the structural features of sulfamidase will greatly facilitate the discovery of suitable compounds and drugs to assist in managing the disease and its debilitating effects.

Story Source:

The above story is based on materials provided by International Union of Crystallography. The original article was written by Jonathan Agbenyega. Note: Materials may be edited for content and length.

Journal Reference:

Navdeep S. Sidhu, Kathrin Schreiber, Kevin Pröpper, Stefan Becker, Isabel Usón, George M. Sheldrick, Jutta Gärtner, Ralph Krätzner, Robert Steinfeld. Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. Acta Crystallographica Section D Biological Crystallography, 2014; 70 (5): 1321 DOI: 10.1107/S1399004714002739

Bipolar disease in children, adolescents: Discharge rates much higher in the US compared to UK

A study published in the June 2014 issue of the Journal of the American Academy of Child and Adolescent Psychiatry found a very much higher discharge rate for pediatric bipolar (PBD) in children and adolescents aged 1-19 years in the US compared to England between the years 2000-2010.

Using the English NHS Hospital Episode Statistics (HES) dataset and the US National Hospital Discharge Survey (NHDS) to compare US and English discharge rates for PBD over the period 2000-2010, the authors found a 72.1-fold higher discharge rate for pediatric bipolar in youth in the US compared to England. After controlling for cross-national differences in length of stay, discharge rates for PBD remained 12.5 times higher in the US than in England, and for all other child psychiatric diagnoses the discharge rate was 3.9 higher, and for adults with BD 7.2 fold higher, in the US than in England.

Dr. Anthony James, with the University of Oxford, and lead author of the paper, said of the study, "The finding that the disparity between US and English discharge rates for PBD is markedly greater than the disparity for child psychiatric discharge rates overall, and for adult rates for bipolar disorder, is potentially important. However, the study design does not allow us to answer the question whether US clinicians are too liberal in assigning the diagnosis of bipolar disorder to youth or, alternatively, whether English clinicians fail to recognize or diagnose these illnesses. It is clear that the reasons for the disparity in the case of PBD warrant further study."

Story Source:

The above story is based on materials provided by Elsevier. Note: Materials may be edited for content and length.

Journal References:

Anthony James, Uy Hoang, Valerie Seagroatt, Joe Clacey, Michael Goldacre, Ellen Leibenluft. A Comparison of American and English Hospital Discharge Rates for Pediatric Bipolar Disorder, 2000 to 2010. Journal of the American Academy of Child & Adolescent Psychiatry, 2014; 53 (6): 614 DOI: 10.1016/j.jaac.2014.02.008
Argyris Stringaris, Eric Youngstrom. Unpacking the Differences in US/UK Rates of Clinical Diagnoses of Early-Onset Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 2014; 53 (6): 609 DOI: 10.1016/j.jaac.2014.02.013

Alcoholism treatment: Kappa opioid receptors a new target

The list of brain receptor targets for opiates reads like a fraternity: Mu Delta Kappa. The mu opioid receptor is the primary target for morphine and endogenous opioids like endorphin, whereas the delta opioid receptor shows the highest affinity for endogenous enkephalins. The kappa opioid receptor (KOR) is very interesting, but the least understood of the opiate receptor family.

Until now, the mu opioid receptor received the most attention in alcoholism research. Naltrexone, a drug approved by the U.S. Food and Drug Administration for the treatment of alcoholism, acts by blocking opiate action at brain receptors and is most potent at the mu opioid receptor. In addition, research has suggested that a variant of the gene that codes for the mu opioid receptor (OPRM1) may be associated with the risk for alcoholism and the response to naltrexone treatment.

However, naltrexone also acts at the kappa opioid receptor and it has not been clear whether this effect of naltrexone is relevant to alcoholism treatment. A growing body of research in animals implicates the KOR in alcoholism. Stimulation of the KOR, which occurs with alcohol intake, is thought to produce unpleasant and aversive effects. This receptor is hypothesized to play a role in alcohol dependence, at least in part, by promoting negative reinforcement processes.

In other words, the theory postulates that during development of alcohol dependence, the KOR system becomes overstimulated, producing dysphoria and anhedonia, which then leads to further alcohol seeking and escalation of alcohol intake that serves to self-medicate those negative symptoms.

