Science Today

Endophenotypes: Missing Synapse Protein and Abnormal Behaviors

noreply@blogger.com (John) — Tue, 06 Dec 2011 15:29:00 +0000

Although many mental illnesses are uniquely human, animals sometimes exhibit abnormal behaviors similar to those seen in humans with psychological disorders. Such behaviors are called endophenotypes. Now, researchers at the California Institute of Technology (Caltech) have found that mice lacking a gene that encodes a particular protein found in the synapses of the brain display a number of endophenotypes associated with schizophrenia and autism spectrum disorders.

The new findings appear in a recent issue of The Journal of Neuroscience, with Mary Kennedy, the Allen and Lenabelle Davis Professor of Biology at Caltech, as the senior author.

The team created mutations in mice so that they were missing the gene for a protein called densin-180, which is abundant in the synapses of the brain, those electro-chemical connections between one neuron and another that enable the formation of networks between the brain's neurons. This protein sticks to and binds together several other proteins in a part of the neuron that's at the receiving end of a synapse and is called the postsynapse. "Our work indicates that densin-180 helps to hold together a key piece of regulatory machinery in the postsynaptic part of excitatory brain synapses," says Kennedy.

In mice lacking densin-180, the researchers found decreased amounts of some of the other regulatory proteins normally located in the postsynapse. Kennedy and her colleagues were especially intrigued by a marked decrease in the amount of a protein called DISC1. "A mutation that leads to loss of DISC1 function has been shown to predispose humans to development of schizophrenia and bipolar disorder," Kennedy says.

In the study, the researchers compared the behavior of typical mice with that of mice lacking densin. Those without densin displayed impaired short-term memory, hyperactivity in response to novel or stressful situations, a deficit of normal nest-building activity, and higher levels of anxiety. "Studies of mice with schizophrenia and autism-like features have reported similar behaviors," Kennedy notes.

"We do not know precisely how the molecular defect leads to the behavioral endophenotypes. That will be our work going forward," Kennedy says. "The molecular mechanistic links between a gene defect and defective behavior are complicated and, as yet, mostly unknown. Understanding them goes to the very heart of understanding brain function."

Indeed, she adds, the findings point to the need for a better understanding of the interactions that occur between proteins at synapses. Studies of these interactions could provide information needed to screen for new and better pharmaceuticals for the treatment of mental illnesses. "This study really reinforces the idea that small changes in the molecular structures at synapses are linked to major problems with behavior," Kennedy says.

Caltech coauthors of the paper, "Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction," include Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences; Holly Carlisle; Tinh Luong; Andrew Medina-Marino; Leslie Schenker; Eugenia Khorosheva; Keith Gunapala; and Andrew Steele. The paper's other authors are Tim Indersmitten and Thomas O'Dell of the David Geffen School of Medicine at the University of California, Los Angeles. The work was supported by the National Institutes of Health, the Gordon and Betty Moore Foundation Center for Integrative Study of Cell Biology, the Howard Hughes Medical Institute, the National Science Foundation, the McGrath Foundation, and the Broad Fellows in Brain Circuitry program.

H. J. Carlisle, T. N. Luong, A. Medina-Marino, L. Schenker, E. Khorosheva, T. Indersmitten, K. M. Gunapala, A. D. Steele, T. J. O'Dell, P. H. Patterson, M. B. Kennedy. Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction. Journal of Neuroscience, 2011; 31 (45): 16194 DOI: 10.1523/JNEUROSCI.5877-10.2011

California Institute of Technology.

Cancer Treatment Might Improve With Neurotransmitter Dopamine

noreply@blogger.com (John) — Tue, 06 Dec 2011 15:26:00 +0000

Doses of a neurotransmitter might offer a way to boost the effectiveness ofanticancer drugs and radiation therapy, according to a new study led by researchers at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Using animal models of human breast and prostate cancers, the researchers found that injections of the neurotransmitter dopamine can improve blood flow to tumors and improve delivery of an anticancer drug, doubling the amount of the drug in tumors and increasing its effectiveness. The increasedblood flow also raised tumor oxygen levels, a condition that typically improves the effectiveness of both chemotherapy and radiation therapy.

The study also found that dopamine plays an important role in maintaining the structure of normal blood vessels, and that it does this by working through the D2 dopamine receptor, which is present in normal blood-vessel cells called endothelial cells and pericytes. Dopamine was absent in tumor blood-vessel cells.

The findings are published online in the Proceedings of the National Academy of Sciences.

"Our study indicates a use for dopamine in the treatment of cancer and perhaps other disorders in which normalizing abnormal and dysfunctional blood vessels might improve therapeutic responses," says principal investigator Dr. Sujit Basu, associate professor of pathology and a researcher in the OSUCCC -- James Experimental Therapeutics Program.

"Since dopamine and related agents are already used in the clinic for other disorders, these comparatively inexpensive drugs might be applied to the treatment of cancer to increase the therapeutic responses of chemotherapy and radiotherapy," he says.

The blood vessels that develop inside tumors are structurally abnormal, chaotic and leaky and do a poor job of supplying blood to the tumor, Basu notes. This hinders the delivery of chemotherapeutic agents, and it leaves tumors oxygen deprived. This oxygen deprivation makes tumor cells resistant to chemotherapy and radiation.

Basu and his colleagues found that the dopamine treatment normalizes the structure of abnormal tumor blood vessels, indicating an important role for a neurotransmitter in the remodeling of blood vessels. Other key findings include the following:

The tumor tissue used in the study showed the absence of dopamine.

After dopamine treatment, tumor blood vessels in both cases resembled normal vessels in regard to leakiness and architecture. Pretreatment with a dopamine receptor antagonist negated this effect.

Subcutaneous human colon tumors in mice treated with dopamine and the chemotherapeutic drug 5-fluorouracil (5-FU) accumulated twice the amount of 5-FU as tumors in mice treated with the drug only, and the tumors were less than one-third the size of tumors in mice treated with 5-FU only.

"Overall, our findings suggest that the normalization of tumor blood vessels using the neurotransmitter dopamine might be an important approach for improving therapeutic efficacy in the treatment of cancer patients," Basu says.

Funding from the National Cancer Institute, U.S. Department of Defense Grant mainly supported this research; a grant from the American Heart Association partially supported one of the investigators.

The other researchers involved in this study were Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang and Zhongfa Liu of Ohio State University; and Partha Sarathi Dasgupta of Chittaranjan National Cancer Institute, Kolkata, India.

Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang, Zhongfa Liu, Partha Sarathi Dasgupta, Sujit Basu. Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108696108

Ohio State University Medical Center.

Cerebral Gray Matter Reductions in Adolescents

noreply@blogger.com (John) — Tue, 06 Dec 2011 15:23:00 +0000

Childhood maltreatment is associated with reductions in cerebral gray matter volume, and even if adolescents reporting exposure to maltreatment do not have symptoms that meet full criteria for psychiatric disorders, they may have cerebral gray matter changes that place them at risk for behavioral difficulties, according to a report in the December issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.

"An estimated 3.7 million children are assessed for childhood maltreatment (CM) each year in the United States; because many cases do not come to professional attention, this likely is an underestimate of the number of children experiencing maltreatment," the authors write as background information in the article. "Converging data support adverse effects of early life stress on morphologic development of corticostriatal-limbic structures. Magnetic resonance imaging studies show decreased corticostriatal-limbic gray matter volume in children and adults reporting exposure to CM."

Erin E. Edmiston, B.A., then of Yale University, New Haven, Conn., now with Vanderbilt University, Nashville, Tenn., and colleagues compiled data on 42 adolescents (age range 12 to 17 years) without a psychiatric diagnosis to examine the association between exposure to childhood maltreatment and cerebral gray matter volume abnormalities. Participants were recruited from a sample of children identified at birth to be at high risk for CM, and additional participants were also recruited to allow for a sample of adolescents reporting a spectrum of CM severity. Data were collected through a self-report questionnaire, and included questions related to five subtypes of CM: physical abuse, physical neglect, emotional abuse, emotional neglect, and sexual abuse.

Self-reported scores on the Childhood Trauma Questionnaire (CTQ) were associated with a negative correlation with cerebral gray matter volume in the prefrontal cortex, striatum, amygdala, sensory association cortices and cerebellum. The authors also found that self-reported physical abuse, physical neglect and emotional neglect subtypes of CM were all associated with reductions in gray matter volume of the rostral prefrontal cortex. No significant results were found for emotional abuse or for sexual abuse.

"Although preliminary, results of exploratory analyses support prominent reductions in prefrontal cortex volume common across physical abuse, physical neglect, and emotional neglect CM subtypes, as well as patterns of additional regional gray matter volume decreases in the CM subtypes," the authors write. "Findings in girls were in regions associated with emotion regulation, whereas findings in boys were in regions subserving impulse control."

"Together, these results highlight the critical need for improved understanding of effects of childhood abuse and neglect in adolescents and of possible differences in the effects of different CM subtypes on brain development," the authors conclude. "Although adolescents with a history of CM may have symptoms and behaviors that may not yet meet criteria for psychiatric diagnoses, detection and early intervention may help improve functioning and reduce risk for the development of mood, addictive, and other psychiatric disorders."

Editorial: Conceptual and Methodological Issues in Neuroimaging Studies of the Effects of CM

In an accompanying editorial, Philip A. Fisher, Ph.D., and Jennifer H. Pfeifer, Ph.D., both of the University of Oregon, Eugene, write, "the extensive scientific literature on child maltreatment (CM) has provided strong evidence of the globally negative effects of abuse, neglect, and emotional maltreatment on healthy development and of the remarkable resilience of individuals who manage to prosper even in the face of these adverse experiences."

The authors also note that the study by Edmiston et al "broke new ground in four important ways." These include showing that cerebral gray matter volume decreases in adults and children, examining differences in gray matter according to subtypes of CM, analyzing differences in gray matter volume associated with male sex compared with female sex, and also conducting analysis of participants who do not meet criteria for a mental health disorder.

"Given the importance of the study by Edmiston et al, we believe that an expansion of research on the developmental neurobiology of CM subtypes is warranted," the authors write. "Research in these areas has great potential to address the needs for more effective prevention and treatment programs for individuals with specific CM subtypes."

