Posts tagged science

ScienceDaily (July 2, 2012) — Researchers at Moffitt Cancer Center working with colleagues at three other institutions have validated a link between a rare genetic variant and the risk of glioma, the most common and lethal type of brain tumor. The validation study also uncovered an association between the same rare genetic variant and improved rates of survival for patients with glioma.

The study, the first to confirm a rare susceptibility variant in glioma, appeared in a recent issue of the Journal of Medical Genetics, a journal published by the British Medical Association.

"Glioma is a poorly understood cancer with high morbidity and devastating outcomes," said study lead author Kathleen M. Egan, Sc.D., interim program leader of Cancer Epidemiology and vice chair of the Department of Cancer Epidemiology. "However, the discovery of the association of the TP53 genetic variant rs78378222 with glioma provides new insights into these tumors and offers better prospects for identifying people at risk."

According to the authors, their study “genotyped’ the single nucleotide polymorphism (SNP, or “snip”) rs78378222 in TP53, an important tumor suppressor gene. The researchers said the SNP disrupts the TP53 signal and, because of its activity, has been linked to a variety of cancers. This study linked the presence of the rare form of rs78378222 to deadly glioma.

The researchers conducted a large, clinic-based, case-control study of individuals age 18 and older with a recent glioma diagnosis. A total of 566 glioma cases and 603 controls were genotyped for the rs78378222 variant.

Study results reveal that the odds of developing glioma were increased 3.5 times among the rare variant allele carriers. However, when researchers examined the impact of rs78378222 on survival, they found an approximately 50 percent reduction in death rates for those who were variant allele carriers.

"That the variant increased survival chances was an unexpected finding," Egan said. "It is tempting to speculate that the presence of the risk allele could direct tumor development into a less aggressive path."

The researchers concluded that their study results “may shed light on the etiology and progression of these tumors.”

Source: Science Daily

ScienceDaily (July 2, 2012) — Researchers are closer to understanding the biology behind GHB, a transmitter substance in the brain, best known in its synthetic form as the illegal drug fantasy.

In the 1960s, gamma-hydroxybutyric acid (GHB) was first discovered as a naturally occurring substance in the brain. Since then it has been manufactured as a drug with a clinical application and has also developed a reputation as the illegal drug fantasy and as a date rape drug. Its physiological function is still unknown.

Now a team of researchers at the Department of Drug Design and Pharmacology at the University of Copenhagen has shown for the first time exactly where the transmitter substance binds in the brain under physiologically relevant conditions. The results have recently been published in the Proceedings of the National Academy of Sciences.

"We have discovered that GHB binds to a special protein in the brain — more specifically a GABA_A-receptor. The binding is strong even at very low dosage. This suggests that we have found the natural receptor, which opens new and exciting research opportunities, in that we have identified an important unknown that can provide the basis for a full explanation of the biological significance of the transmitter,” says Laura Friis Eghorn, PhD student.

Illegal use and possible antidote

Fantasy is also used as a so-called date rape drug, because in moderate amounts it has sedative, sexually stimulating and soporific effects. The compound is also abused for its euphoric effect, but in combination with alcohol, for example, it is a deadly cocktail that can lead to a state of deep unconsciousness or coma.

"GHB is registered for use as a drug to treat alcoholism and certain types of sleep disorders, but the risk of abuse presents difficulties. In the long-term, understanding how GHB works will enable us to develop new and better pharmaceuticals with a targeted effect in the brain, without the dangerous side-effects of fantasy," explains Laura Friis Eghorn, Department of Drug Design and Pharmacology.

Fantasy is an extremely toxic euphoriant, because the difference between a normal intoxicating dose and a fatal dose is so small. A better understanding of the biological mechanisms behind GHB-binding in the brain will benefit research into a life-saving antidote for this drug. Today there is no known antidote.

Statistics from Denmark in 2010 show that 8-10 percent of young people who frequent night clubs have had experience with Fantasy. However, since the drug is often also used in private for its sedative effect, it is difficult to estimate the extent of abuse.

Researchers on a targeted fishing expedition

The new research findings are the result of a collaboration between researchers at the University of Sydney in Australia and medicinal chemists at the Faculty of Health and Medical Sciences:

"Our chemist colleagues designed and produced special ligands — that are mimics of GHB in several variations. This enabled us to go on a targeted fishing expedition in the brain. We have slowly found our way to the receptor, which we have also been able to test pharmacologically. In itself, it is not unusual to find new receptors in the brain for known compounds. However, when we find a natural match rooted in the brain’s transmitter system, the biological implications are extremely interesting," explains Petrine Wellendorph, associate professor and head of the responsible research group that produced the pioneering results.

