One in five patients with chronic kidney disease is depressed, even before beginning long-term dialysis therapy or developing end-stage renal disease, UT Southwestern Medical Center researchers have found.

The study, based on a pool of 272 participants, is the first to examine the rate of depression among these patients using the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV), which is considered the gold-standard in evaluating depression.

“Because patients in the early stages of chronic kidney disease are at increased risk for clinical depression, we as nephrologists should consider screening our patients for depression in clinic,” said Dr. Susan Hedayati, assistant professor of internal medicine at UT Southwestern and a staff nephrologist at the Dallas Veterans Affairs Medical Center. She is the lead author of the study, available online and in the current issue of the American Journal of Kidney Diseases.

Previous research has shown that depression rates in the general community are 2 percent to 4 percent; among diabetes patients, 11 percent; among congestive heart failure patients, 14 percent; and among coronary artery disease after heart attack patients, 16 percent.

“Chronic kidney disease patient depression numbers may be higher due to the presence of the same simultaneously occurring conditions that resulted in progressive kidney disease, such as diabetes and atherosclerotic vascular disease,” Dr. Hedayati said. “Alternatively, patients such as diabetics, who are depressed, may develop progressive kidney disease because of non-adherence to medications and physicians’ advice.”

Earlier estimates of depression among chronic kidney disease patients were based on self-report depression scales that can emphasize symptoms such as lack of appetite, weight loss and fatigue. Such symptoms can overlap with other medical conditions, so UT Southwestern researchers took a novel approach.

From May 2005 to November 2006, researchers invited patients at the Dallas VA Medical Center who were visiting the clinic for chronic kidney disease appointments to join the study. Patients who agreed to participate then underwent a structured clinical interview to determine if they had a current major depressive episode, based on the DSM IV definition of major depressive disorder.

Fifty-seven patients, or 21 percent, were found to be depressed. The mean age of depressed patients was about 65; two were women; and nearly 56 percent were white. All patients were veterans.

The researchers also found that diabetic patients were twice as likely to be depressed as those without diabetes; 63 percent of patients had at least three other medical conditions; and 41 percent had at least four other diseases.

Twenty-six million people in America have chronic kidney disease and millions more are at increased risk, according to the National Kidney Foundation. If treatment does not begin early, the condition progresses to end-stage renal disease. At that point, a patient’s kidneys have failed to the point where dialysis ““ a filtering of toxic chemicals in the blood and removing fluid to help control blood pressure ““ or a kidney transplant is needed.

According to the U.S. Renal Data System Annual Report, expenditures for end-stage renal disease patients totaled $15.5 billion, which is approximately 6 percent of the entire Medicare budget, and are projected to consume $28 billion by 2010.

Dr. Hedayati is now conducting the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) to determine whether antidepressant medication would be tolerated in kidney-disease patients and whether such treatment can improve depression.

Other UT Southwestern researchers involved in this study were Dr. Abu Minhajuddin, assistant professor of clinical sciences; Dr. Robert Toto, professor of internal medicine and clinical sciences; and Dr. David Morris, assistant professor of psychiatry. Also involved in the study was Dr. A. John Rush, a former professor of clinical sciences and psychiatry at UT Southwestern, now vice dean of Duke-NUS Graduate Medical School Singapore.

The study was funded by the Veterans Integrated Service Network 17, Veterans Affairs North Texas Health Care System Research Corporation, the National Institutes of Health and the UT Southwestern O’Brien Kidney Research Core Center.

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On the Net:

• UT Southwestern Medical Center
• American Journal of Kidney Diseases

Almost a quarter of a million individuals addicted to heroin are incarcerated in the United States each year. However, many prison systems across the country still do not offer medical treatment for heroin and opiate addiction, despite the demonstrated social, medical and economic benefits of opiate replacement therapy (ORT).

According to new research from The Miriam Hospital, Brown University and their affiliated Center for Prisoner Health and Human Rights, just half of all federal and state prison systems offer ORT with the medications methadone and buprenorphine, and only in very limited circumstances. Similarly, only twenty-three states provide referrals for some inmates to treatment upon release from prison. These policies are counter to guidelines issued by both the World Health Organization (WHO) and the Centers for Disease Control and Prevention, which say prisoners should be offered ORT for treatment of opiate dependence.

The study’s findings are published online by Drug and Alcohol Dependence.

“Pharmacological treatment of opiate dependence is a proven intervention, is cost-effective and reduces drug-related disease and reincarceration rates, yet it remains underutilized in U.S. prison systems,” said Amy Nunn, ScD, the study’s lead author and an assistant professor of medicine (research) at The Warren Alpert Medical School of Brown University. “Improving correctional policies for addiction treatment could dramatically improve prisoner and community health as well as reduce both taxpayer burden and reincarceration rates.”

“Opiate addiction, like all forms of addiction, causes long-term changes to the structure and functioning of the brain, which is why it is classified as a disease. Addiction requires treatment just as other chronic diseases, like diabetes and cancer, do. Unfortunately, there is a large gap between the number of prisoners who require addiction treatment and those who actually receive it,” added senior author Josiah Rich, MD, MPH, co-director of the Center for Prisoner Health and Human Rights at The Miriam Hospital and Alpert Medical School.

The U.S. has the world’s highest incarceration rate, with approximately 10 million individuals incarcerated each year. More than half of inmates have a history of substance use and more than 200,000 people with heroin addiction are incarcerated annually. Inmates face disproportionately higher burdens of mental illness, substance use and infectious diseases, including HIV/AIDS. Meanwhile, their transition back to their communities is often associated with increased sexual health and drug-related risks, and more than half will relapse within one month of their release.

For the past four decades, methadone has been the treatment of choice for opiate dependence. It prevents withdrawal symptoms and drug cravings, blocks the euphoric effects of other opiates, and reduces the risk of relapse, infectious disease transmission and overdose death. The drug buprenorphine is a newer treatment for opiate replacement that has less likelihood of overdose and is associated with less social stigma. Like methadone, it prevents withdrawal symptoms when an individual stops taking opioid drugs by producing similar effects. Both methadone and buprenorphine are included in WHO’s “Essential Medicines” list of drugs that should be made available at all times by health systems to patients.

The Miriam/Brown research team surveyed the medical directors at the 50 state departments of corrections, along with the Federal Bureau of Prisons and the District of Columbia prison, about their facilities’ ORT prescribing policies and referral programs for inmates leaving prison. They received a total of 51 of 52 responses.

Although it appears methadone is offered more frequently that buprenorphine, only 28 facilities (55 percent) offer it under any circumstances, although more than half of these provide it only to pregnant women or for chronic pain management. Approximately 45 percent of facilities provided some community linkage to methadone treatment post-release. Meanwhile, only seven prison systems (14 percent) offer buprenorphine in some circumstances, while 15 facilities (29 percent) offer referrals for some inmates to community buprenorphine providers upon release.