E. E. Edmiston, F. Wang, C. M. Mazure, J. Guiney, R. Sinha, L. C. Mayes, H. P. Blumberg. Corticostriatal-Limbic Gray Matter Morphology in Adolescents With Self-reported Exposure to Childhood Maltreatment. Archives of Pediatrics and Adolescent Medicine, 2011; 165 (12): 1069 DOI: 10.1001/archpediatrics.2011.565

P. A. Fisher, J. H. Pfeifer. Conceptual and Methodological Issues in Neuroimaging Studies of the Effects of Child Maltreatment. Archives of Pediatrics and Adolescent Medicine, 2011; 165 (12): 1133 DOI: 10.1001/archpediatrics.2011.1046

JAMA and Archives Journals.

Rice as a Source of Fetal Arsenic Exposure

noreply@blogger.com (John) — Tue, 06 Dec 2011 15:21:00 +0000

A study just published by a Dartmouth team of scientists in the Proceedings of the National Academy of Sciences (PNAS) advances our understanding of the sources of human exposure to arsenic and focuses attention on the potential for consuming harmful levels of arsenic via rice.

Arsenic occurs naturally in the environment and in elevated concentrations it can be harmful to human health. Common in groundwater, the World Health Organization set guideline limits for Arsenic levels in drinking water (currently 10 micrograms per liter). Concerns about arsenic exposure are now extending beyond water to rice, as underscored in the new PNAS publication. Rice is susceptible to arsenic contamination due to its ability to extract arsenic from the environment into the rice plant.

"Arsenic exposure during pregnancy is a public health concern due to potential health risks to the fetus," says Margaret Karagas, professor of community and family medicine at Dartmouth Medical School and senior author of the paper.

Karagas, director of the Children's Environmental Health and Disease Prevention Center at Dartmouth, and her colleagues have been active in the area of arsenic and human health for over 15 years, including work linking arsenic and bladder cancer and other conditions. She notes that research elsewhere has related arsenic at very high levels to infant mortality, reduced birth weight, hampered immune function, and increased mortality from lung cancer later in life.

"The study presented in the PNAS paper is based upon a sample of 229 pregnant New Hampshire women whose urine was tested for arsenic concentration," says Diane Gilbert-Diamond '98, a postdoctoral fellow and co-lead author on the paper. The women in the study were divided into two groups based on whether or not they had eaten rice in the two days before urine collection. The tap water in their homes also was tested for arsenic concentration.

"This enabled our team to separate the potential for exposure to arsenic from drinking water from that of rice," says Gilbert-Diamond. The urinary arsenic analyses were performed at the University of Arizona by co-author Professor A. Jay Gandolfi and colleagues and water testing was performed at Dartmouth's Trace Element Analysis Facility by co-author Brian Jackson, PhD.

According to the U.S. Department of Agriculture, Americans consume an average of a half-cup of rice per day, but this varies by ethnic group. Asian Americans, for example, consume an average of more than two cups per day.

Urinary arsenic concentrations for the 73 study subjects who ate rice showed a median of 5.27 micrograms per liter, while the median for the 156 non-rice eaters showed 3.38 micrograms per liter, a statistically significant difference between the two groups.

The authors conclude that their findings highlight the need to monitor arsenic in food, noting that China already has statutory limits on arsenic content in rice (0.15 micrograms of inorganic arsenic per kilogram of food) but the U.S. and the E.U. do not. Rice concentrations vary widely throughout the world and between species and growing conditions. Karagas emphasizes, "While this study reveals the potential for exposure to arsenic from rice, much additional research is needed before we can determine if there are actual health impacts from this source of exposure." Tracy Punshon, research assistant professor of biological sciences and co-author says, "Rice is a nutritious food source worldwide. Ultimately any health risks, if found, would then need to be weighed against the obvious nutritional benefits of rice consumption."

The authors also conclude that the results of the study reinforce the concern that private well water in New Hampshire is a potential source of arsenic exposure. In this study, over 10 percent of the women consumed water containing arsenic concentrations currently above the World Health Organization (WHO) guideline and U.S. Environmental Protection Agency standard for public water systems.

"We strongly recommend that all homeowners who use a private well have their water tested regularly for arsenic," says Kathryn Cottingham, co-lead author and professor of biological sciences. "Although health risks of rice consumption are not yet clear, the risks posed by contaminated water are well established."

The work was supported by the National Institute for Environmental Health Sciences (NIEHS) and the U.S. Environmental Protection Agency (EPA), both of which support the Children's Environmental Health and Disease Prevention Center at Dartmouth. Funding also was provided by NIEHS's Superfund Research Program to Dartmouth's Toxic Metals Superfund Research Program.

"The NIEHS and EPA programs supporting this research seek not only to advance the science in which we are engaged but, at the same time, be relevant to society," says Dartmouth Provost Carol Folt, the Dartmouth Professor of Biological Sciences, associate director of the center and a co-author of the PNAS paper. "Our results are highly consistent with both goals, and the team effort needed to successfully implement such work is a hallmark of Dartmouth's research programs."

Other co-authors on the study reported by PNAS include Joann Gruber, a member of Dartmouth's Class of 2011; Emily Baker, MD, professor of obstetrics and gynecology; and Vicki Sayarath, MPH, RD, research translation and community engagement coordinator for the Children's Environmental Health and Disease Prevention Center.

Diane Gilbert-Diamond, Kathryn L. Cottingham, Joann F. Gruber, Tracy Punshon, Vicki Sayarath, A. Jay Gandolfi, Emily R. Baker, Brian P. Jackson, Carol L. Folt, Margaret R. Karagas. Rice consumption contributes to arsenic exposure in US women. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1109127108

Dartmouth College.

Dopamine-deficient Worms For Identifying Parkinson's Drugs

noreply@blogger.com (John) — Tue, 06 Dec 2011 15:19:00 +0000

Researchers at The University of Texas at Austin have devised a simple test, using dopamine-deficient worms, for identifying drugs that may help people with Parkinson's disease.

The worms are able to evaluate as many as 1,000 potential drugs a year. The researchers have received federal funding that could increase that to one million drug tests a year.

The test is based on the difficulty that these "parkinsonian" C. elegans worms have in switching from swimming to crawling when they're taken out of water.

"They can crawl fine," says Jon Pierce-Shimomura, assistant professor of neurobiology. "They go into a puddle and can swim fine. But as soon as the puddle goes away they crash. In some cases an individual will remain rigid for about a half hour."

Pierce-Shimomura led a team of researchers, including Andres Vidal-Gadea, Stephen Topper and Layla Young, to identify this "motor switching" problem. Their findings were published last month in the Proceedings of the National Academy of Science.

"We take these motor transitions for granted," says Pierce-Shimomura, "like getting up out of a chair or walking through a doorway from one surface to another. But people with Parkinson's have a terrible time with this. They freeze at the threshold. It looks like we have a very simple worm model for this now."

To identify potential therapeutics, Pierce-Shimomura begins with worms that have been mutated to be deficient in producing dopamine. It's the loss of dopamine-producing cells in the brain that causes Parkinson's disease in humans.

The dopamine-deficient worms are put through the same paces that lead to the immobility, but in the presence of a drug.

If they become immobile as they normally would when water is removed, the researchers move on to the next drug. But if somehow a drug helps the worms' brains overcome the dopamine deficiency and they transition to crawling, the lab has a potential therapeutic.

Pierce-Shimomura says that although humans have a vastly more complex nervous system than the worms, the two species share an "ancient and conserved" genetic structure to their dopaminergic systems. What works to overcome a dopamine deficiency in the worms may do something similar in humans, and it can be tested in worms with extraordinary speed.

Pierce-Shimomura has already begun testing potential drugs for Parkinson's. So far he's found one compound that shows promising effects in the worms. The particular compound has already been approved for use in humans for treatment of another condition.

Working with the university's Office of Technology Commercialization, he's filed a patent application for the worm model for testing of neurodegenerative diseases such as Alzheimer's and Parkinson's.

About half a million Americans suffer from Parkinson's disease, a degenerative disorder of the central nervous system. Early symptoms of the disease include shaking, rigidity, and slowness of movement. As it progresses, the physical symptoms can advance to the point of incapacity, and cognitive impairments, including early dementia, can arise as well.

A huge barrier to preventing or treating diseases such as Parkinson's is the amount of time it takes to identify drugs that work effectively. Typically, drugs are tested on mice -- a process that is expensive and requires one to two years for mice to age while testing just a few dozen drugs at a time.

With the help of a few undergraduates Pierce-Shimomura believes that he can test about 1,000 drugs a year. The number could rise to one million a year if the process can be automated.

He recently received a $3 million Transformative Research Projects Award from the National Institutes of Health with mechanical engineering professor Adela Ben-Yakar, to develop just such an automation process for parkinsonian worms as well as worms mutated to have other neurodegenerative diseases, including a C. elegans version of Alzheimer's.

"These worms are so simple to work with, we can do these drug screens at massive scale," says Pierce-Shimomura. "Right now the more hands we have, the more targets we can test."

University of Texas at Austin.

Variation in BDNF Affects Mental Performance

noreply@blogger.com (John) — Tue, 01 Nov 2011 18:18:00 +0000

A tiny difference in the coding pattern of a single gene significantly affects the rate at which men's intellectual function drops with advancing age, investigators at the Stanford University School of Medicine and the Veterans Affairs Palo Alto Health Care System have learned.

In a study to be published online Oct. 25 in Translational Psychiatry, the researchers tested the skills of experienced airplane pilots and found that having one version of the gene versus the other version doubled the rate at which the participants' performance declined over time.

The particular genetic variation, or polymorphism, implicated in the study has been linked in previous studies to several psychiatric disorders. But this is the first demonstration of its impact on skilled task performance in the healthy, aging brain, said the study's senior author, Ahmad Salehi, MD, PhD, clinical associate professor of psychiatry and behavioral sciences at Stanford.

The study also showed a significant age-related decline in the size of a key brain region called the hippocampus, which is crucial to memory and spatial reasoning, in pilots carrying this polymorphism.

"This gene-associated difference may apply not only to pilots but also to the general public, for example in the ability to operate complex machinery," said Salehi, who is also a health-science specialist at the VA-Palo Alto.

The gene in question codes for a well-studied protein called brain-derived neurotropic factor, or BDNF, which is critical to the development and maintenance of the central nervous system. BDNF levels decline gradually with age even in healthy individuals; researchers such as Salehi have suspected that this decline may be linked with age-related losses of mental function.