Source: Science Daily

July 2, 2012

The medication fingolimod reduced inflammatory lesion activity and reduced brain volume loss in patients with multiple sclerosis who participated in a two-year placebo-controlled clinical trial and were assessed by magnetic resonance imaging (MRI) measures, according to a report published Online First by Archives of Neurology.

Fingolimod is the first in a new class of drugs called the sphingosine 1-phosphate receptor (S1PR) modulators that was recently approved at 0.5 mg once daily for the treatment of relapsing multiple sclerosis (MS), a debilitating disease of the central nervous system, according to the study background.

The inflammatory pathology of MS can be seen by counting gadolinium (Gd)-enhancing lesions on T1-weighted images or new and enlarging T2 lesions on serial MRI scans. The extent of hyperintense areas on T2-weighted images provides an indication of the overall burden of disease, the study background explains.

The study by Ernst-Wilhelm Radue, M.D., of the Medical Image Analysis Center, University Hospital, Basel, Switzerland, and colleagues included 1,272 patients who were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial, a worldwide, multicenter effort. Patients received once-daily fingolimod capsules of 0.5 mg or 1.25 mg, or placebo.

"The anti-inflammatory effects of fingolimod therapy, as depicted by Gd-enhancing lesions and new/newly enlarged T2 lesions, were evident as early as 6 months after treatment initiation and were sustained over two years. Approximately half the patients receiving fingolimod therapy were free from any new inflammatory lesions throughout this 2-year study, compared with only 21 percent of patients receiving placebo," the authors comment.

Fingolimod, 0.5 mg (licensed dose), “significantly reduced” brain volume loss during the trial versus placebo, according to the study results. Brain atrophy is recognized as a useful way to monitor MS disease progression.

"These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution," the study concludes.

Provided by JAMA and Archives Journals

Source: medicalxpress.com

ScienceDaily (July 2, 2012) — Botulinum toxin may help prevent shaking or tremor in the arms and hands of people with multiple sclerosis (MS), according to new research published in the July 3, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"Treatments in use for tremor in MS are not sufficiently effective and new alternatives are needed," said study author Anneke van der Walt, MD, consultant neurologist at The Royal Melbourne Hospital and research fellow with the University of Melbourne in Australia.

For the study 23 people with MS were given botulinum toxin type A injections or a saline placebo for three months. Then they received the opposite treatment for the next three months. Scientists measured the tremor severity and their ability to write and draw before, during and after receiving the treatments. Video assessments were also taken every six weeks for six months.

The study found that people saw significant improvement in tremor severity, writing and drawing at six weeks and three months after the botulinum toxin treatment compared to after placebo. In tremor severity, the participants improved an average of two points on a 10-point scale, bringing their tremor from moderate to mild. In writing and drawing, participants improved by an average of one point on a 10-point scale.

"Our study suggests a new way to approach arm tremor related to MS where there are currently major treatment challenges and it also sets the framework for larger studies," said van der Walt.

Muscle weakness developed in 42 percent of people after treatment with botulinum toxin compared to six percent after placebo. The weakness was generally mild and went away within two weeks.

Source: Science Daily

ScienceDaily (July 2, 2012) — Investigators from Boston University School of Medicine (BUSM) and Boston University’s Slone Epidemiology Center report research findings that may shed light on influences on obesity during adulthood. Appearing in the journal Pediatrics, the study found an association of severity of sexual and physical abuse during childhood and adolescence with obesity during adulthood.

The findings were based on the ongoing Black Women’s Health Study, which has followed a large cohort of African-American women since 1995. Information provided in 2005 by more than 33,000 participants on early life experiences of abuse was assessed in relation to two measures of obesity: body mass index of 30 kg/m2 or more as a measure of overall obesity and waist circumference greater than 35 inches as a measure of central obesity.

The risk of obesity in 2005 by either measure was estimated to be approximately 30 percent greater among women in the highest category of physical and sexual abuse than in women who reported no abuse. The association was dampened but not fully explained by allowance for reproductive history, diet, physical activity and depressive symptoms, which might have been intermediates between abuse and weight gain.

According to the researchers, the findings add to growing evidence that experiences during childhood may have long-term health consequences. “Abuse during childhood may adversely shape health behaviors and coping strategies, which could lead to greater weight gain in later life,” explained Renee Boynton-Jarrett, MD, the lead investigator of the study and a pediatric primary care physician at Boston Medical Center. She also noted that metabolic and hormonal disruptions resulting from abuse could have that effect and that childhood abuse could be a marker for other adversities. “Ultimately, greater understanding of pathways between early life abuse and adult weight status may inform obesity prevention and treatment approaches.” Boynton-Jarrett cautioned that further studies are needed to clarify just which factors are responsible for the association of abuse with obesity and noted there is a consensus that pediatric providers should screen for abuse.