When asked why these treatments are not available in their prison system, the majority of facilities indicated they prefer drug-free detoxification over ORT. A number of prison systems also cited security concerns about providing methadone and buprenorphine to inmates. Interestingly, 27 percent of medical directors said they did not know how beneficial methadone is for treating inmates with opiate addiction, while half were unaware of the benefits of buprenorphine.

A major barrier to providing ORT after incarceration appears to be the lack of partnerships with community ORT providers. Many providers also cited their focus on inmate health during incarceration, rather than upon release, as another reason for not linking inmates to ORT after they’ve been released.

“In spite of overwhelming scientific evidence demonstrating that pharmacological treatment for addiction has greater health and social benefits than abstinence-only policies, many prison directors are philosophically opposed to treating substance use. Most prisons also do not provide referrals for substance use treatment for prisoners upon release,” said Nunn. “These trends contribute to high reincarceration rates and have detrimental impacts on community health. Our interviews with prison medical directors suggest that changing these policies may require an enormous cultural shift within correctional systems.”

The study was supported by grants from the National Institute of Health’s National Institute on Drug Abuse (NIDA/NIH) and Center for AIDS Research (CFAR); and the Tufts Nutrition Collaborative. In addition to Nunn and Rich, co-authors include Nickolas Zeller and Ank Nijhawan from both The Miriam Hospital and Alpert Medical School; Samuel Dickman from Brown University; and Catherine Trimbur from the University of Rochester School of Medicine and Dentistry.

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On the Net:

• Lifespan
• The Miriam Hospital
• The Warren Alpert Medical School of Brown University
• Drug and Alcohol Dependence

84 percent of all causes of blindness are either preventable or treatable, study finds

By 2020, 1.4 million Nigerians over age 40 will lose their sight, and the vast majority of the causes are either preventable or treatable, according to the Nigeria National Blindness and Visual Impairment Study Group.

In the September issue of Investigative Ophthalmology and Visual Science, the group shares the second half of the results of the study, which examined almost 15,000 Nigerians over 40 between 2005 and 2007. The goal of the study (Causes of Blindness and Visual Impairment in Nigeria: The Nigeria National Blindness and Visual Impairment Survey) was to help Nigeria create a plan for its participation in the World Health Organization’s VISION 2020: The Right to Sight Initiative, which is working globally to eliminate preventable blindness. The first half of the study appeared in Investigative Ophthalmology earlier this year.

About 23 percent had some sort of visual impairment, and 4.2 percent were blind. Cataracts were the most common cause of blindness, with glaucoma second. Refractive errors (which cause nearsightedness, farsightedness and astigmatisms) were frequently the cause of less serious visual impairments. Other common treatable or preventable causes of visual impairment included complications from diabetes, trachoma (a bacterial infection of the eye) and the parasite onchocerciasis, which is transmitted to humans through the bite of a black fly and is prevalent in Africa.

“The high proportion of avoidable blindness “¦ means that appropriate and accessible refraction and surgical services need to be provided,” the report states. “If priority attention is not given, the number of blind and severely visually impaired adults in Nigeria will increase by greater than 40 percent over the next decade.”

The study noted that groups that had less access to health care were particularly vulnerable to preventable visual impairment.

According to the study, “The difference in the prevalence of vision loss due to cataract between men and women, urban and rural areas, and levels of education in Nigeria almost certainly reflects access to services.” The authors recommended vision care plans that target women, rural residents and the less educated.

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On the Net:

• Association for Research in Vision and Ophthalmology
• Investigative Ophthalmology and Visual Science

Chronic periodontitis, a form of gum disease, is an independent risk factor for head and neck squamous cell carcinoma. This suggests the need for increased efforts to prevent and treat periodontitis as a possible means to reduce the risk of this form of cancer.

“Prevent periodontitis; if you have it already, get treatment and maintain good oral hygiene,” said Mine Tezal, D.D.S., Ph.D., assistant professor in the Department of Oral Diagnostic Sciences, School of Dental Medicine, University at Buffalo, and NYS Center of Excellence in Bioinformatics and Life Sciences at the University of Buffalo. She is also a research scientist in the Department of Dentistry and Maxillofacial Prosthetics at Roswell Park Cancer Institute, which is where the study was conducted.

Results of this study are published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Chronic periodontitis is characterized by progressive loss of the bone and soft tissue attachment that surround the teeth. The researchers assessed the role of chronic periodontitis on head and neck squamous cell carcinoma, as well as the individual roles on three subsites: oral cavity, oropharyngeal and laryngeal. They used radiographic measurement of bone loss to measure periodontitis among 463 patients; 207 of whom were controls.

Findings showed that chronic periodontitis might represent a clinical high-risk profile for head and neck squamous cell carcinoma. The strength of the association was greatest in the oral cavity, followed by the oropharynx and larynx, according to Tezal.

When they stratified the relationship by tobacco use, they found that the association persisted in those patients who never used tobacco. The researchers did not expect the periodontitis-head and neck squamous cell carcinoma association to be weaker in current smokers compared to former and never smokers, according to Tezal. However, this interaction, although statistically significant, was not very strong.

“Confirmatory studies with more comprehensive assessment of smoking, such as duration, quantity and patterns of use, as well as smokeless tobacco history are needed,” she said.

“Our study also suggests that chronic periodontitis may be associated with poorly differentiated tumor status in the oral cavity. Continuous stimulation of cellular proliferation by chronic inflammation may be responsible for this histological type. However, grading is subjective and we only observed this association in the oral cavity. Therefore, this association may be due to chance and needs further exploration,” Tezal added.

Andrew Olshan, Ph.D., said these results lend further support to the potential importance of poor oral health in this form of cancer. Olshan is professor and chair of the Department of Epidemiology at the Gillings School of Global Public Health, and professor in the Department of Otolaryngology/Head and Neck Surgery, School of Medicine, University of North Carolina at Chapel Hill.

“The study of poor oral health including the possible carcinogenic role of microorganisms is part of a rapidly growing interest in how a community of microbes that live in the various environments of the human body can affect health,” Olshan said. “Although the study is comparatively small, the researchers were able to also see an association between bone loss and the risk of head and neck cancer.”

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On the Net:

• American Association for Cancer Research
• Cancer Epidemiology, Biomarkers & Prevention

A study that tracked genetic mutations through the human equivalent of about 5,000 years has demonstrated for the first time that oxidative DNA damage is a primary cause of the process of mutation – the fuel for evolution but also a leading cause of aging, cancer and other diseases.

The research, just published in Proceedings of the National Academy of Sciences, also indicated that natural selection is affecting the parts of the genome that don’t contain genes ““ supposedly “junk” DNA that increasingly appears to have important roles in life processes that are very poorly understood.

The analysis was done by scientists at Oregon State University, Indiana University, the University of Florida and University of New Hampshire, in studies supported by the National Institutes of Health.

This research was unusual, scientists say, because the model animal used for the study, a type of roundworm called C. elegans, was tracked through 250 generations and in that period of time accumulated 391 genetic mutations through normal life processes. That’s more than 10 times as many mutations as have ever before been tracked in a study such as this.