A new study in Biological Psychiatry, led by Dr. Brendan Walker at Washington State University, used a rat model of alcohol dependence to directly investigate the KOR system following chronic alcohol exposure and withdrawal. They found that the KOR system is dysregulated in the amygdala of alcohol-dependent rats, a vital brain region with many functions, including regulation of emotional behavior and decision-making. Chronic alcohol consumption is known to cause neuroadaptations in the amygdala.

In this study specifically, they found increased dynorphin A and increased KOR signaling in the amygdala of alcohol-dependent rats. When the rats were in acute alcohol withdrawal, the researchers administered different drugs, each of which target the KOR system in precise ways, directly into the amygdala. Using this site-specific antagonism, they observed that alcohol dependence-related KOR dysregulation directly contributes to the excessive alcohol consumption that occurs during withdrawal.

"These data provide important new support for the hypothesis that kappa opioid receptor blockers might play a role in the treatment of alcoholism," said Dr. John Krystal, Editor of Biological Psychiatry. "This study suggests that one role might be to prevent a relapse to alcohol use among patients recently withdrawn from alcohol."

"This dataset demonstrates the extensive nature of the neuroadaptations the brain undergoes when chronically exposed to alcohol. The implications of these results are far reaching and should help guide pharmacotherapeutic development efforts for the treatment of alcohol use disorders," said Walker. "Pharmacological compounds that alleviate the negative emotional / mood states that accompany alcohol withdrawal, by attenuating the excessive signaling in the dynorphin / kappa-opioid receptor system, should result in enhanced treatment compliance and facilitate the transition away from alcohol dependence."

Additional extensive research will be necessary to identify and test the effectiveness of specific drugs that act on the KOR system, but these findings provide researchers with a potentially successful path forward to developing new drugs for the treatment of alcoholism.

Story Source:

The above story is based on materials provided by Elsevier. Note: Materials may be edited for content and length.

Journal Reference:

Jessica L. Kissler, Sunil Sirohi, Daniel J. Reis, Heiko T. Jansen, Raymond M. Quock, Daniel G. Smith, Brendan M. Walker. The One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors. Biological Psychiatry, 2014; 75 (10): 774 DOI: 10.1016/j.biopsych.2013.03.014

Quotations

1. Don't be afraid to take a big step. You can't cross a chasm in two small jumps. — David Lloyd George (1863-1945)

2. Boredom is the feeling that everything is a waste of time; serenity, that nothing is. — Thomas Szasz (1920- )

3. Writing is a way of talking without being interrupted. — Jules Renard (1864-1910)

4. We never really grow up; we only learn how to act in public. — Bryan White (1974- )

5. Each morning when I open my eyes I say to myself: I, not events, have the power to make me happy or unhappy today. I can choose which it shall be. Yesterday is dead, tomorrow hasn't arrived yet. I have just one day, today, and I'm going to be happy in it. — Groucho Marx (1890-1977)

6. I accept the whole damn thing. It is neither all beautiful nor all terrible, but a wash of multitudinous despairs and exhilarations about which we know nothing. Our history is so small, our experience so limited, our science so inadequate, our theologies so crammed in mere matchboxes, that we know we stand on the outer edge of a beginning and our greatest history lies before us, frightening and lovely, much darkness and much light. — Ray Bradbury (1920- )

7. Someone once said that a democratic society cannot survive for long after 51 percent of the people decide that they want to live off the other 49 percent. Yet that is the direction in which we are being pushed by those who are promoting envy under its more high-toned alias, "social justice". — Thomas Sowell (1930- )

8. American culture is, one way or another, business culture, and our business is service. Once we were a great industrial nation. Now we are a service economy. Which means we are forced to interact with each other, every day, in person and by phone and email. And it's making us all a little mad. — Peggy Noonan (1950- ) in "We Pay Them to Be Rude to Us" in the WSJ.com Opinion Journal

9. While college students may be computer-literate, they are not, as a rule, research-literate. And there's a huge difference between the two. — Todd Gilman in "Not Enough Time in the Library" in The Chronicle of Higher Education

10. We cannot undo the past,but we are bound to pass it in review in order to draw from it such lessons as may be applicable to the future. — Winston S. Churchill (1874-1965)

11. To be without some of the things you want is an indispensable part of happiness. — Bertrand Russell (1872-1970)

12. The longer you can look back, the farther you can look forward. — Winston S. Churchill (1874-1965)

13. It is better to be both right and consistent. But if you have to choose—you must choose to be right. — Winston S. Churchill (1874-1965)