Genes, which are blueprints for proteins, are linear sequences of DNA composed of four different chemical units all connected like beads on a string. The most common version of the BDNF gene dictates that a particular building block for proteins, called valine, be present at a particular place on the protein. A less common -- though far from rare -- variation of the BDNF gene results in the substitution of another building block, methionine, in that same spot on the protein. That so-called "val/met" substitution occurs in about one in three Asians, roughly one in four Europeans and Americans, and about one in 200 sub-Saharan Africans. Such a change can affect a protein's shape, activity, level of production, or distribution within or secretion by cells in which it is made.

It appears that the alternative "met" version of BDNF doesn't work as well as the "val" version. This variant has been linked to higher likelihood of depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behavior and schizophrenia.

So Salehi and his colleagues decided to look at whether this polymorphism actually affected human cognitive function. To do this, they turned to an ongoing Stanford study of airplane pilots being conducted by two of the paper's co-authors -- Joy Taylor, PhD, clinical associate professor of psychiatry and behavioral sciences, and Jerome Yesavage, MD, professor of psychiatry and behavioral sciences -examining a wide array of neurological and psychiatric questions.

For this new research, Salehi and his colleagues followed 144 pilots, all healthy Caucasian males over the age of 40, who showed up for three visits, spaced a year apart, spanning a two-year period. During each visit, participants -- recreational pilots, certified flight instructors or civilian air-transport pilots -- underwent an exam called the Standard Flight Simulator Score, a Federal Aviation Administration-approved flight simulator for pilots.

This test session employs a setup that simulates flying a small, single-engine aircraft. Each participant went through a half-dozen practice sessions and a three-week break before his first visit. Each annual visit consisted of morning and afternoon 75-minute "flights," during which pilots confronted flight scenarios with emergency situations, such as engine malfunctions and/or incoming air traffic. Resulting test scores pooled several variables, such as pilots' reaction times and their virtual planes' deviations from ideal altitudes, directions and speed. A pilot's score represented the overall skill with which he executed air-traffic control commands, avoided airborne traffic, detected engine emergencies and approached landing strips.

Blood and saliva samples collected on the pilots' first visits allowed the Stanford investigators to genotype all 144 pilots, of whom 55 (38.2 percent) turned out to have at least one copy of a BDNF gene that contained the "met" variant. In their analysis, the researchers also corrected for pilots' degree of experience and the presence of certain other confounding genetic influences.

Inevitably, performance dropped in both groups. But the rate of decline in the "met" group was much steeper.

"We saw a doubling of the rate of decline in performance on the exam among met carriers during the first two years of follow-up," said Salehi.

About one-third of the pilots also underwent at least one round of magnetic resonance imaging over the course of a few years, allowing the scientists to measure the size of their hippocampi. "Although we found no significant correlation between age and hippocampal size in the non-met carriers, we did detect a significant inverse relationship between age and hippocampal size in the met carriers," Salehi said.

Salehi cautioned that the research covered only two years and that the findings need to be confirmed by following participants over a multiyear period. This is now being done, he added.

No known drugs exist that mimic BDNF's action in the brain, but there is one well-established way to get around that: Stay active. "The one clearly established way to ensure increased BDNF levels in your brain is physical activity," Salehi said.

The National Institute of Aging and the U.S. Department of Veterans Affairs funded the study. First authorship was shared by Martha Millan Sanchez, MD, postdoctoral scholar in the Department of Psychiatry and Behavioral Sciences, and Devsmita Das, MD, a VA-Palo Alto visiting scholar. VA-Palo Alto health-science specialist Arthur Noda also was a co-author.

Information about Stanford's Department of Psychiatry and Behavioral Sciences, which also supported this work, is available at http://psychiatry.stanford.edu.

M Millan Sanchez, D Das, J L Taylor, A Noda, J A Yesavage, A Salehi. BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals. Translational Psychiatry, 2011; 1 (10): e51 DOI: 10.1038/tp.2011.47

Stanford University Medical Center.

5-hydroxymethylcytosine and Its Function in Brain

noreply@blogger.com (John) — Tue, 01 Nov 2011 18:14:00 +0000

In 2009, the DNA alphabet expanded. Scientists discovered that an extra letter or "sixth nucleotide" was surprisingly abundant in DNA from stem cells and brain cells.

Now, researchers at Emory University School of Medicine have mapped the patterns formed by that letter in the brains of mice, observing how its pattern of distribution in the genome changes during development and aging.

Those patterns, stable or dynamic depending on the gene, suggest that 5-hydroxymethylcytosine (5-hmC) has its own distinct functions, which still need to be fully brought to light.

"Our data tells us that 5-hmC is not just an intermediate state," says senior author Peng Jin, PhD, associate professor of human genetics at Emory University School of Medicine. "It looks like it has specific functions in stem cells and brain. 5-hmC may poise a gene to be turned on after being repressed."

The results were published online Oct. 30 by the journal Nature Neuroscience. The paper is the first report on how the patterns of 5-hmC's distribution change in mouse brain during development, and also contains data on 5-hmC in DNA samples from human brain.

Postdoctoral fellow Keith Szulwach and instructor Xuekun Li are co-first authors, and collaborators from the University of Chicago and the University of Wisconsin-Madison contributed to the paper.

5-hydroxymethylcytosine (5-hmC) is an epigenetic modification of cytosine, one of the four bases or "letters" making up DNA. Epigenetic modifications are changes in the way genes are turned on or off, but are not part of the underlying DNA sequence. 5-hmC resembles 5-methylcytosine (5-mC), another modified DNA base that scientists have been studying for decades. Until recently, chemical techniques did not allow scientists to tell the difference between them.

In contrast to 5-mC, 5-hmC appears to be enriched on active genes, especially in brain cells. 5-mC is generally found on genes that are turned off or on repetitive "junk" regions of the genome. When stem cells change into the cells that make up blood, muscle or brain, 5-mC helps shut off genes that aren't supposed to be turned on. Changes in 5-mC's distribution also underpin a healthy cell's transformation into a cancer cell.

It looks like 5-hmC can only appear on DNA where 5-mC already was present. This could be a clue that 5-hmC could be a transitory sign that the cell is going to remove a 5-mC mark. Jin says the patterns his team sees tell a different story, at least for some genes. On those genes, the level of 5-hmC is stably maintained and increases with age.

The Emory team used a method for chemically labeling 5-hmC they developed in cooperation with scientists at the University of Chicago. They find that 5-hmC is ten times more abundant in brain than in stem cells, and it is found more in the body of some genes, compared to stem cells.

In addition, the researchers found a relative lack of 5-hmC on X chromosomes in both males and females. That result is a surprise, Jin says, because it was already known that the X chromosome is subject to a special form of regulation in females only. Males have one X chromosome and females have two, and in female cells one of the X chromosomes is inactivated.

Jin's team is beginning to map how 5-hmC changes in neurological disorders, including Rett syndrome and autism, and refining techniques for detecting 5-hmC in DNA at high resolution.

The research was supported by the National Institutes of Health, the Simons Foundation and the Emory Genetics Discovery Initiative.

Keith E Szulwach, Xuekun Li, Yujing Li, Chun-Xiao Song, Hao Wu, Qing Dai, Hasan Irier, Anup K Upadhyay, Marla Gearing, Allan I Levey, Aparna Vasanthakumar, Lucy A Godley, Qiang Chang, Xiaodong Cheng, Chuan He, Peng Jin. 5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature Neuroscience, 2011; DOI: 10.1038/nn.2959

Source: Emory University.

Major Step Towards Beneficial Treatment for Rapidly Progressive Glomerulonephritis (RPGN)

noreply@blogger.com (John) — Mon, 26 Sep 2011 04:04:00 +0000

Source: North Carolina State University.

Effects of a particularly devastating human kidney disease may be blunted by making a certain cellular protein receptor much less receptive, according to new research by scientists from North Carolina State University and a number of French universities and hospitals.

The findings take a major step toward suggesting a beneficial treatment for rapidly progressive glomerulonephritis (RPGN), a rare but debilitating kidney disease that causes renal failure and death in humans.

In a paper published online in Nature Medicine, the researchers show that blocking the ability of the epidermal growth factor (EGF) receptor -- an important component in wound healing -- to bind with certain molecules in the kidneys of mice can eliminate the harmful effects of a mimic version of RPGN.

EGF receptors act like important keyholes on a cell's surface, says Dr. David Threadgill, professor and head of NC State's Department of Genetics and a co-author of the paper. Certain keys, or in this case molecules, can fit with the receptor and "open the door" to a cascade of cellular processes leading to inflammation, which can be good when your body needs to heal a wound or a cut. It's bad, however, when the inflammation runs amok, as when RPGN takes hold.

How important are EGF receptors in RPGN? When EGF receptors were taken out of the equation -- through special mice from Threadgill's lab that were genetically engineered without EGF receptors -- the disease was unable to take hold and degenerate kidney tissues.

The study also showed that certain drugs that inhibit EGF receptors -- think of them as pieces of gum in the keyholes -- not only prevented mouse kidneys from degrading but also reversed the harmful effects four days after mice were exposed to the RPGN mimic.

"EGF receptors are essential components for life, but are implicated in not only RPGN but also a number of cancers like colon cancer and breast cancer," Threadgill says. "They must be tightly regulated. If we can inhibit these receptors for short periods of time, we may be able to stop out-of-control cell proliferation and inflammation and thus prevent or treat certain cancers or diseases."

The Department of Genetics is part of NC State's College of Agriculture and Life Sciences.

Guillaume Bollée, Martin Flamant, Sandra Schordan, Cécile Fligny, Elisabeth Rumpel, Marine Milon, Eric Schordan, Nathalie Sabaa, Sophie Vandermeersch, Ariane Galaup, Anita Rodenas, Ibrahim Casal, Susan W Sunnarborg, David J Salant, Jeffrey B Kopp, David W Threadgill, Susan E Quaggin, Jean-Claude Dussaule, Stéphane Germain, Laurent Mesnard, Karlhans Endlich, Claude Boucheix, Xavier Belenfant, Patrice Callard, Nicole Endlich, Pierre-Louis Tharaux. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nature Medicine, 2011; DOI: 10.1038/nm.2491

Stopping Breast Cancers From Coming Back

noreply@blogger.com (John) — Mon, 26 Sep 2011 04:01:00 +0000

Source: University of Leeds.

Medical researchers at the University of Leeds have come a step closer to understanding how to stop breast cancers from coming back. Their findings, published in the International Journal of Cancer, suggest that some novel drugs that are being developed to tackle other cancers should be considered as a future treatment for breast cancer too.