Several Nobel Prizes have been awarded based on studies done with this roundworm, which was the first animal to have its entire genome sequenced. And despite their vast evolutionary separation as life forms, this tiny roundworm and humans still share comparable forms of DNA maintenance.

“Genetic mutations in animals are actually pretty rare, they don’t happen very often unless they are induced by something,” said Dee Denver, an assistant professor of zoology at OSU and principal investigator on the study. “The value of using this roundworm is that it reaches reproductive age in about four days, so we can study changes that happen through hundreds of generations, using advanced genome sequencing technology.”

Genetic mutations can take various forms, such as a disruption in the sequence of DNA bases, larger deletions of whole sections of DNA, or other events. They are a fundamental part of the biological process of life and the basis of evolution, allowing organisms to change ““ sometimes in ways that are good and lead to greater survival value, sometimes bad and leading to decline or death. But the process is difficult to study and a real understanding of the driving forces behind mutation, its frequency, and the types of mutation that happen most often has been elusive, researchers say.

A primary finding of the new study is that a predominant number of genetic mutations ““ most, but not all of them ““ are linked to guanine, one of the four basic nucleotides that make up DNA and form the genetic code of life. Guanine is known to be particularly sensitive to oxidative damage.

“Most life on Earth depends in some form on oxygen, which is great at the production of energy,” Denver said. “But we pay a high price for our dependence on oxygen, because the process of using it is not 100 percent efficient, and it can result in free oxygen radicals that can damage proteins, fats and DNA. And this process gets worse with age, as free radicals accumulate and begin to cause disease.”

This is one of the first studies, Denver said, that is clearly demonstrating the effects of oxidative damage at a genome-wide scale.

“The research showed that the majority of all DNA mutations bear the signature of oxidative stress,” Denver said. “That’s exactly what you would expect if you believe that oxidative stress is an underlying cause of aging and disease.”

Beyond that, however, the study also found that mutation and natural selection is also operating in the “junk DNA” parts of the roundworm, which actually comprises about 75 percent of its genome but traditionally was not thought to play any major role in life and genetic processes. This suggests that these poorly-understood and little appreciated parts of the genome may have important biological roles that are not yet known, Denver said.

Oxidative stress for decades has been suspected as a mechanism for some of the processes that lead to aging and disease, and it has been studied extensively for that reason. This research provides a better fundamental understanding of the genetic impacts of oxidative stress and its role in both genetic disease and evolution, researchers say.

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On the Net:

• Oregon State University
• Proceedings of the National Academy of Sciences

Researchers at the University of North Carolina at Chapel Hill School of Medicine have now discovered that establishing the neural wiring necessary to function normally depends on the ability of neurons to make finger-like projections of their membrane called filopodia.

 In laying down the neural circuitry of the developing brain, billions of neurons must first migrate to their correct destinations and then form complex synaptic connections with their new neighbors.

When the process goes awry, neurodevelopmental disorders such as mental retardation, dyslexia or autism may result. Researchers at the University of North Carolina at Chapel Hill School of Medicine have now discovered that establishing the neural wiring necessary to function normally depends on the ability of neurons to make finger-like projections of their membrane called filopodia.

The finding, published as the cover story of the Sept. 4 issue of the journal Cell, indicates that the current notion regarding how cells change shape, migrate or differentiate needs to be revisited.

Scientists have thought that the only way for a cell to morph and move is through the action of the cytoskeleton or the scaffold inside the cell, pushing membrane forward or sucking it in, said senior study investigator Franck Polleux, Ph.D., associate professor of pharmacology at the UNC School of Medicine.

But Polleux’s study shows that the brain protein srGAP2 can also impose cell shape by directly bending membranes, forming filopodia as a mean to control the migration and branching of neurons during brain development.

Interestingly, srGAP2 is one of a family of proteins that have been implicated in a severe mental retardation syndrome called the 3p- syndrome. Therefore this research could also yield important insights into the underlying causes of this and other forms of mental retardation.

Polleux and his colleagues began looking at srGAP2 because the gene was almost exclusively “turned on” or expressed during brain development. The brain protein contains a unique combination of domains ““ small functional chunks of protein sequence that may be common to other proteins as well. The star of these domains is one called the F-BAR domain, one of a handful of similarly termed “BAR domains” that have recently become a hotbed of research.

The UNC researchers were among the first to master a laboratory technique that enabled them to manipulate which genes are turned on or off in neurons, a notoriously difficult cell type.

Working with slices of mouse brain, they used electrical current to introduce pieces of genetic material that would either ramp up or, conversely, knock down the action of the protein’s F-BAR domain. They then cultured brain slices in petri dishes allowing researchers to watch how the neurons behaved ‘in the wild’ in their native environment. When the researchers ramped up the activity of the domain, they saw that the neurons formed the finger-like filopodia which blocked migration by inducing too many branches.

“The textbook notion is that F-BAR proteins fold inward, but here we show it can do the opposite” said Polleux. “This is a completely novel mechanism for producing filopodia.”

The researchers then found that when they reduced the expression of this protein, the neurons migrated at a faster rate and branched less. Under a microscope, neurons move like little inchworms. In front, the long thin cellular protrusion of the neuron extends, pauses, then drags the bulbous cell body behind it, then extends again, and so on.

Polleux says the F-BAR domain of srGAP2 appears to tightly control the amount of branching neurons undergo so they can be more streamlined when they need to migrate, and branch when they need to establish connections with other neurons.

Because disruptions in these critical connections would have detrimental effects on brain development, Polleux will now collaborate with clinicians at UNC to determine whether mutations in the srGAP2 gene are involved in autism or in other forms of mental retardation in addition to the 3p- syndrome. His laboratory is also interested in determining the function of approximately 25 other genes containing F-BAR-like domains, many of which are expressed in the developing brain.

Funding for the studies led at UNC came from the National Institutes of Health and the Pew Charitable Trusts. Study co-authors from UNC include Sabrice Guerrier, Ph.D., former graduate student; Jaeda Coutinho-Budd, graduate student; Takayuki Sassa, Ph.D., former postdoctoral fellow; Aur©lie Gresset, graduate student; and Nicole Vincent Jordan, graduate student.

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On the Net:

• University of North Carolina at Chapel Hill School of Medicine
• Cell

A government agency in Sweden is recommending that children under the age of 3 not be given the H1N1 swine flu vaccine.

The Swedish Medical Products Agency says a proper dose for that age group hasn’t been established, Sweden’s The Local newspaper reported Friday.

Before this data is compiled … the vaccine is considered suitable only for children with underlying risk factors, the agency said in a statement.

A risk/benefit analysis indicates children younger than 6 months should not be given the H1N1 flu vaccine at all, the agency says.

In the case of pregnant women, the agency is recommending the vaccine be given as early as possible.

The agency recommendations were compiled in cooperation with the Swedish Pediatric Association and are supported by the country’s National Board of Health and Welfare, The Local said.