Source: Science Daily

ScienceDaily (July 2, 2012) — Researchers have identified genetic markers that may influence whether a person finishes high school and goes on to college, according to a national longitudinal study of thousands of young Americans.

The study is in the July issue of Developmental Psychology, a publication of the American Psychological Association.

"Being able to show that specific genes are related in any way to academic achievement is a big step forward in understanding the developmental pathways among young people," said the study’s lead author, Kevin Beaver, PhD, a professor at the College of Criminology and Criminal Justice at Florida State University.

The three genes identified in the study — DAT1, DRD2 and DRD4 — have been linked to behaviors such as attention regulation, motivation, violence, cognitive skills and intelligence, according to the study. Previous research has explored the genetic underpinnings of intelligence but virtually none has examined genes that potentially contribute to educational attainment in community samples, said Beaver.

He and his colleagues analyzed data from the National Longitudinal Study of Adolescent Health, also known as Add Health. Add Health is a four-wave study of a nationally representative sample of American youths who were enrolled in middle or high school in 1994 and 1995. The study continued until 2008, when most of the respondents were between the ages of 24 and 32. The participants completed surveys, provided DNA samples and were interviewed, along with their parents. The sample used for this analysis consisted of 1,674 respondents.

The genes identified in this research are known as dopamine transporter and receptor genes. Every person has the genes DAT1, DRD2 and DRD4, but what is of interest are molecular differences within the genes, known as alleles, according to Beaver. Subjects who possessed certain alleles within these genes achieved the highest levels of education, according to the findings.

Dopamine transporter genes assist in the production of proteins that regulate levels of the neurotransmitter dopamine in the brain, while dopamine receptor genes are involved in neurotransmission. Previous research has shown that dopamine levels play a role in regulating impulsive behavior, attention and intelligence.

The presence of the alleles alone did not guarantee higher levels of education, the study found. Having a lower IQ was more strongly associated with lower levels of education. Also, living in poverty and essentially “running with a bad crowd” resulted in lower levels of education despite the genetic effects.

Even though the genetic variants were found to be associated with educational levels, having a specific allele does not determine whether someone will graduate from high school or earn a college degree, according to Beaver. Rather, these genes work in a probabilistic way, with the presence of certain alleles simply increasing or decreasing the likelihood of educational outcomes, he said. “No one gene is going to say, ‘Sally will graduate from high school’ or ‘Johnny will earn a college degree,’” he said. “These genetic effects operate indirectly, through memory, violent tendencies and impulsivity, which are all known predictors of how well a kid will succeed in school. If we can keep moving forward and identify more genetic markers for educational achievement, we can begin to truly understand how genetics play a role in how we live and succeed in life.”

Source: Science Daily

July 2nd, 2012

Third-generation sequencing debugged to glimpse parrots’ ability to imitate.

Scientists say they have assembled more completely the string of genetic letters that could control how well parrots learn to imitate their owners and other sounds.

The research team unraveled the specific regions of the parrots’ genome using a new technology, single molecule sequencing, and fixing its flaws with data from older DNA-decoding devices. The team also decoded hard-to-sequence genetic material from corn and bacteria as proof of their new sequencing approach.

The results of the study appeared online July 1 in the journal Nature Biotechnology.

Single molecule sequencing “got a lot of hype last year” because it generates long sequencing reads, “supposedly making it easier to assemble complex parts of the genome,” said Duke University neurobiologist Erich Jarvis, a co-author of the study.

He is interested in the sequences that regulate parrots’ imitation abilities because they could give neuroscientists information about the gene regions that control speech development in humans.

This male budgie from the Fort Worth Zoo is like the parrots Erich Jarvis uses to study vocal learning behaviors, but probably without the text bubble. Image adapted from an image credited to Jerry Tillery via Wikimedia Commons. More info in notes below.

Jarvis began his project with collaborators by trying to piece together the genome regions with what are known as next-generation sequencers, which read chunks of 100 to 400 DNA base pairs at a time and then take a few days to assemble them into a draft genome. After doing the sequencing, the scientists discovered that the read lengths were not long enough to assemble the regulatory regions of some of the genes that control brain circuits for vocal learning.

University of Maryland computational biologists Adam Phillippy and Sergey Koren — experts at assembling genomes — heard about Jarvis’s sequencing struggles at a conference and approached him with a possible solution of modifying the algorithms that order the DNA base pairs. But the fix was still not sufficient.