Hormone therapies, such as tamoxifen, that target a protein responsible for tumour growth, have dramatically improved the treatment of breast cancer. Survival rates have improved considerably for patients whose breast cancer is spotted at an early stage and many patients with advanced disease can now have a much better quality of life.

But hormone therapies do not work in all patients and the tumours continue to grow and spread. In other patients, the hormone therapies work well at first but then their cancer often develops resistance and the tumour starts to grow again.

Leeds researchers have now pointed the finger at a key protein that they believe helps breast cancer to become resistant to hormone treatments. Laboratory studies on breast cancer tissue revealed that resistant tumours contained excessive levels of a protein known as FGFR3. Levels of this protein were much, much lower in tumours that had responded to hormone treatment. This suggests an important link between FGFR3 and resistance to hormone treatment.

"The options available for treating breast cancers that return are relatively limited at the moment. It is therefore of utmost importance to identify the factors that cause this resistance to help promote the development of novel drugs that can be used to target recurrent breast cancers," said Dr Darren Tomlinson, lead author of the research.

"Drugs are currently being made to target this protein -- FGFR3 -- in other types of cancers. Our work suggests that these drugs could potentially be made available to treat some breast cancers too and help tackle this problem of resistance.

"Similar work has already been done on different proteins that belong to the same family. We've added to this research by identifying a further family member. If drugs could be developed to target these different family members, then in the future, patients could be given a personalised treatment programme, depending on how their particular cancer was trying to evade the hormone therapy," he said.

The work is very encouraging. We know that resistance to breast cancer is complex, so identifying the proteins involved brings us closer to understanding how to prevent breast cancer from coming back," said Dr Valerie Speirs, the study's principal investigator.

The work was funded by the Association for International Cancer Research.

D.C. Tomlinson, M.A. Knowles, V. Speirs. Mechanisms of FGFR3 actions in endocrine resistant breast cancer. International Journal of Cancer, 2011; DOI: 10.1002/ijc.26304

Why Chemo Causes Drop in Platelet Numbers

noreply@blogger.com (John) — Mon, 26 Sep 2011 03:59:00 +0000

Source: Walter and Eliza Hall Institute.

Scientists at the Walter and Eliza Hall Institute have identified a way that chemotherapy causes platelet numbers to drop, answering in the process a decade-old question about the formation of platelets, tiny cells that allow blood to clot.

Platelets are formed by a process called 'shedding' where small fragments break off megakaryocytes (large cells normally found in the bone marrow).

Drs Emma Josefsson, Chloé James and Benjamin Kile from the institute's Molecular Medicine and Cancer and Haematology divisions have been investigating how the survival of platelet- forming megakaryocytes is controlled at a molecular level.

The life-or-death decisions of cells are controlled by the Bcl-2 family of proteins. Some 'pro-death' Bcl-2 family proteins cause cells to die, while an opposing 'pro-survival' faction prevents cell death, allowing cells to survive.

In the past decade it has been thought that platelets are formed by megakaryocytes through a process similar to cell death, Dr Josefsson said. "Our research tested this assumption by examining the molecules that are required for programmed cell death. We found that, at a molecular level, platelet formation does not occur by a death-like process.

"We found that pro-death Bcl-2 family proteins were not required for platelet formation from megakaryocytes," Dr Josefsson said. "In fact, pro-survival Bcl-2 family proteins are essential for keeping megakaryocytes alive so they can make platelets."

Low platelet numbers are a side-effect of chemotherapy and, whilst this has long been ascribed to the death of megakaryocytes and their precursors, the mechanisms responsible have remained unclear. The research team showed that chemotherapy kills megakaryocytes by its action on Bcl-2 family proteins, Dr Josefsson said. "Our work has shown that chemotherapy activates 'pro-death' Bcl-2 proteins to kill megakaryocytes, meaning patients are less capable of producing platelets as they recover from cancer treatment." The research was published in the Journal of Experimental Medicine.

Institute scientist Professor Don Metcalf has researched blood formation for the past 50 years and was part of the research team. "For the past decade many researchers around the world have been wondering what role Bcl-2-family proteins play in platelet formation," he said. "This study is important for resolving a longstanding debate about platelet formation, and in the long term may lead to new strategies to prevent chemotherapy-induced thrombocytopenia (a deficiency in platelets)."

The research was supported by the National Health and Medical Research Council, the Sylvia and Charles Viertel Foundation, the Leukaemia Foundation of Australia, the Leukemia & Lymphoma Society (USA), the Swedish Research Council, the European Molecular Biology Organisation, the Victorian Cancer Agency, Cancer Council Victoria, the Australian Cancer Research Fund, the Victorian Government and the Australian Government.

E. C. Josefsson, C. James, K. J. Henley, M. A. Debrincat, K. L. Rogers, M. R. Dowling, M. J. White, E. A. Kruse, R. M. Lane, S. Ellis, P. Nurden, K. D. Mason, L. A. O'Reilly, A. W. Roberts, D. Metcalf, D. C. S. Huang, B. T. Kile. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. Journal of Experimental Medicine, 2011; DOI: 10.1084/jem.20110750

Virus kills Cancer Cells And Stops Expression of Certain Types of Cancer Cells

noreply@blogger.com (John) — Mon, 19 Sep 2011 15:12:00 +0000

In a new project, researchers from LIFE -- the Faculty of Life Sciences at the University of Copenhagen -- document that the vesicular stomatitis virus (VSV) plays a previously unknown dual role in the prevention of a number of cancers. The new findings show that the virus both kills cancer cells and stops the expression of the molecules which certain types of cancer cells produce to hide from the immune system.

Certain types of cancer cells express far too many liquid immunostimulatory molecules, blocking the immune system's ability to recognize them, and enabling them to continue the development of cancer.

"The overexpression seen in cancer types such as melanoma, testicular cancer, ovarian cancer and certain types of leukemia significantly impairs the immune system, thereby reducing the patient's chance of recovery," says associate professor in immunology Søren Skov from LIFE.

Skov is heading a research team which has just launched a major European project to study the potential for improving cancer treatment by strengthening the immune system.

Oncolytic virus

As part of the research project, PhD student Helle Jensen has infected human cancer cells with VSV.

"We were able to demonstrate that the virus kills cancer cells. The results also show that VSV effectively blocks the production of the immunostimulatory molecules which certain types of cancer overexpress to destroy the immune system and thus the chances of survival," Skov says.

Researchers believe the work is a major step towards better cancer treatment. The advance would enable the immune system to stop the development of cancer more effectively. In addition, it is possible to mutate the virus and adapt it to the relevant type of cancer. There is thus a potential for a future alternative to chemotherapy, tailored to the individual patient, says Skov.

"The next step will be clinical trials in humans. Such trials are already being conducted in the USA," says Jensen, who has carried out the research project at LIFE in collaboration with the Faculty of Health Sciences at the University of Copenhagen and the National Veterinary Institute at the Technical University of Denmark (DTU).

Source: University of Copenhagen.

Risk of Pancreatic And Thyroid Cancer From Type 2 Diabetes Drugs

noreply@blogger.com (John) — Mon, 19 Sep 2011 15:09:00 +0000

Two newer drugs used to treat Type 2 diabetes could be linked to a significantly increased risk of developing pancreatitis and pancreatic cancer, and one could also be linked to an increased risk of thyroid cancer, according to a new UCLA study.

Researchers from the Larry L. Hillblom Islet Research Center at UCLA examined the U.S. Food and Drug Administration's database for adverse events reported between 2004 and 2009 among patients using the drugs sitagliptin and exenatide. They found a six-fold increase in the odds ratio for reported cases of pancreatitis with these drugs, compared with four other diabetes therapies they used as controls. They also found that patients who took the two drugs were more likely to have developed pancreatic cancer than those who were treated with the other therapies.

The study is published in the journal Gastroenterology.

"We undertook these studies because several studies in animal models by several investigators had suggested that this form of therapy may have unintended actions to promote growth of the ducts (tubes) in the pancreatic gland that convey digestive juices from the pancreas to the gut," said Dr. Peter Butler, director of the Hillblom Center and a study co-author. "This is a concern if it happens in humans since it might be expected to increase the risk for pancreatitis and pancreatic cancer. While the FDA data base has limitations, it does have advantages in being very large, openly accessible and independent from companies that market the drugs.

"Taken together the animals studies and the FDA data base analysis suggest that further work needs to be undertaken to at least rule out that this now widely available new drug class for diabetes does not increase the risk of pancreatic cancer," Butler, who is also a member of UCLA's Jonsson Comprehensive Cancer Center, added.

Sitagliptin and exenatide are drugs that enhance the actions of a gut hormone known as glucagon-like peptide 1 (GLP-1), which has been shown to be effective in lowering blood sugar in individuals with Type 2 diabetes. Sitagliptin, marketed as Januvia by Merck & Co. Inc., works by inhibiting dipeptidyl peptidase-4 (DDP-4), an enzyme that degrades GLP-1. Exenatide, manufactured by Amylin Pharmaceuticals and sold as Byetta, mimics the action of GLP-1 and resists DDP-4 degradation.

Previous research by UCLA Hillblom Center researchers suggested there might be a link between drugs that enhance the actions of GLP-1 and pancreatitis, possibly resulting from an increase in the rate of formation of cells that line the pancreatic ducts. That research, based on studies in rats, was published in 2009 in the journal Diabetes.

In addition to the six-fold increase in reported cases of pancreatitis, the researchers also found a 2.9-fold greater rate of pancreatic cancer in patients using exenatide and a 2.7-fold higher rate of pancreatic cancer in patients on sitagliptin, compared with the other therapies. Additionally, they found a statistically significant increase in the risk of thyroid cancer among the exenatide group, but not among the sitagliptin group.

The FDA data did not indicate links between the two diabetes drugs and any other form of cancer.

The researchers caution that the FDA's adverse events database "is not the ideal mechanism to compare adverse event rates between drugs," given its known limitations, such as incomplete data and reporting biases. They stress that more study is needed.

"Randomized, controlled clinical trials remain the gold standard for such assessment," the researchers wrote.

The Larry L. Hillblom Foundation funded this study. Study co-authors are Michael Elashoff, Aleksey V. Matveyenko, Belinda Gier, and Robert Elashoff, all of UCLA

Michael Elashoff, Aleksey V. Matveyenko, Belinda Gier, Robert Elashoff, Peter C. Butler. Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1–Based Therapies. Gastroenterology, 2011; 141 (1): 150 DOI: 10.1053/j.gastro.2011.02.018

Source: University of California - Los Angeles Health Sciences.