The rise in obesity and the onset of type 2 diabetes is increasing at epidemic rates, affecting more than 180 million people worldwide. A group from the Ecole Polytechnique F©d©rale de Lausanne (EPFL) may have found a new weapon in the fight against these disorders.

The study demonstrates that activation of the protein TGR5 can treat type 2 diabetes and reduce weight gain. In collaboration with Prof. Roberto Pellicciari and colleagues at the University of Perugia, Italy, and Intercept Pharmaceuticals, New York, the group at the EPFL, led by Dr Kristina Schoonjans and Prof. Johan Auwerx, have identified a selective molecule that can activate the TGR5 protein. It is called INT-777.

The authors based their research on knowledge that TGR5 controls the secretion of the gut-derived hormone Glucagon-Like Peptide 1 (GLP-1), which plays a critical role in pancreatic function and the regulation of blood sugar levels. In collaboration with Prof. Pellicciari, who designed the TGR5 activator INT-777, the group at the EPFL has shown under laboratory conditions that this compound can effectively treat diabetes and reduce fat mass.

Charles Thomas, first author of the study, was quoted as saying, “Recently, two classes of drugs exploiting the properties of the hormone GLP-1 have been marketed for the treatment of type 2 diabetes. The first strategy aims to increase the blood levels of GLP-1 by limiting its degradation in the body. The second is to mimic the effects of GLP-1 using drugs activating the GLP-1 receptor (GLP-1R). “

In the current study, the authors propose a third therapeutic option based on increasing GLP-1 secretion by administering INT-777. The researchers found that, in addition to stimulating the secretion of GLP-1, INT-777 activated TGR5 in other tissues leading to an increase in energy expenditure and a resulting reduction in fat mass and obesity.

SOURCE: Cell Metabolism, September 2, 2009

Extra pounds do not keep men from asking women out and 54 percent of men say heavier women are better in bed, a poll conducted by dating Web sites indicated.

Dating sites Date.com, Matchmaker.com and Amor.com polled thousands of members during July and August to see what they think about dating overweight men or women.

Eighty-five percent of men agreed with the statement, A couple of extra pounds are fine by me, while 80 percent of men say overweight women are less bitchy than thin women.

Almost 70 percent of the men say what matters is what’s on the inside, not on the outside.

However, 90 percent of women think men find extra weight unattractive and that heavy women have a much harder time dating. Seventy-four percent say they prefer health conscious men.

These poll results show such a significant discrepancy in the way men feel about dating overweight women, and what women think men are looking for when it comes to relationships, Shira Zwebner, relationship adviser for Date.com, Matchmaker.com and Amor.com, says in a statement. Unfortunately, these types of misconceptions between the sexes are extremely common, and result in a lot of missed dating and relationship opportunities.

Technique could lead to improved detection, diagnostics capabilities

Researchers at the U.S. Department of Energy’s Argonne National Laboratory have developed a systematic method to improve the stability of antibodies. The technique could lead to better biosensors, disease therapeutics and diagnostic reagents and non-laboratory applications, including environmental remediation.

Antibodies are proteins produced by humans and animals to defend against infections; they are also used to diagnose and treat some diseases and detect toxins and pathogens. “The primary issues with antibodies is that they are fragile and short-lived outside of cooler temperature-controlled environments, making their usefulness usually limited to laboratory applications,” said Argonne senior biophysicist Fred Stevens, the project’s principle investigator.

Specifically, “stabilized antibodies, with full functionality, could be used in diagnostic and detection kits that can survive in less than optimal environments and be stockpiled for years at a time,” Stevens said. “They could be used to combat diseases like cancer. They can also be used as the basis for biosensors that can continuously detect for pathogens like botulinum, ricin and anthrax in places such as airports and subway stations ““ locations where it is not currently possible to provide ongoing detection of pathogens because antibodies cannot tolerate the environmental conditions.”

Argonne has provided funding toward Stevens’ research. Earlier research funded by the National Institutes of Health showed that it was possible to stabilize antibodies after a team led by Stevens unexpectedly discovered that natural antibodies contain stabilizing amino acid replacements.

Antibodies are made up of four polypeptides — two light chains and two heavy chains. These chains are made up of modules known as constant and variable domains. The light and heavy chain each has a variable domain, which come together to form the antigen binding site. Because of the great diversity of amino acids in the variable domains, different antibodies are capable of interacting with an effectively unlimited number of targets.

Sometimes this variability comes at a price; the amyloid-forming light chains were less stable than their normal counterparts. However, even amyloid-forming light chains have amino acid substitutions that improve stability. When seven of these amino acid changes were introduced into an amyloid-forming variable domain, a billion-fold improvement in thermodynamic stability was obtained reflecting a much higher ratio of native protein folds to unfolded proteins ““ a major determinate of antibody shelf life.

“Our work at this detailed level has taught us that antibody stabilization was possible, but we needed to find out if antibodies could be stabilized without compromising their function and do so with moderate experimental investment,” Stevens said. Recent work suggests these goals are potentially achievable. To proactively improve the stability of a different antibody variable domain, Argonne researchers drew up a short list of 11 candidate amino acid changes. Four of the amino acid changes improved antibody stability and when combined together in the original domain provided a 2,000-fold improvement in stability.

A follow up experiment using a functional antibody fragment was able to improve antibody stability comparably, with no loss of antibody functionality. Both experiments required approximately one month to accomplish instead of the potentially open-ended time required for most protein stabilization projects.

There is a correlation between thermodynamic stability and thermal stability, the billion fold improvement in thermodynamic stability increased the thermal resistance of the protein to heating, resulting in a “melting temperature” of about 160 degrees Fahrenheit. “However, still unanswered is whether it is possible to be confident about improving the stability of any antibody generated against a particular target,” Stevens said. “Our research indicates that stabilization of antibodies is possible. We project that it could be possible to generate the data to guide stabilization of every future antibody in the near future.”

Argonne’s Office of Technology Transfer is actively seeking participation from industry for licensing as well as funding for further development of this technology.

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On the Net:

• DOE/Argonne National Laboratory

University of Michigan researchers have identified a gene that acts as a master switch to control obesity in mice. When the switch is turned off, even high-fat-diet mice remain thin.

Deleting the gene, called IKKE, also appears to protect mice against conditions that, in humans, lead to Type 2 diabetes, which is associated with obesity and is on the rise among Americans, including children and adolescents.

If follow-up studies show that IKKE is tied to obesity in humans, the gene and the protein it makes will be prime targets for the development of drugs to treat obesity, diabetes and complications associated with those disorders, said Alan Saltiel, the Mary Sue Coleman Director of the U-M Life Sciences Institute.

“We’ve studied other genes associated with obesity ““ we call them ‘obesogenes’ ““ but this is the first one we’ve found that, when deleted, stops the animal from gaining weight,” said Saltiel, senior author of a paper to be published in the Sept. 4 edition of the journal Cell.