Last year, 1000 base-pair reads by Roch 454 became available, as did the single molecule sequencer by Pacific Biosciences. The Pacbio technology generates strands of 2,250 to 23,000 base pairs at a time and can draft an entire genome in about a day.

Jarvis and others thought the new technologies would solve the genome-sequencing challenges. Through a competition, called the Assemblathon, the scientists discovered that the Pacbio machine had trouble accurately decoding complex regions of the parrot, Melopsittacus undulates, genome. The machine had a high error rate, generating the wrong genetic letter at every fifth or sixth spot in a string of DNA. The mistakes made it nearly impossible to create a genome assembly with the very long reads, Jarvis said.

But with a team, including scientists from the DOE Genome Science Institute and Cold Spring Harbor in New York, Phillippy, Koren and Jarvis corrected the Pacbio sequencer’s errors using shorter, more accurate codes from the next-generation devices. The fix reduces the single-molecule, or third-generation, sequencing machine’s error rate from 15 percent to less than one-tenth of one percent.

“Finally we have been able to assemble the regulatory regions of genes, such as FoxP2 and egr1, that are of interest to us and others in vocal learning behavior,” Jarvis said.

He explained that FoxP2 is a gene required for speech development in humans and vocal learning in birds that learn to imitate sounds, like songbirds and parrots. Erg1 is a gene that controls the brain’s ability to reorganize itself based on new experiences.

By being able to decode and organize the DNA that regulates these regions, neuroscientists may be able to better understand what genetic mechanism causes birds to imitate and sing well. They may also be able to collect more information about genetic factors that affect a person’s ability to learn how to communicate well and to speak, Jarvis said. He and his team plan to describe the biology of the parrot’s genetic code they sequenced in more detail in an upcoming paper.

Jarvis added that as more scientists use the hybrid sequencing approach, they could possibly decode complex, elusive genes linked to how cancer cells develop and to the sequences that control other brain functions.

Source: Neuroscience News

July 2, 2012

After stroke, patients often suffer from dysphagia, a swallowing disorder that results in greater healthcare costs and higher rates of complications such as dehydration, malnutrition, and pneumonia. In a new study published in the July issue of Restorative Neurology and Neuroscience, researchers have found that transcranial direct current stimulation (tDCS), which applies weak electrical currents to the affected area of the brain, can enhance the outcome of swallowing therapy for post-stroke dysphagia.

"Our pilot study demonstrated that ten daily sessions of tDCS over the affected esophageal motor cortex of the brain hemisphere affected by the stroke, combined with swallowing training, improved post-stroke dysphagia. We observed long-lasting effects of anodal tDCS over three months,” reports lead investigator Nam-Jong Paik, MD, PhD, of the Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Sixteen patients with acute post-stroke dysphagia were enrolled in the trial. They showed signs of swallowing difficulties such as reduced tongue movements, coughing and choking during eating, and vocal cord palsy. Patients underwent ten 30-minute sessions of swallowing therapy and were randomly assigned to a treatment or control group. Both groups were fitted with an electrode on the scalp, on the side of the brain affected by the stroke, and in the region associated with swallowing. For the first 20 minutes of their sessions, tDCS was administered to the treatment group and then swallowing training alone continued for the remaining 10 minutes. In the control group, the direct current was tapered down and turned off after thirty seconds. Outcomes were measured before the experiment, just after the experiment, and again three months after the experiment. A patient from each group underwent a PET scan at before and just after the treatment to view the effect of the treatment on metabolism.

All patients underwent interventions without any discomfort or fatigue. There were no significant differences in age, sex, stroke lesion site, or extent of brain damage. Evaluation just after the conclusion of the sessions found that dysphagia improved for all patients, without much difference between the two groups. However, at the three month follow-up, the treatment group showed significantly greater improvement than the control group.

In the PET study, there were significant differences in cerebral metabolism between the first PET scan and the second PET scan in the patient who had received tDCS. Increased glucose metabolism was observed in the unaffected hemisphere, although tDCS was only applied to the affected hemisphere, indicating that tDCS might activate a large area of the cortical network engaged in swallowing recovery rather than just the areas stimulated under the electrode.

"The results indicate that tDCS can enhance the outcome of swallowing therapy in post-stroke dysphagia," notes Dr. Paik. "As is always the case in exploratory research, further investigation involving a greater number of patients is needed to confirm our results. It will be important to determine the optimal intensity and duration of the treatment to maximize the long-term benefits."

Provided by IOS Press

Source: medicalxpress.com