Alcoholics' Gait to Recover With Long-term Abstinence

noreply@blogger.com (John) — Mon, 19 Sep 2011 15:05:00 +0000

Chronic alcoholism is often associated with a disturbed gait and balance, likely caused by alcohol damage to neural systems. While some studies have suggested that abstinence can lead to partial recovery of gait and balance functions, questions remain about duration of abstinence and sample size. This study of both short- and long-term abstinence has found that alcoholics' gait and balance can continue to recover with long-term abstinence from alcohol but that deficits can persist, especially eyes-closed standing balance.

Results will be published in the December 2011 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"Chronic alcohol abuse consistently damages the cerebellum, a complex structure located at the back of the brain below the cerebrum," explained Stan Smith, a neurobehavioral scientist with Neurobehavioral Research and corresponding author for the study. "The cerebellum has multiple functions, including control of balance and coordination. Alcohol also damages subcortical white matter, the myelinated fiber tracts that connect different parts of the cortex, and other central nervous systems [such as] motor effector and feedback systems. Long-term alcohol dependence also results in impaired dopamine transmission in the striatum, an important area for motor control."

This study examined 70 (49 men, 21 women) short-term (6 to 15 weeks) abstinent and 82 (48 men, 34 women) long-term (minimum of 18 months, a mean of 7.38 years) abstinent alcoholics, as well as 52 (32 women, 20 men) control individuals. The two alcoholic groups did not differ in terms of lifetime drinking, family drinking density, or years of education. Study authors also looked at gender and alcohol-use variables.

"Our study used a large sample, which enhances generalizability," said Smith. "Our long-term abstinent alcoholics also had very extended abstinence, more than seven years on average, compared to previous studies. Our results provide evidence that recovery of gait and balance, when visual support is available, may be attained with extended abstinence."

On the other hand, said Smith, the eyes-closed measures require greater balance and motor control. "Visual feedback makes balance easier by providing visual reference points for motor adjustment. Yet even with extended abstinence, structures important for balance -- like the cerebellum -- may not fully recover, so impaired performance on the more difficult balance measures persists."

Some previous studies have suggested that women metabolize alcohol differently than men, added Smith, and that impairment of brain functions in women, including cognitive processes, occurs with less lifetime alcohol misuse than for men. "Our finding of more impaired function in women than in men with short-term abstinence is consistent with this," said Smith. "However, the good news is that women in our long-term abstinent group performed similarly to men, suggesting that they recover to a comparable level with extended abstinence."

The bottom line, said Smith, is that impaired brain functions in alcoholics appear to recover with an extended abstinence, even if there is relatively little recovery with short-term abstinence. "This means there is hope for significant recovery of balance function with extended abstinence," he said.

Stan Smith, George Fein. Persistent but Less Severe Ataxia in Long-Term Versus Short-Term Abstinent Alcoholic Men and Women: A Cross-Sectional Analysis. Alcoholism: Clinical & Experimental Research, 2011; DOI: 10.1111/j.1530-0277.2011.01567.x

Source: Alcoholism: Clinical & Experimental Research.

Brain-scan Data to Distinguish Autistic Kids From Normal Children

noreply@blogger.com (John) — Mon, 19 Sep 2011 15:02:00 +0000

Researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital have used a novel method for analyzing brain-scan data to distinguish children with autism from typically developing children. Their discovery reveals that the gray matter in a network of brain regions known to affect social communication and self-related thoughts has a distinct organization in people with autism.

The findings are published online in Biological Psychiatry.

While autism diagnoses are now based entirely on clinical observations and a battery of psychiatric and educational tests, researchers have been making advances toward identifying anatomical features in the brain that would help to determine whether a person is autistic.

"The new findings give a uniquely comprehensive view of brain organization in children with autism and uncover a relationship between the severity of brain-structure differences and the severity of autism symptoms," said Vinod Menon, PhD, a professor of psychiatry and behavioral sciences and of neurology and neurological sciences, who led the research.

"We are getting closer to being able to use brain-imaging technology to help in the diagnosis and treatment of individuals with autism," said child psychiatrist Antonio Hardan, MD, who is the study's other senior author and an associate professor of psychiatry and behavioral sciences at Stanford. Hardan treats patients with autism at Packard Children's.

Brain scans are not likely to completely replace traditional methods of autism diagnosis, which rely on behavioral assessments, Hardan added, but they may eventually aid diagnosis in toddlers.

Autism occurs in about one in every 110 children. It is a disabling developmental disorder that impairs a child's language skills, social interactions and the ability to sense how one is perceived by others.

The study compared MRI data from 24 autistic children aged 8 to 18 with scan data from 24 age-matched, typically developing children. The data was collected at the University of Pittsburgh.

"We jumped at the results," Menon said. "Our approach allows us to examine the structure of the autistic brain in a more meaningful manner." The new findings expand scientists' basic knowledge of the core brain deficits in autism, he added.

The analysis method, called "multivariate searchlight classification," divided the brain with a three-dimensional grid, then examined one cube of the brain at a time, and identified regions in which the pattern of gray matter volume could be used to discriminate between children with autism and typically developing children.

Instead of comparing the sizes of individual brain structures, as prior studies have done, the new analysis generated something akin to a topographical map of the entire brain. The scientists essentially mapped the autistic brain's distinct cliffs and valleys, uncovering subtle differences in the physical organization of the gray matter.

Such analysis may be a more useful approach than previous tacks. Earlier studies, for instance, suggested that people with autism may have larger brains in toddlerhood or have a large defect in one brain structure. This study took a different approach and discovered several autism-associated differences in the Default Mode Network, a set of brain structures important for social communication and self-related thoughts. Specific structures that differed included the posterior cingulate cortex, the medial prefrontal cortex and the medial temporal lobes. These findings align well with recent theoretical and functional MRI studies of the autistic brain, which also point to differences in the Default Mode Network, Menon said.

Once Menon and his team had found where the differences in autistic brains were located, they were able to use their analysis to classify whether individual children in the study had autism. They used a subset of their data to "train" the mathematical algorithm, then ran the remaining brain scans through the algorithm to classify the children.

"We could discriminate between typically developing and autistic children with 92 percent accuracy on the basis of gray matter volume in the posterior cingulate cortex," said Lucina Uddin, PhD, the study's first author. Uddin is an instructor in psychiatry and behavioral sciences at Stanford.

In addition, the children with the most severe communication deficits, as measured on a standard behavioral scale for diagnosing individuals with autism, had the biggest brain structure differences. Severe impairments in social behavior and repetitive behavior also showed a trend toward association with more severe brain differences.

Menon and his team plan to repeat the study in younger children and to extend it to larger groups of subjects. If the results are upheld, the new method offers the possibility of several applications in autism diagnosis and treatment. For instance, brain scans might eventually help distinguish autism from other behavioral disorders such as attention deficit hyperactivity disorder, or might predict whether high-risk children, such as those with autistic siblings, will go on to develop autism themselves. Brain scanning might also be able to predict what type of deficits will occur in a child with a new autism diagnosis, allowing clinicians to target their treatments to a child's predicted deficits.

"Scans would likely be used alongside clinical expertise, giving that extra hint from the brain data," Uddin said.

When such integrated assessments are possible, the researchers hope they will allow clinicians to build detailed profiles of each patient. "We hope we'll eventually be able to tell parents, 'Your child will probably respond to this treatment, or your child is unlikely to respond to that treatment,'" Hardan said. "In my mind, that's the future."

Other Stanford scientists who collaborated on the project were research scientist Srikanth Ryali, PhD; postdoctoral scholar Tianwen Chen, PhD; and research assistants Christina Young and Amirah Khouzam. Nancy Minshew, MD, from the University of Pittsburgh, also contributed to the project.

The research was supported by funding from the Singer Foundation, the Stanford Institute for Neuro-Innovation & Translational Neurosciences, the National Institute of Child Health & Human Development, the National Institute of Deafness & Other Communication Disorders, the National Institute of Mental Health, the National Institute of Neurological Disorders & Stroke and the National Science Foundation. Uddin was also supported by a postdoctoral fellowship from the Stanford University Autism Working Group. Additional information about the Department of Psychiatry and Behavioral Sciences, which also supported this work, is available at http://psychiatry.stanford.edu/

Lucina Q. Uddin, Vinod Menon, Christina B. Young, Srikanth Ryali, Tianwen Chen, Amirah Khouzam, Nancy J. Minshew, Antonio Y. Hardan. Multivariate Searchlight Classification of Structural Magnetic Resonance Imaging in Children and Adolescents with Autism. Biological Psychiatry, 2011; DOI: 10.1016/j.biopsych.2011.07.014

Source: Stanford University Medical Center.

Turmeric Suppresses Head and Neck Cancer Pathways

noreply@blogger.com (John) — Wed, 14 Sep 2011 15:44:00 +0000

Curcumin, the main component in the spice turmeric used in curry, suppresses a cell signaling pathway that drives the growth of head and neck cancer, according to a pilot study using human saliva by researchers at UCLA's Jonsson Comprehensive Cancer Center.

The inhibition of the cell signaling pathway also correlated with reduced expression of a number of pro-inflammatory cytokines, or signaling molecules, in the saliva that promote cancer growth, said Dr. Marilene Wang, a professor of head and neck surgery, senior author of the study and a Jonsson Cancer Center researcher.

"This study shows that curcumin can work in the mouths of patients with head and neck malignancies and reduce activities that promote cancer growth," Wang said. "And it not only affected the cancer by inhibiting a critical cell signaling pathway, it also affected the saliva itself by reducing pro-inflammatory cytokines within the saliva."

The study appears Sept. 15 in Clinical Cancer Research, a peer-reviewed journal of the American Association of Cancer Research.

Turmeric is a naturally occurring spice widely used in South Asian and Middle Eastern cooking and has long been known to have medicinal properties, attributed to its anti-inflammatory effects. Previous studies have shown it can suppress the growth of certain cancers. In India, women for years have been using turmeric as an anti-aging agent rubbed into their skin, to treat cramps during menstruation and as a poultice on the skin to promote wound healing.