“The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising,” he said.

Obesity is associated with a state of chronic, low-grade inflammation that leads to insulin resistance, which is usually the first step in the development of Type 2 diabetes. In the Cell paper, Saltiel and his colleagues show that deleting, or “knocking out,” the IKKE gene not only protected high-fat-diet mice from obesity, it prevented chronic inflammation, a fatty liver and insulin resistance, as well.

The high-fat-diet mice were fed a lard-like substance with 45 percent of its calories from fat. Control mice were fed standard chow with 4.5 percent of its calories from fat. The dietary regimen began when the mice were 8 weeks old and continued for 14 to 16 weeks.

The gene IKKE produces a protein kinase also known as IKKE. Protein kinases are enzymes that turn other proteins on or off. The IKKE protein kinase appears to target proteins which, in turn, control genes that regulate the mouse metabolism.

When the high-fat diet is fed to a normal mouse, IKKE protein-kinase levels rise, the metabolic rate slows, and the animal gains weight. In that situation, the IKKE protein kinase acts as a brake on the metabolism.

Knockout mice placed on the high-fat diet did not gain weight, apparently because deleting the IKKE gene releases the metabolic brake, allowing it to speed up and burn more calories, instead of storing those calories as fat.

“The knockout mice are not exercising any more than the control mice used in the study. They’re just burning more energy,” Saltiel said. “And in the process, they’re generating a little heat, as well ““ their body temperature actually increases a bit.”

Saltiel’s team is now searching for small molecules that block IKKE protein-kinase activity. IKKE inhibitors could become candidates for drug development.

“If you find an inhibitor of this protein kinase, you should be able to obtain the same effect as knocking out the gene. And that’s the goal,” Saltiel said. If successful candidates are identified and drug development is pursued, a new treatment for obesity and diabetes is likely a decade away, he said.

First author of the Cell paper is Shian-Huey Chiang of the Life Sciences Institute. Co-authors are U-M researchers Merlijn Bazuine, Carey Lumeng, Lynn Geletka, Jonathan Mowers, Nicole White, Jing-Tyan Ma, Jie Zhou, Nathan Qi, Dan Westcott and Jennifer Delproposto. Timothy Blackwell and Fiona Yull of the Vanderbilt University School of Medicine also are co-authors.

The research was funded by the National Institutes of Health and the American Diabetes Association. All animal use was conducted in compliance with the Institute of Laboratory Animal Research’s Guide for the Care and Use of Laboratory Animals and was approved by the University Committee on Use and Care of Animals at the University of Michigan.

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On the Net:

• University of Michigan
• Life Sciences Institute
• Saltiel Lab
• Cell

Pigs might also be getting new vaccinations against the swine flu by the time cold weather brings the yearly influenza season.

The U.S. Department of Agriculture has given several animal vaccine manufacturers the “master seed virus” from the swine flu strain that is circulating among humans.  One of the companies said Wednesday that it is developing a vaccination for pigs that will contract the virus from infected people.

According to the Centers for Disease Control and Prevention, flu viruses can pass from a human to a pig mostly from coughing and sneezing.

 A pig vaccination for H1N1 would help livestock producers prevent their animals from catching the virus, as well as help derail the development of other flu strains.

Pigs are considered mixing vessels where the viruses mutate together into novel variations because of them being so susceptible to avian and human flu strains.

“Through that mutation they can become more virulent and could cause problems in humans,” said Dr. John Clifford, chief veterinarian for the USDA’s animal-health division. “Also, for pigs themselves, if the virus changes, current vaccinations may not work.”

The swine flu that has caused a pandemic alert around the world has not turned up in U.S. pig herds so far.  However, it has been found in herds in Canada, Argentina and Australia. 

Officials in Canada were the first to announce that the human H1N1 virus jumped from person to pigs on a farm in May.

Although there are enormous demands expected when the human swine flu vaccination is released this fall, it is still not determined how much demand there will be for a pig vaccination.  Clifford said the USDA would not require hog farmers to vaccinate against the human strain.  The USDA is responsible for approving any swine flu vaccination for pigs.

Officials are encouraging hog farmers to vaccinate their animals in response to any swine flu outbreaks in U.S. pig herds.

However, many farmers are pinching pennies right now because of the hog market being low.

Jerry Brink, a hog farmer in Elkader, Iowa, said he would not buy the vaccine unless there is an outbreak in the area surrounding his farm.

“The common thinking is, don’t vaccinate if you don’t have to,” Brink said.

Dan Warner of the National Pork Producers Council said that hog farmers also are accustomed to their animals getting the flu, and then getting over it fairly quickly with minimal damage.

“Pigs get the flu, it’s a regular thing and they get over it and they’re fine,” Warner said. The vaccine being developed, he said, “would just be an added expense they couldn’t afford.”

Vaccines for various swine flu strains have yet to hit the human population and are administered only to pigs that are already on the market.

Clifford would not identify which veterinary medicine manufacturers were working on the new vaccine, but Pfizer confirmed on Wednesday that it was working on one at its Lincoln, Nebraska plant.

Pfizer officials said the vaccine might go on the market by the normal start of flu season, but demand would be significantly dampened without a requirement for pigs to be vaccinated. 

“We wouldn’t require it,” Clifford said Wednesday. “If we start seeing a lot of cases in swine, we’d certainly encourage swine producers to use it.”

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On the Net:

• USDA
• CDC

A British prison inmate serving a life sentence for double murder won the right to have the country’s National Health Service remove his birthmark.

Denis Harland Roberts, an inmate at Durham’s Frankland Prison, went to court to seek laser surgery to remove a congenital birthmark from the left side of his face, The Daily Mail reported.

He said he received laser treatments, the last in 2007, that lightened and removed about 30 percent of the birthmark after a dermatologist cited not only the embarrassment it caused but also nodules he began developing.

Roberts contended his violent temper was linked to childhood bullying he endured because of the birthmark. He said after the most recent treatments stopped, he became depressed, and his attorney, Adam Sraw, said the depression caused his client’s violent temper to resurface.

Roberts’ case called attention to a British law that stipulates that inmates are entitled to the same medical services as any other Briton. But the law restricts inmates’ access to cosmetic and other non-urgent treatments.

Roberts was convicted in 1991 of breaking into an elderly couple’s home and stabbing them to death.

The REVISE Study (Reveal in the Investigation of Syncope and Epilepsy) found that 1 in 8 adult patients in the United Kingdom, previously thought to be suffering from epilepsy or in whom this diagnosis was in doubt, in fact had symptoms as a result of an abnormal pattern of heart beating, commonly found in patients with syncope (fainting).

REVISE is the first study to show that, by means of an implantable ECG recorder, 1 in 8 patients who were previously thought to have epilepsy or in whom this diagnosis was in doubt, have an abnormality in their heart rhythm as a cause of their symptoms. Eighty percent of those who underwent a pacemaker insertion based on the results of the ECG loop recorder were subsequently found to be free of their symptoms.