14. To try to be safe everywhere is to be strong nowhere. — Winston S. Churchill (1874-1965)

15. Sometimes good things fall apart so better things can fall together. — Donna Westmoreland Oneal (1949- )

16. The game of life is the game of boomerangs. Our thoughts, deeds and words return to us sooner or later with astounding accuracy. — Florence Scovel Shinn (1871-1940)

17. How often in life must one be content with what one can get! — Winston S. Churchill (1874-1965)

18. It is wonderful how well men can keep secrets they have not been told. — Winston S. Churchill (1874-1965)

19. Men of lofty genius when they are doing the least work are most active. — Leonardo da Vinci (1452-1519)

20. Money often costs too much. — Ralph Waldo Emerson (1803-1882)

21. The best evidence of the fairness of any settlement is the fact that it fully satisfies neither party. — Winston S. Churchill (1874-1965)

22. Out of intense complexities, intense simplicities emerge. — Winston S. Churchill (1874-1965)

23. Faced with the choice between changing one's mind and proving that there is no need to do so, almost everyone gets busy on the proof. — John Kenneth Galbraith (1908-2006)

24. These are not books, lumps of lifeless paper, but minds alive on the shelves. — Gilbert Highet (1906-1978)

25. All social reform... which is not founded upon a stable medium of internal exchange becomes a swindle and a fraud. — Winston S. Churchill (1874-1965)

26. It is pretty tough to reshape human society in an after-dinner speech. — Winston S. Churchill (1874-1965)

27. Enough is as good as a feast. — Winston S. Churchill (1874-1965)

28. Intolerance of ambiguity is the mark of an authoritarian personality. — Theodor Adorno (1903-1969)

29. You can preach a better sermon with your life than with your lips. — Oliver Goldsmith (1730-1774)

30. You may try to destroy wealth, and find that all you have done is to increase poverty. — Winston S. Churchill (1874-1965)

31. Fearthought is futile worrying over what cannot be averted or will probably never happen. — Winston S. Churchill (1874-1965)

32. You can always count on the Americans to do the right thing—after they have tried everything else. — Winston S. Churchill (1874-1965)

33. Some cause happiness wherever they go; others whenever they go. — Oscar Wilde (1854-1900)

34. Every generation of faculty seems to have to rediscover what really works in pedagogy. — Larry G. Richards (1939- )

35. Because we don't understand the brain very well we're constantly tempted to use the latest technology as a model for trying to understand it. In my childhood we were always assured that the brain was a telephone switchboard. (What else could it be?) And I was amused to see that Sherrington, the great British neuroscientist, thought that the brain worked like a telegraph system. Freud often compared the brain to hydraulic and electromagnetic systems. Leibniz compared it to a mill, and now, obviously, the metaphor is the digital computer. — John R. Searle (1932- )

36. In the case of good books, the point is not how many of them you can get through, but rather how many can get through to you. — Mortimer J. Adler (1902-2001)

37. Be the master of your will and the slave of your conscience. — Hasidic Saying

38. In winter why do we try to keep the house as warm as it was in summer when we complained about the heat? — Unknown

39. Pedantry and mastery are opposite attitudes toward rules. To apply a rule to the letter, rigidly, unquestioningly, in cases where it fits and in cases where it does not fit, is pedantry ... To apply a rule with natural ease, with judgment, noticing the cases where it fits, and without ever letting the words of the rule obscure the purpose of the action or the opportunities of the situation, is mastery. — George Polya (1887-1985)

40. Miss Mae West / Is one of the best: / I would rather not / Say the best what. — E. W. Fordham (1845-1925)

41. "I quite realized," said Columbus, / "That the earth was not a rhombus, / But I am a little annoyed / To find it an oblate spheroid." — E. Clerihew Bentley (1875-1956)

42. Henry the Eighth / Took a thucthethtion of mateth. / He inthithted that the monkth / Were a lathy lot of thkunkth. — E. Clerihew Bentley (1875-1956)

43. "Susaddad!" exclaimed Ibsen, / "By dose is turdig cribson! / I'd better dot kiss you. / Atishoo! Atishoo!" — E. Clerihew Bentley (1875-1956)

44. Edgar Allen Poe / Was passionately fond of roe. / He always liked to chew some / When writing anything gruesome. — E. Clerihew Bentley (1875-1956)