A 2005 study by Wang and her team first showed that curcumin suppressed the growth of head and neck cancer, first in cells and then in mouse models. In the animal studies, the curcumin was applied directly onto the tumors in paste form. In a 2010 study, also done in cells and in mouse models, the research team found that the curcumin suppressed head and neck cancer growth by regulating cell cycling, said scientist Eri Srivatsan, an adjunct professor of surgery, article author and a Jonsson Cancer Center researcher who, along with Wang, has been studying curcumin and its anti-cancer properties for seven years.

The curcumin binds to and prevents an enzyme known as IKK, an inhibitor of kappa β kinase, from activating a transcription factor called nuclear factor kappa β (NFκβ), which promotes cancer growth.

In this study, 21 patients with head and neck cancers gave samples of their saliva before and after chewing two curcumin tablets totaling 1,000 milligrams. One hour later, another sample of saliva was taken and proteins were extracted and IKKβ kinase activity measured. Thirteen subjects with tooth decay and five healthy subjects were used as controls, Wang said.

Eating the curcumin, Wang said, put it in contact not just with the cancer but also with the saliva, and the study found it reduced the level of cancer enhancing cytokines.

An independent lab in Maryland was sent blind samples and confirmed the results -- the pro-inflammatory cytokines in the saliva that help feed the cancer were reduced in the patients that had chewed the curcumin and the cell signaling pathway driving cancer growth was inhibited, Wang said.

"The curcumin had a significant inhibitory effect, blocking two different drivers of head and neck cancer growth," Wang said. "We believe curcumin could be combined with other treatments such as chemotherapy and radiation to treat head and neck cancer. It also could perhaps be given to patients at high risk for developing head and neck cancers -- smokers, those who chew tobacco and people with the HPV virus -- as well as to patients with previous oral cancers to fight recurrence."

The curcumin was well tolerated by the patients and resulted in no toxic effects. The biggest problem was their mouths and teeth turned bright yellow.

"Curcumin inhibited IKKβ kinase activity in the saliva of head and neck cancer patients and this inhibition correlated with reduced expression of a number of cytokines," the study states. "IKKβ kinase could be a useful biomarker for detecting the effects of curcumin in head and neck cancer."

To be effective in fighting cancer, the curcumin must be used in supplement form. Although turmeric is used in cooking, the amount of curcumin needed to produce a clinical response is much larger. Expecting a positive effect through eating foods spiced with turmeric is not realistic, Wang said.

The next step for Wang and her team is to treat patients with curcumin for longer periods of time to see if the inhibitory effects can be increased. They plan to treat cancer patients scheduled for surgery for a few weeks prior to their procedure. They'll take a biopsy before the curcumin is started and then at the time of surgery and analyze the tissue to look for differences.

"There's potential here for the development of curcumin as an adjuvant treatment for cancer," Wang said. "It's not toxic, well tolerated, cheap and easily obtained in any health food store. While this is a promising pilot study, it's important to expand our work to more patients to confirm our findings."

Finding ways to better treat head and neck cancers is vital as patients often require disfiguring surgery, often losing parts of their tongue or mouth. They also experience many side effects, including difficulty swallowing, dry mouth and have the potential for developing another oral cancer later.

The study was funded by Veterans Affairs Greater Los Angeles Health System, West Los Angeles Surgical Education Research Center, UCLA Academic Senate, the National Institutes of Health and the Veterans Administration.

S. G. Kim, M. S. Veena, S. K. Basak, E. Han, T. Tajima, D. W. Gjertson, J. Starr, O. Eidelman, H. B. Pollard, M. Srivastava, E. S. Srivatsan, M. B. Wang. Curcumin Treatment Suppresses IKK Kinase Activity of Salivary Cells of Patients with Head and Neck Cancer: A Pilot Study. Clinical Cancer Research, 2011; DOI: 10.1158/1078-0432.CCR-11-1272.

Source: University of California - Los Angeles Health Sciences.

Gene Therapy Boosts Chemotherapy

noreply@blogger.com (John) — Wed, 14 Sep 2011 15:41:00 +0000

Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

"There are no effective methods to target BCICs, and they're urgently needed, especially for relapsed breast cancer patients," said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology. "This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance."

Special delivery system targets cells

Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload -- a Bik mutant gene called BikDD known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously.

This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.

Stem cells frequently stymie treatment

Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.

The Bcl-2 family of proteins -- especially the subtypes Bcl-2, Bcl-xL and Mcl-1 -- is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.

This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.

VISA-claudin4-BikDD cuts tumor burden

The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.

Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.

They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.

In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.

Agent energizes lapatinib, other drugs

BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.

Moving discovery forward

Hung said this approach is promising for breast cancer treatment, especially recurrent disease.

"VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth," he said. "It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents."

Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.

This work was supported by grants from the National Cancer Institute, including MD Anderson's Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson's Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.

In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.

Jing-Yu Lang, Jennifer L. Hsu, Funda Meric-Bernstam, Chun-Ju Chang, Qingfei Wang, Yi Bao, Hirohito Yamaguchi, Xiaoming Xie, Wendy A. Woodward, Dihua Yu, Gabriel N. Hortobagyi, Mien-Chie Hung. BikDD Eliminates Breast Cancer Initiating Cells and Synergizes with Lapatinib for Breast Cancer Treatment. Cancer Cell, 2011; 20 (3): 341 DOI: 10.1016/j.ccr.2011.07.017

Source: University of Texas M. D. Anderson Cancer Center.

The Risk of Gastrointestinal Bleeding with Asprin

noreply@blogger.com (John) — Wed, 14 Sep 2011 15:38:00 +0000

The risk of gastrointestinal (GI) bleeding needs to be considered when determining the potential preventive benefits associated with low-dose aspirin for cardiovascular disease and cancer. According to a new study in Clinical Gastroenterology and Hepatology, the use of low-dose aspirin increases the risk for GI bleeding, with the risk being increased further with accompanying use of cardiovascular disease-preventing therapies, such as clopidogrel and anticoagulants. In patients who took proton pump inhibitors (PPIs), bleeding risk decreased.

"The use of aspirin has been proven beneficial in reducing cardiac events and deaths in patients who have cardiovascular disease, and has even been shown to reduce cancer risk," said Angel Lanas, MD, PhD, of University Hospital Lozano Blesa and lead author of this study. "However, clinicians need to be more proactive in their efforts to reduce potential risk factors associated with all doses of aspirin, especially gastrointestinal bleeding. New low-dose aspirin studies should report more precisely on the incidence of bleedings, especially gastrointestinal bleedings, to better determine the balance between risks and benefits ."

Low-dose aspirin -- commonly defined as 75 to 325 mg daily -- is a mainstay of therapy for cardiovascular disease. In fact, patients with prior cardiovascular disease have fewer cardiovascular events and deaths with the use of low-dose aspirin compared with patients who do not use it. It is now likely to also be used for cancer prevention, especially GI and colon cancer.

A major factor limiting the widespread use of aspirin is concern about the development of GI adverse events, especially GI bleeding. However, damage may vary depending on the dose taken, other medication being consumed along with aspirin and patients' risk profiles. For example, certain patients have an increased likelihood of experiencing bleeding: those with long-term pharmacotherapy use, patients using combinations of low-dose aspirin with clopidogrel and anticoagulants, and patients with previous GI ulcers or bleedings.

In this study, doctors searched 10 electronic databases and collected data on adverse events in studies that evaluated low doses of aspirin alone or in combination with anticoagulants, clopidogrel or PPIs. They found that low doses of aspirin alone decreased the risk of death. However, the risk of major GI bleeding increased with low doses of aspirin alone compared with placebo. The risk also increased when aspirin was combined with clopidogrel (compared with aspirin alone), anticoagulants versus low doses of aspirin alone, or in studies that included patients with a history of GI bleeding or of longer duration. Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of aspirin.

Angel Lanas, Ping Wu, Jennie Medin, Edward J. Mills. Low Doses of Acetylsalicylic Acid Increase Risk of Gastrointestinal Bleeding in a Meta-Analysis. Clinical Gastroenterology and Hepatology, 2011; 9 (9): 762 DOI: 10.1016/j.cgh.2011.05.020

Source: American Gastroenterological Association

Poorer Movement Skills at Seven Months in Children at Risk of Autism

noreply@blogger.com (John) — Wed, 07 Sep 2011 15:29:00 +0000

Poorer movement skills detected as early as 7 months old are observed in children at a higher risk of developing Autistic Spectrum Disorder (ASD) than children in the general population. These are the findings of a study being presented on 7th September 2011 at the British Psychological Society's Developmental Section Conference in Newcastle.

The study was carried out by a team led by Dr. Elisabeth Hill at Goldsmiths (University of London), Dr. Hayley Leonard (Goldsmiths) and the British Autism Study of Infant Siblings (BASIS) based at Birkbeck University of London. The researchers examined infants with a diagnosed older sibling with ASD. Siblings are known to share a higher risk of developing the disorder.

The researchers assessed the infants using a longitudinal follow-up design at 7, 14, and 24 months. Two groups of infants participated in the study: (1) 54 infants at-risk of a diagnosis of ASD based on a sibling diagnosis and (2) 50 low-risk infants without a diagnosed sibling. The infants were assessed on a range of standardised measures of motor skills. Parent reports were also documented.

Statistical analyses revealed that the at-risk group had significantly poorer motor skills than the low-risk group detected as early as 7 months old. Both gross motor skills such as the ability to hold up the head/roll over/walk and fine motor skills such as grasping and manipulating small objects were found to be poorer in the group of children at-risk for the disorder. This poorer motor ability was still evident at the 24 month assessment stage..

Dr. Hayley Leonard, the presenter of the study findings at the conference said "These data are extremely important because even if the at-risk infants do not go on to be diagnosed with ASD, research suggests that poorer motor development could have a negative impact on their language, social and cognitive development over time. This poorer motor development could impact on their development of social skills, school achievement and longer-term employment outcomes."

Source: British Psychological Society (BPS), via AlphaGalileo.

Deep Brain Stimulation Stops Limb Tremors in Parkinson's Patients

noreply@blogger.com (John) — Wed, 07 Sep 2011 15:26:00 +0000

Deep brain stimulation stops limb tremors in Parkinson's patients. But positioning the stimulation electrode in the brain must be done very precisely to avoid undesired side-effects. To make this possible, researcher Ellen Brunenberg of Eindhoven University of Technology (TU/e) has developed a method for precise, external localization of the right part of the brain: the motor area of the subthalamic nucleus. She has found an ingenious way to localize this 'magic area': by using MRI to visualize the pathways in the brain that lead to it.