Four of the 5 patients who underwent a pacemaker as part of this study were subsequently free of symptoms. The average duration of follow-up was 9 months. This study was carried out at the Manchester Heart Centre, Manchester Royal Infirmary, Manchester, UK in collaboration with the Greater Manchester Centre for Neurosciences, Hope Hospital, Salford, UK. A small metallic device * about the size of a memory stick or a packet of gum, was used to record the heart rhythm of patients in this study. This device was inserted underneath the skin, on the left side of the chest in a small, low risk, 20 minute operation. Study patients also underwent a number of other brain and heart tests.

Previous scientific studies, mainly from the United Kingdom, have shown that up to 1 in 4 patients thought to be suffering from epilepsy do not actually have this condition. This conclusion was based on reviewing medical records of patients known to have epilepsy and on the results of the tilt table test, a test in which patients are made to stand at an angle of 60 degrees on a bed with a footboard support in an attempt to induce a blackout. Moreover, the All Party Parliamentary Group on Epilepsy, in their report published in June 2007, found that 74,000 patients in the United Kingdom were taking drugs for epilepsy, which they did not need. Patients with syncope (fainting) as well as epilepsy present with transient loss of consciousness (T-LOC) or ‘blackouts’. In some patients syncope (fainting) can mimic epilepsy. A temporary decrease in blood supply to the brain which occurs in syncope (fainting) can result in irritation of brain cells causing abnormal movements, which to a lay person can look very similar to epilepsy. In the general population, syncope (fainting) is much more common than epilepsy, affecting 25% of the population at any given time, more so in the elderly.

Patients symptomatic with T-LOC/’blackouts’ were considered for inclusion in this study if on review by the neurologists there was a suspicion of misdiagnosis of epilepsy or there was a doubt regarding the diagnosis. Patients had to have suffered at least 3 blackouts in the year before enrolment. In addition, they had to have had a normal or equivocal recording of their heart rhythm (standard ECG and an external recording for at least 24 hours), brain waves (EEG), a scan of the heart (echocardiogram) and of the brain (CT scan or MRI). Once included, all patients underwent a Reveal® Plus/Reveal® DX implant for monitoring their heart rhythm and tilt table testing. The study protocol allowed for treatment, based on the results of the implantable ECG monitor. The main aim of the study was to record the heart rhythm at the time of the patients symptoms of T-LOC/blackouts by means of the implantable ECG monitor. This study also aimed to determine the value of the tilt table test, a test commonly used in the investigation of patients with T-LOC/blackouts, in this group of patients.

Of the 119 patients screened, 40 were found suitable for inclusion in the study. Two thirds of patients were females and the average age was 39 years. The oldest patient in the study was 80 years of age. The implantable ECG monitor recorded a heart rhythm at the time of symptoms in two thirds of patients. Six patients were found to have an abnormal heart rhythm, viz. severe slowing of the heart beats, to the point of an absent heart rhythm, for a few seconds. In four other patients, the heart rhythm was found to slow but not as severely as the previous group. In 4 others, the implantable ECG monitor recorded signals due to muscle shaking in a pattern commonly seen in patients with epilepsy, thus giving the doctors a clue to the diagnosis. All but one of the six patients with severe slowing of the heart beats underwent a pacemaker. Four of the five (80%) who had pacemakers were subsequently free of symptoms over the following 9 months. Tilt table testing was positive in 5 of 40 patients. None of the patients with a positive tilt table test showed severe slowing of the heart rhythm on the implantable ECG monitor.

REVISE is the first study to show, that by means of an implantable ECG recorder, 1 in 8 patients who were previously thought to have epilepsy or in whom this diagnosis was in doubt, have an abnormality in their heart rhythm as a cause of their symptoms. Eighty percent of those who underwent a pacemaker insertion based on the results of the ECG loop recorder were subsequently found to be free of their symptoms. The implantable ECG loop recorder was also helpful in pointing towards a diagnosis of epilepsy by the pattern of the signals recorded on it. The findings of this small study will need confirmation in a larger group of patients.

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On The Net:

European Society of Cardiology

 Atrial fibrillation ablation is one of the fastest growing techniques in cardiology and due to the very high number of patients that might be candidates to this procedure, a significant number of resources will have to be devoted to it to be able to treat them in the following years.

Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia. Its prevalence increases with age affecting more than 5% of the population older than 75 years of age. Overall it is estimated that more than 3.000.000 patients in Europe suffer from atrial fibrillation. Atrial fibrillation doubles the possibility of death mainly due to the higher incidence of thromboembolic events and occurrence of heart failure in patients suffering this arrhythmia.

One treatment objective is directed to avoid the negative consequences of the arrhythmia by trying to maintain normal sinus rhythm. Two strategies exist to obtain this result:

1.    Chronic treatment with antiarrhythmic drugs (AAD)

2.    Catheter ablation of atrial fibrillation

1.    AAD treatment tries to block or modulate the electrical activity of the heart avoiding initiation and perpetuation of the arrhythmia. It is effective in about 60% of patients and requires long-term treatment. Many of the drugs used have side effects, some of them disabling for the patient. Many drugs are available and combination of them might be used in case of failure. Compliance of the treatment is basic for long-term success.

2.    Catheter ablation has emerged as an alternative to obtain stable sinus rhythm in this population. It has been demonstrated that a significant number of AFepisodes initiate in the area of the pulmonary veins located in the left atrium. Using one or several catheters inserted through the femoral veins, they are inserted into the heart and brought to the left atrium through a transseptal approach. Once in the left atrium energy (radiofrequency, cold) is delivered in different areas (mainly around the pulmonary veins) to create lesions that block the electrical activity responsible for the arrhythmia. The effectiveness of this technique is around 70% and in about 25% a second procedure is needed to finish the ablation lines. As any invasive procedure some major complications may occur like cardiac tamponade (1%), thromboembolic events (0.5%) or atrio-esophageal fistula (1/1000). In case of success the patient does not requires continuation with AAD and the arrhythmia is cured.

The decision of which treatment to be used will have to be based on a number of considerations: type of patient, willingness of the patient, experience of the centre in ablative techniques, etc.

It is estimated than more than 10.000 atrial fibrillation ablation procedures are performed annually in Europe and the number is increasing exponentially since over the last years availability of more sophisticated techniques and equipment has produced a marked increase in the number of centers performing atrial fibrillation ablation. Three dimensional mapping systems, robotic techniques, new energy sources and new and more reliable catheters are easing the procedure and improving efficacy and safety.

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On The Net:

European Society of Cardiology

Gene Signal, a company focused on developing innovative drugs to manage angiogenesis based conditions, today announced the publication of interim results from a phase II study suggesting that the antisense oligonucleotide GS-101 (eye drops) is safe and effective at inhibiting and regressing corneal neovascularisation (abnormal new blood vessel growth). Neovascularisation in this part of the eye is a major risk factor in corneal graft rejection, the most common transplantation procedure that saves the sight of approximately 46,000 people worldwide each year.