45. Before we set our hearts too much on anything, let us examine how happy are those who already possess it. — Francois de La Rochefoucauld (1613-1680)

46. I slept and dreamt that life was joy. I awoke and saw that life was service. I acted and behold, service was joy. — Rabindranath Tagore (1861-1941)

47. If writers were good businessmen, they'd have too much sense to be writers. — Irvin S. Cobb (1876-1944)

48. May we each be the person someone else is grateful for. — Arlyn Newcomb (1966- )

49. We are all tattooed in our cradles with the beliefs of our tribe; the record may seem superficial, but it is indelible. You cannot educate a man wholly out of the superstitious fears which were implanted in his imagination, no matter how utterly his reason may reject them. — Oliver Wendell Holmes, Sr. (1809-1894)

50. In heaven, the police are British, the chefs are French, the mechanics are German, the lovers are Italian, and everything is organized by the Swiss. In hell, the police are German, the chefs are British, the mechanics are French, the lovers are Swiss, and everything is organized by the Italians. — Unknown

Stem-cell research: A new genetic switching element

Slight modifications in their genome sequences play a crucial role in the conversion of pluripotent stem cells into various differentiated cell types. A team at Ludwig-Maximilians-Universitaet (LMU) in Munich has now identified the factor responsible for one class of modification.

Every cell contains stored hereditary information, encoded in the sequence of nucleobases that make up its DNA. However, in any given cell type, only a fraction of this information is actually used. Which genes are activated and which are turned off is in part determined by a second tier of information which is superimposed on the nucleotide sequences that provide the blueprints for protein synthesis. This so-called epigenetic level of control is based on the localized, and in principle reversible, attachment of simple chemical tags to specific nucleotides in the genome. This system plays a major role in the regulation of gene activity, and enables the selective expression of different functions in differentiated cell types.

This explains why such DNA modifications play a major role in the differentiation of stem cells. "Several unusual nucleobases have been found in the genomes of stem cells, which are produced by targeted chemical modification of the known building blocks of DNA. These 'atypical' bases are thought to be important in determining what types of differentiated cells can be derived from a given stem cell line," says Professor Thomas Carell from the Department of Chemistry at LMU. All of the unconventional bases so far discovered are derived from the same standard base -- cytosine. Furthermore, Carell and his team have shown in earlier work that so-called Tet enzymes are always involved in their synthesis.

Base oxidation regulates gene activity In cooperation with colleagues at LMU, as well as researchers based in Berlin, Basel and Utrecht, Carell and his group have now shown, for the first time, that a standard base other than cytosine is also modified in embryonic stem cells of mice. Moreover, Tet is at work here too. "During the development of specialized tissues from stem cells, enzymes belonging to the Tet family also oxidize the thymidine base, as we have now shown with the aid of highly sensitive analytical methods based on mass spectrometry. The product of the reaction, hydroxymethyluracil, was previously -- and as it now turns out, erroneously -- thought to be synthesized by a different pathway," Carell explains.

The precise function of hydroxymethyluracil remains unclear. However, using an innovative method for the identification of factors capable of binding to and "reading" the chemical tags that characterize unconventional DNA bases, Carell and colleagues have shown that stem cells contain specific proteins that recognize hydroxymethyluracil, and could therefore contribute to the regulation of gene activity in these cells. "We hope that these new insights will make it possible to modulate the differentiation of stem cells -- causing them to generate cells of a particular type," says Carell. "It would be wonderful if we were one day able to generate whole organs starting from differentiated cells produced, on demand, by stem cell populations."

Story Source:

The above story is based on materials provided by Ludwig-Maximilians-Universitaet Muenchen (LMU). Note: Materials may be edited for content and length.

Journal Reference:

Toni Pfaffeneder, Fabio Spada, Mirko Wagner, Caterina Brandmayr, Silvia K Laube, David Eisen, Matthias Truss, Jessica Steinbacher, Benjamin Hackner, Olga Kotljarova, David Schuermann, Stylianos Michalakis, Olesea Kosmatchev, Stefan Schiesser, Barbara Steigenberger, Nada Raddaoui, Gengo Kashiwazaki, Udo Müller, Cornelia G Spruijt, Michiel Vermeulen, Heinrich Leonhardt, Primo Schär, Markus Müller, Thomas Carell. Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1532