"If you take away the towns and cities on a map, you can still see where they are located from the pattern of the roads," says Brunenberg, who will earn her PhD on Sept. 8 for her thesis entitled 'Hitting the right target'.

Deep brain stimulation has been used since the 1980s on patients with a severe form of Parkinson's disease. Symptoms of this incurable brain disease include the well-known tremors of arms and legs. In deep brain stimulation, an electrode is introduced into the subthalamic nucleus of the patient's brain, an area the size of a cashew nut. The pulses from the electrode cause the tremors to virtually disappear. But there are often side-effects, ranging from memory loss and behavioral abnormalities through to depression and extreme susceptibility to addiction. This is because the pulses stimulate not only the motor area of the subthalamic nucleus, but also the areas associated with emotions and thought. It is therefore important to position the electrode precisely: not just in the subthalamic nucleus itself, but also in the right part of it. But how can physicians see exactly where this tiny area is located in a patient's brain?

Ellen Brunenberg of Eindhoven University of Technology. (Credit: Photo courtesy of Eindhoven University of Technology/Bart van Overbeeke).

Brunenberg and her colleagues have developed a technique that for the first time allows non invasive imaging of the different areas in the subthalamic nucleus. They do this using advanced MRI technology. "It's difficult to image the nucleus directly with MRI, because it is too much like the surrounding brain tissue. But as my supervisor professor Bart ter Haar Romeny says: if you take away the towns and cities on a map, you can still see where they should be located from the pattern of the roads."

By using a few complicated techniques, Brunenberg can see the 'roads' in the brain. "MRI allows you to make an image of the structures along which water molecules move through the brain. And that in turn shows the paths of the transport fibers through the various areas: the 'roads' on the map of the brain, which lead to the subthalamic 'city center'. From the links between the subthalamic nucleus and motor areas elsewhere in the brain, you can see which part of the nucleus is the motor area," Brunenberg explains.

This research is an important step towards more effective treatment of Parkinson's patients. The new technique should in the near future make it possible to tell brain surgeons before an operation exactly where to introduce the electrode for an optimal result with the minimum possible side effects. But before that can be done, research first has to be carried out with Parkinson's patients. "Up to now we've worked with healthy volunteers. But one of the problems with Parkinson's patients is that it's more difficult for them to lie still." It's also not yet certain whether the brain of someone with Parkinson's looks the same on an MRI scan. Other researchers at TU/e now plan to continue the research.

Ellen Brunenberg received a Top Talent grant from the Netherlands Organisation for Scientific Research (NWO) for her research. She carried out this research in the TU/e Biomedical Image Analysis group in cooperation with the Neurosurgery department of Academic Hospital Maastricht. Her supervisors are prof. Bart ter Haar Romeny (TU/e) and Veerle Visser-Vandewalle (Maastricht University).

Source: Eindhoven University of Technology, via AlphaGalileo.

Potential Health Effects of Phthalates on Children

noreply@blogger.com (John) — Wed, 07 Sep 2011 15:23:00 +0000

A newly published study by researchers at Columbia University's Mailman School of Public Health heightens concerns over the potential health effects on children of a group of ubiquitous chemicals known as phthalates. Phthalates are a class of chemicals that are known to disrupt the endocrine system, and are widely used in consumer products ranging from plastic toys, to household building materials, to shampoos.

Recent studies of school-age children have provided preliminary links between prenatal exposure to phthalates and developmental problems. The study is the first to examine prenatal phthalate exposure and the prevalence of mental, motor and behavioral problems in children who are in the preschool years. The paper, published online in Environmental Health Perspectives, adds to rising concerns about the risks associated with exposures to phthalates during pregnancy.

The study followed the children of 319 non-smoking inner-city women who gave birth between 1999 and 2006. Researchers, led by Robin M. Whyatt, DrPH, deputy director of the Columbia Center for Children's Environmental Health, measured metabolites of four phthalates in maternal urine as markers of prenatal exposure. The phthalates were: di-2-ethylhexyl phthalate, di-isobutyl phthalate, di-n-butyl phthalate and butylbenzyl phthalate. The study evaluated associations between prenatal exposures to these phthalates and child mental, motor and behavioral development at age 3 years.

The scientists used the Bayley Scales of Infant Development II, a well validated developmental test, to assess the mental and motor development of the children. Behavioral problems were measured by asking mothers to complete the widely used 99-item Child Behavior Checklist (for ages 1½-5 years). Overall, researchers found that higher prenatal exposures to two of the phthalates significantly increased the odds of motor delay, an indication of potential future problems with fine and gross motor coordination. Among girls, one of the phthalates was associated with significant decreases in mental development. Prenatal exposures to three of the phthalates were also significantly associated with behavior problems including emotionally reactive behavior, anxiety/depression, somatic complaints and withdrawn behavior. These effects differed somewhat by child sex but were statistically significant among both boys and girls.

"Our results suggest that prenatal exposure to these phthalates adversely affects child mental, motor and behavioral development during the preschool years," said Dr. Whyatt, who is also professor of clinical Environmental Health Sciences. "The results add to a growing public health concern about the widespread use of phthalates in consumer products."

The actual mechanisms by which phthalates may affect the developing brain are still being explored. Dr. Whyatt points out that phthalates are endocrine disrupters -- substances that affect hormone systems in the body. Evidence suggests that they impact the function of the thyroid gland. They also lower production of testosterone, which plays a critical role in the developing brain. "More work is needed to understand the biological effects of these commonplace substances," noted Dr. Whyatt.

"The results are concerning since increasing exposures from the lowest 25% to the highest 25% among the women in our study was associated with a doubling or tripling in the odds of motor and/or behavioral problems in the children," explained Pam Factor-Litvak, PhD, the senior epidemiologist on the study. "However, the number of children with clinical disorders was small," stated Dr. Factor-Litvak. The authors point out that the phthalate exposures among the women in the study varied widely reflecting the range of exposures found in the U.S. population.

The study was conducted in collaboration with Dr. Antonia Calafat from the Centers for Disease Control and Prevention, who measured the phthalate metabolites in the maternal prenatal urine. Other members of the Columbia research team included Dr. Xinhua Liu, Dr. Virginia A. Rauh, Allan C. Just, Lori Hoepner, Diurka Diaz, James Quinn, Dr. Jennifer Adibi, and Dr. Frederica P. Perera.

The work was supported by a grant from the National Institute of Environmental Health Sciences.

Robin M. Whyatt, Xinhua Liu, Virginia A. Rauh, Antonia M. Calafat, Allan C. Just, Lori Hoepner, Diurka Diaz, James Quinn, Jennifer Adibi, Frederica P. Perera, Pam Factor-Litvak. Maternal Prenatal Urinary Phthalate Metabolite Concentrations and Child Mental, Psychomotor and Behavioral Development at Age Three Years. Environmental Health Perspectives, 2011; DOI: 10.1289/ehp.1103705

Source: Columbia University's Mailman School of Public Health.

Realizing The Concept of Cultured Meat

noreply@blogger.com (John) — Wed, 07 Sep 2011 15:19:00 +0000

Late last week, an international group of scientists took a step closer to their goal to produce cultured meat. They agreed on important common positions about how to bring the research forward during a workshop in Gothenburg, Sweden, arranged by Chalmers University of Technology and the European Science Foundation.

Many technology components are now coming into place in order to realize the concept of cultured meat. This includes a cell source that is possible to use, several alternative processes to turn these cells into muscle cells for meat, and nutrients free of animal components which can be produced from sunlight and carbon dioxide.

In addition, a life cycle assessment of cultured meat compared to traditionally produced meat was recently published. It shows that the environmental benefits of cultured meat are very large (see attached fact sheet). For example, compared to the rearing of cattle, cultured meat would entail dramatic reductions of greenhouse gas emissions, land use and water use.

Despite these obvious advantages, the area is still very poorly funded. The interdisciplinary group of scientists has decided to form a community to try to attract more funding and to create a faster development in the area of cultured meat. During the workshop last week, they also reached consensus about important issues in the research field. For instance, the nutrients for growing the cells for meat must be produced with renewable energy and without animal products. The best source for this is to use a photosynthetic organism, such as blue-green algae. Many important decisions remain about how to proceed in the research and development on cultured meat, and the scientists now feel that it is time to spread the discussion outside the research community.

Muscle stem cells growing in a nutrient gel, on velcro. (Credit: Bart van Overbeeke, Eindhoven University of Technology).

"We want to invite all stakeholders into discussions to tackle these issues and identify in which directions to go," says Julie Gold, associate professor in biological physics at Chalmers, and one of the convenors of the workshop. "To date, there are only limited dedicated research activities in cultured meat. To move forward, research activities have to increase substantially."

The workshop in Sweden engaged an interdisciplinary group of 25 scientists who all have special interest in cultured meat. Some of them have specialties in tissue engineering, stem cells and food technology. Others are environmental scientists, ethicists, social scientists and economists. All of these areas have been discussed during the workshop. The result is encouraging regarding the possibility to actually be able to supply consumers with cultivated meat in the future, and the scientists have not found any crucial arguments against cultured meat. "On the contrary, several ethical problems would be solved, especially concerning animal welfare issues," says Stellan Welin, Professor in Biotechnology, Culture and Society, one of the convenors of the workshop. A European Science Foundation representative took part in the workshop and appreciated the energy from all involved. "The proposal for sponsoring the exploratory workshop on In vitro meat was enthusiastically accepted by the European Science Foundation, which recognizes in this topic a brand new scientific field, to be deeply explored, given the great potentiality for improving human welfare," says Giovanni Pacini, ESF. Source: Chalmers University of Technology.

Irregular Heartbeat Raises Risk of Dementia

noreply@blogger.com (John) — Tue, 30 Aug 2011 14:44:00 +0000

The most common kind of chronically irregular heartbeat, known as atrial fibrillation, is associated with a greater risk of dementia, including Alzheimer's disease. This discovery by scientists at Group Health Research Institute and their collaborators was published online in advance of print on August 1 in the Journal of the American Geriatrics Society.

"Both atrial fibrillation and dementia increase with age," said Sascha Dublin, MD, PhD, a Group Health Research Institute assistant investigator who led the research. "Before our prospective cohort study, we knew that atrial fibrillation can cause stroke, which can lead to dementia. Now we've learned that atrial fibrillation may increase dementia risk in other, more subtle ways as well."