The data were published in the September 2009 issue of Ophthalmology by researchers led by Claus Cursiefen, MD, from the Department of Ophthalmology at the Friedrich-Alexander University Erlangen-Nrnberg, in Erlangen, Germany. Gene Signal is now conducting an international phase III trial with GS-101 for the prevention of pathologic corneal neovascularisation and thereby corneal graft rejection. GS-101 has been granted Orphan Drug status for this indication in Europe.

“Compared to the placebo group in which 100% of patients suffered from progression of corneal neovascularisation, the optimal GS-101 treatment group showed regression in 86% of patients. We are very encouraged by these results as they represent real progress in the development of GS-101 as a new treatment to combat corneal graft rejection,” explained Dr. Claus Cursiefen of the Department of Ophthalmology, Friedrich-Alexander University Erlangen-Nrnberg. “We urgently need new options for the thousands of graft recipients, whose current treatment options for threatened rejection such as immunosuppressants are not ideal due to side effects. GS-101 is the first specific angiogenesis inhibitor that has demonstrated activity at the anterior part of the eye, where numerous diseases associated with pathologic angiogenesis endanger vision.”

“The publication of these positive phase II results for GS-101 is a major milestone for Gene Signal. As a novel approach to the management of ophthalmic angiogenesis, we are keen to provide rigorous scientific backup to support our ongoing clinical development program. We also recently published data in the Journal of Pharmacology and Experimental Therapeutics confirming that GS-101 prevents in vivo expression of IRS-1, a protein associated with new blood vessel formation (angiogenesis), and we intend to present additional data on GS-101 at various scientific forums in the near future,” noted Eric Viaud, CEO of Gene Signal.

Study Data

The aim of this randomised, double-blind, multicenter phase II clinical study was to test the efficacy and tolerability of GS-101 (eye drops), an antisense oligonucleotide against insulin receptor substrate-1 (IRS-1), versus placebo, against progressive corneal neovascularisation (excessive or harmful angiogenesis). Forty patients non-responsive to conventional therapy participated in the study. Four groups of 10 patients were treated for three months comparing three doses of GS-101 (eye drops: 2x/day; 43, 86 and 172 ï­g/day total) to placebo (10 patients per group). The primary endpoint was measured by the reduction in area covered by pathologic corneal blood vessels measured morphometrically on digitised slit-lamp pictures using image analysis techniques.

Treatment with GS-101 was generally well tolerated, with no associated serious side effects. At 86 micro g/day GS-101 eye drops produced a significant inhibition and regression of corneal neovascularisation (-2.04 ±1.57% of total corneal area; p=0.0047). The low dose tended to stabilise growth (0.07±2.94; p=0.2088) compared to placebo (0.89±2.15), where corneal neovascularisation progressed in all patients in the 3 month period. The high dose of GS-101 was found to have no additional benefit.

About Corneal Grafts and GS101

Every year, approximately 46,000 corneal grafts are performed worldwide to cure or prevent blindness making this procedure the most frequently performed transplant surgery. However, the 5 year failure rate for corneal grafts is currently around 35%. As with many other graft procedures, donor grafts are always in limited supply, with waiting times for the procedure ranging from6 months to 2 years. One of the main reasons for graft failure is the natural immune response of the body.

Normally, the cornea is avascular, or deprived of blood and lymphatic vessels, protecting the donor cornea from being rejected. However, under certain circumstances, abnormal new blood vessel creation or neovascularisation occurs, inducing an immune response against the donor graft that can lead to immunological corneal graft rejection.

As currently there is no therapy available, Gene Signal is working on new ways to prevent this syndrome. With GS-101, its antisense oligonucleotide approach, which benefits from orphan designation in Europe, the company aims to block the pathways leading to the formation of blood vessels in the cornea. This approach uses short DNA fragments that specifically target and block the production of IRS-1, a protein required for the formation and growth of new blood vessels.

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On The Net:

Halsin Partners

Researchers at the Yerkes National Primate Research Center, Emory University, have demonstrated that prairie voles may be a useful model in understanding the neurochemistry of social behavior. By influencing early social experience in prairie voles, researchers hope to gain greater insight into what aspects of early social experience drive diversity in adult social behavior. The study is currently available online in a special edition of Frontiers in Behavioral Neuroscience that is focused on the long-term impact of early life experiences.

Prairie voles are small, highly social, hamster-sized rodents that often form stable, life-long bonds between mates. In the wild, there is striking diversity in how offspring are reared. Some pups are reared by single mothers, some by both parents (with the father providing much of the same care as the mother), and some in communal family groups.

Researchers Todd Ahern, a graduate student in the Emory University Neuroscience Program, and Larry Young, PhD, professor of psychiatry and behavioral sciences at the Yerkes Research Center and Emory University School of Medicine, compared pups raised by single mothers (SM) to pups raised by both parents (BP) to determine the effects of these types of early social environments on adult social behavior.

“Our findings demonstrate that SM- and BP-reared animals experienced different levels of care during the neonatal period and that these differences significantly influenced bonding social behaviors in adulthood,” says Ahern.

“These results suggest naturalistic variation in social rearing conditions can introduce diversity into adult nurturing and attachment behaviors. SM-raised pups were slower to make life-long partnerships, and they showed less interest in nurturing pups in their communal families,” says Young.

Researchers also found differences in the oxytocin system. Oxytocin is best known for its roles in maternal labor and suckling, but, more recently, it has been tied to prosocial behavior, such as bonding, trust and social awareness.

“Very simply, altering their early social experience influenced adult bonding,” says Ahern. Further studies will look at the altered oxytocin levels in the brain to determine how these hormonal changes affect relationships.

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On The  Net:

Emory University

Scientific dogma has long asserted that females are born with their entire lifetime supply of eggs, and once they’re gone, they’re gone. New findings suggest that in nematode worms, at least, this is not necessarily so.

Molecular physiologist Marc Van Gilst, Ph.D., and colleagues at Fred Hutchinson Cancer Research Center in Seattle report that during starvation, sexually mature adult worms stop ovulating and the germline component of their reproductive system ““ the sex cells, including mature and maturing eggs ““ dies off and leaves behind nothing but a few stem cells. However, once normal food conditions resume, the conserved stem cells can produce a brand new crop of sex cells, complete with youthful fertile eggs. This turning back of the reproductive clock took place in tiny C. elegans soil worms that were up to15 times older than worms in their reproductive prime that were fed normally.

“For many, it has been assumed that cells and organs remain relatively stable during periods of starvation or caloric restriction,” Van Gilst, an assistant member of the Hutchinson Center’s Basic Sciences Division, who authored the study with postdoctoral research fellow Giana Angelo, Ph.D is quoted as saying. “The idea that an entire system would kill itself off during starvation and then regenerate upon food restoration was very surprising. The fact that extremely old worms could generate new eggs and produce healthy offspring long after their normally fed counterparts had reproduced and died was also unexpected.”