The results of Dr. Dublin's study suggest a relationship between atrial fibrillation and dementia beyond the connection through stroke. The people in the study had a mean age of 74 years when the study began. None had dementia or a history of stroke. At the beginning of the study, 4.3 percent had atrial fibrillation, and an additional 12.2 percent developed it during the study. In the course of the study, 18.8 percent developed some type of dementia. People with atrial fibrillation were more likely to have other cardiovascular risk factors and disease than were those without the condition. So the researchers looked to see if atrial fibrillation increased dementia risk more than just through its association with other kinds of heart disease.

Participants were followed for an average of seven years. Over this time, those with atrial fibrillation had a 40 percent to 50 percent higher risk of developing dementia of any type, including probable Alzheimer's disease, compared to those without atrial fibrillation. This was true even for people who did not also have a stroke during the follow-up period.

The research was part of Adult Changes in Thought (ACT), an ongoing joint project of the Group Health and University of Washington studying risk factors for dementia in older adults. Started in 1994 ACT is led by Dr. Dublin's co-author Group Health Vice President for Research and Group Health Research Institute Executive Director Eric B. Larson, MD, MPH. ACT focuses on finding ways to delay or prevent dementia, including Alzheimer's disease, and declines in memory and thinking. It aims to deepen understanding of how the body -- especially the brain -- ages. ACT participants are members of Group Health Cooperative, a nonprofit health care system in the U.S. Pacific Northwest.

Dr. Dublin's study, which ran from 1994 to 2008, followed 3,045 people. The researchers relied on Group Health's advanced electronic data systems to determine whether participants had atrial fibrillation. The cognitive function of all study participants was evaluated every two years with tests and interviews as part of ACT. Patients whose ACT tests indicated possible dementia had additional tests including physical, neurological, and psychological exams, and many also had brain scans. A panel of experts determined the correct diagnosis for patients with cognitive problems.

Atrial fibrillation affects 3 million Americans. Dr. Dublin says that some ways it might increase dementia risk are:

weakening the heart's pumping ability, leading to less oxygen going to the brain;

increasing the chance of tiny blood clots going to the brain, causing small, clinically undetected strokes;

a combination of these plus other factors that contribute to dementia such as inflammation.

Dr. Dublin said an important next step is studying whether any treatments for atrial fibrillation reduce the risk of developing dementia. The researchers also hope their results reach primary care providers, who are often the main doctors caring for people with atrial fibrillation, dementia, or both.

"Right now, we think we are protecting our patients' brains as long as they don't have a stroke, but tiny insults over time can add up," said Dr. Dublin, who is a primary care physician at Group Health. "This paper is a wakeup call, telling us that we need to learn more about how to protect brain function, while continuing to give patients with atrial fibrillation the best possible care."

The National Institute on Aging, part of the National Institutes of Health, funded this study.

Drs. Dublin and Larson's co-authors are Melissa L. Anderson, MS, Group Health Research Institute senior biostatistician; Sebastien J. Haneuse, PhD, who recently moved from Group Health Research Institute to Harvard School of Public Health; Group Health Research Institute Affiliate Investigators Susan R. Heckbert, MD, PhD, Paul K. Crane, MD, MPH, Linda Teri, PhD, and Susan M. McCurry, PhD, all of the University of Washington; Wayne McCormick, MD, MPH, of the University of Washington; James D. Bowen, MD, of the University of Washington and Swedish Neuroscience Institute; and John C. S. Breitner, MD, MPH, who recently moved from the University of Washington and Veterans Affairs Puget Sound Health Care System to McGill University, in Montreal, Quebec.

Sascha Dublin, Melissa L. Anderson, Sebastien J. Haneuse, Susan R. Heckbert, Paul K. Crane, John C. S. Breitner, Wayne McCormick, James D. Bowen, Linda Teri, Susan M. McCurry, Eric B. Larson. Atrial Fibrillation and Risk of Dementia: A Prospective Cohort Study. Journal of the American Geriatrics Society, 2011; DOI: 10.1111/j.1532-5415.2011.03508.x

Source: Group Health Research Institute, via EurekAlert.

Eat Less for Lunch and Loose Weight

noreply@blogger.com (John) — Tue, 30 Aug 2011 14:42:00 +0000

Losing weight without a grumbling stomach or expensive liquid diet can be as simple as eating a lighter lunch, finds a new Cornell University study to be published in the October issue of the journal Appetite.

Participants who ate portion-controlled lunches did not compensate by eating more calories later in the day, leading researchers to believe the human body does not possess the mechanisms necessary to notice a small drop in energy intake.

"Making small reductions in energy intake to compensate for the increasing number of calories available in our food environment may help prevent further weight gain, and one way of doing this could be to consume portion-controlled lunches a few times a week," said doctoral student Carly Pacanowski, who co-authored the study with David Levitsky, Cornell professor of nutritional sciences and of psychology.

The study closely monitored the food intake of 17 volunteers who ate whatever they wanted from a buffet for one week. For the next two weeks, half the group selected their lunch by choosing from one of six commercially available, portion-controlled foods, such as Chef Boyardee Pasta or Campbell's Soup at Hand, but could eat as much as they wished at other meals or snacks. For the final two weeks, the other half of volunteers followed the same regimen.

While eating portion-controlled lunches, each participant consumed 250 fewer calories per day and lost, on average, 1.1 pounds.

"The results confirm that humans do not regulate energy intake with any precision. Over a year, such a regimen would result in losing at least 25 pounds," said Levitsky, who adds the study demonstrates one simple, low-cost way to consume fewer calories.

David A. Levitsky, Carly Pacanowski. Losing weight without dieting. Use of commercial foods as meal replacements for lunch produces an extended energy deficit. Appetite, 2011; 57 (2): 311 DOI: 10.1016/j.appet.2011.04.015

Source: Cornell University. The original article was written by Stephanie Salato and Susan S. Lang.

Probiotic Bacteria Have The Potential to Alter Brain Neurochemistry

noreply@blogger.com (John) — Tue, 30 Aug 2011 14:39:00 +0000

Probiotic bacteria have the potential to alter brain neurochemistry and treat anxiety and depression-related disorders according to research published in the Proceedings of the National Academy of Sciences.

The research, carried out by Dr Javier Bravo, and Professor John Cryan at the Alimentary Pharmabiotic Centre in University College Cork, along with collaborators from the Brain-Body Institute at McMaster University in Canada, demonstrated that mice fed with Lactobacillus rhamnosus JB-1 showed significantly fewer stress, anxiety and depression-related behaviours than those fed with just broth. Moreover, ingestion of the bacteria resulted in significantly lower levels of the stress-induced hormone, corticosterone.

"This study identifies potential brain targets and a pathway through which certain gut organisms can alter mouse brain chemistry and behaviour. These findings highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, the gut-brain axis, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for stress-related psychiatric disorders such as anxiety and depression," said John F. Cryan, senior author on the publication and Professor of Anatomy and Principal Investigator at the Science Foundation Ireland funded Alimentary Pharmabiotic Centre, at UCC. The APC researchers included Dr Hélène Savignac and Professor Ted Dinan.

Professor John Cryan, Alimentary Pharmabiotic Centre, University College Cork (Credit: Image courtesy of University College Cork).

The researchers also showed that regular feeding with the Lactobacillus strain caused changes in the expression of receptors for the neurotransmitter GABA in the mouse brain, which is the first time that it has been demonstrated that potential probiotics have a direct effect on brain chemistry in normal situations. The authors also established that the vagus nerve is the main relay between the microbiome (bacteria in the gut) and the brain. This three way communication system is known as the microbiome-gut-brain axis and these findings highlight the important role of bacteria in the communication between the gut and the brain, and suggest that certain probiotic organisms may prove to be useful adjunct therapies in stress-related psychiatric disorders.

Javier A. Bravo, Paul Forsythe, Marianne V. Chew, Emily Escaravage, Hélène M. Savignac, Timothy G. Dinan, John Bienenstock, John F. Cryan. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1102999108

Source: University College Cork.

Brain Mechanisms In Storing Information For Short Terms

noreply@blogger.com (John) — Wed, 24 Aug 2011 22:13:00 +0000

Freiburg biologist Dr. Aristides Arrenberg and his American colleagues studied mechanisms used by the brain to store information for a short period of time. The cells of several neural circuits store information by maintaining a persistent level of activity: A short-lived stimulus triggers the activity of neurons, and this activity is then maintained for several seconds. The mechanisms of this information storage have not yet been sufficiently described, although this phenomenon occurs in very many areas of the brain.

The authors of the study, now published in the journal Nature Neuroscience, investigated the persistent activity in a hindbrain circuit responsible for eye movements in zebrafish larvae. This circuit, the so-called oculomotor system, gives the command for rapid eye movement by way of special nerve cells that produce a short-lived succession of action potentials. On the one hand, this "burst of fire" reaches the neurons responsible for movement in the eyes and triggers a "saccade," a rapid movement of the eye. On the other hand, it is also transmitted to a second cell population, the so-called neural integrator for eye movements, where the speed signal is integrated mathematically and a position signal is created. This signal is then transmitted to the motor neurons, thus producing -- in fish as well as in humans -- a stable eye position following the rapid eye movement. The neural integrator keeps up this signal for several seconds, until a new saccade is initiated.

The persistent activity in the neural integrator for eye positions is never perfect, as the eyes gradually drift back to their point of rest after a saccade. The authors thus had the possibility of measuring the dynamics of the system during spontaneous eye movements in the dark and testing the model without the measurements being distorted by saccade commands or visual feedback.

The authors discovered that, contrary to previous belief, the cells of the neural integrator for eye movements do not constitute a homogeneous population and that existing models for explaining persistent activity in the oculomotor system will have to be reconsidered. The scientists demonstrated that the integrator neurons do not posses a uniform dynamics and that the neurons are distributed in the hindbrain with the help of their integrator time constants.

These findings provide new evidence on the organization and functioning of circuits with persistent activity and suggest a potential explanation for their low susceptibility to failure. The study is an important milestone in the quest of network neuroscience to explain the functioning of local circuits and thus close the gap between the functioning of a single neuron and the production of behavior.

Andrew Miri, Kayvon Daie, Aristides B Arrenberg, Herwig Baier, Emre Aksay, David W Tank. Spatial gradients and multidimensional dynamics in a neural integrator circuit. Nature Neuroscience, 2011; DOI: 10.1038/nn.2888

Source: Albert-Ludwigs-Universität Freiburg.