The mechanism behind the preservation and extension of fertility long past the worms’ normal reproductive prime, Van Gilst suspects, is a signaling receptor protein in the cell nucleus called NHR-49, which promotes a major metabolic response to dietary restriction and fasting. While it has been hypothesized that this protein may interface with calorie restriction to extend life span, until now its role in protecting and extending reproductive longevity in the face of starvation had not been known. “In worms that contained an inactive NHR-49 gene, reproductive recovery and fertility after starvation were severely impaired,” he said. “We found that reproductive arrest and recovery are highly dependent on a functioning NHR-49 gene.”

NHR-49 in worms is analogous to various proteins in humans called nuclear receptors. Nuclear receptors, such as estrogen receptors and androgen receptors, are particularly good targets for pharmaceutical intervention. “The identification of a nuclear receptor that turns on and off the beneficial response to nutrient deprivation would be of great interest because it would be a candidate for drugs aimed at tricking the body, or specifically the reproductive system, into thinking they are calorically restricted or starved, even when food intake is normal,” Van Gilst said.

The biomedical implications of model organisms such as flies and worms cannot be overlooked, he said. “Many paradigm-shifting discoveries in C. elegans have since been replicated in humans.” he said. “Therefore, the idea that our findings will be relevant to human reproduction is a possibility that certainly needs exploration.”

Van Gilst was quick to point out, however, that even if this mechanism is conserved in humans, researchers still do not know the degree of caloric restriction that would be required to impact egg production in humans. “If such a process exists in humans, it likely evolved to help our ancestors preserve fertility during periods of famine or food shortage,” he said. “We certainly don’t have a prescription for famine. Consequently, our study should not be used to promote potentially dangerous interventions such as severe caloric restriction and starvation as a means to restore a woman’s fertility.”

In the meantime, Van Gilst and colleagues will continue to study the tiny worm to better understand the mechanisms that control fertility. One question their research may address is how women recovering from radiation and bone marrow transplant ““ which damages or destroys much of the germline, including mature and immature eggs ““ can regain their fertility.

“There is controversy over how this occurs,” Van Gilst said. “On the one hand, it has been argued that new eggs are generated from the woman’s germline stem cells through a process that may mirror the germline regeneration we observed in C. elegans. In fact, there is controversy over whether or not germline stem cells exist in adult women. We believe that our work in C. elegans throws another hat in the ring, raising the possibility that germline stem cells may indeed be present in women and that their activity may surface under conditions of nutrient deprivation or stress,” he said.

This work may also shed new light on cancer. “Cancer cells, when starved, are very susceptible to cell death. However, cancer stem cells, or progenitor cells, often thrive and flourish during starvation in cell-culture experiments. When nutrition is restored, these cells can trigger rapid regrowth,” he said. “Consequently, understanding how germline stem cells in C. elegans survive starvation may help appreciate how cancers survive treatments aimed at starving tumors.”

SOURCE: Science, August 27, 2009

Finding could offer insight into autism and other disorders

In a finding that sheds new light on the neural mechanisms involved in social behavior, neuroscientists at the California Institute of Technology (Caltech) have pinpointed the brain structure responsible for our sense of personal space.

The discovery, described in the August 30 issue of the journal Nature Neuroscience, could offer insight into autism and other disorders where social distance is an issue.

The structure, the amygdala””a pair of almond-shaped regions located in the medial temporal lobes””was previously known to process strong negative emotions, such as anger and fear, and is considered the seat of emotion in the brain. However, it had never been linked rigorously to real-life human social interaction.

The scientists, led by Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology and postdoctoral scholar Daniel P. Kennedy, were able to make this link with the help of a unique patient, a 42-year-old woman known as SM, who has extensive damage to the amygdala on both sides of her brain.

“SM is unique, because she is one of only a handful of individuals in the world with such a clear bilateral lesion of the amygdala, which gives us an opportunity to study the role of the amygdala in humans,” says Kennedy, the lead author of the new report.

SM has difficulty recognizing fear in the faces of others, and in judging the trustworthiness of someone, two consequences of amygdala lesions that Adolphs and colleagues published in prior studies.

During his years of studying her, Adolphs also noticed that the very outgoing SM is almost too friendly, to the point of “violating” what others might perceive as their own personal space. “She is extremely friendly, and she wants to approach people more than normal. It’s something that immediately becomes apparent as you interact with her,” says Kennedy.

Previous studies of humans never had revealed an association between the amygdala and personal space. From their knowledge of the literature, however, the researchers knew that monkeys with amygdala lesions preferred to stay in closer proximity to other monkeys and humans than did healthy monkeys.

Intrigued by SM’s unusual social behavior, Adolphs, Kennedy, and their colleagues devised a simple experiment to quantify and compare her sense of personal space with that of healthy volunteers.

The experiment used what is known as the stop-distance technique. Briefly, the subject (SM or one of 20 other volunteers, representing a cross-section of ages, ethnicities, educations, and genders) stands a predetermined distance from an experimenter, then walks toward the experimenter and stops at the point where they feel most comfortable. The chin-to-chin distance between the subject and the experimenter is determined with a digital laser measurer.

Among the 20 other subjects, the average preferred distance was .64 meters””roughly two feet. SM’s preferred distance was just .34 meters, or about one foot. Unlike other subjects, who reported feelings of discomfort when the experimenter went closer than their preferred distance, there was no point at which SM became uncomfortable; even nose-to-nose, she was at ease. Furthermore, her preferred distance didn’t change based on who the experimenter was and how well she knew them.

“Respecting someone’s space is a critical aspect of human social interaction, and something we do automatically and effortlessly,” Kennedy says. “These findings suggest that the amygdala, because it is necessary for the strong feelings of discomfort that help to repel people from one another, plays a central role in this process. They also help to expand our understanding of the role of the amygdala in real-world social interactions.”

Adolphs and colleagues then used a functional magnetic resonance imaging (fMRI) scanner to examine the activation of the amygdala in a separate group of healthy subjects who were told when an experimenter was either in close proximity or far away from them. When in the fMRI scanner, subjects could not see, feel, or hear the experimenter; nevertheless, their amygdalae lit up when they believed the experimenter to be close by. No activity was detected when subjects thought the experimenter was on the other side of the room.

“It was just the idea of another person being there, or not, that triggered the amygdala,” Kennedy says. The study shows, he says, that “the amygdala is involved in regulating social distance, independent of the specific sensory cues that are typically present when someone is standing close, like sounds, sights, and smells.”

The researchers believe that interpersonal distance is not something we consciously think about, although, unlike SM, we become acutely aware when our space is violated. Kennedy recounts his own experience with having his personal space violated during a wedding: “I felt really uncomfortable, and almost fell over a chair while backing up to get some space.”

Across cultures, accepted interpersonal distances can vary dramatically, with individuals who live in cultures where space is at a premium (say, China or Japan) seemingly tolerant of much closer distances than individuals in, say, the United States. (Meanwhile, our preferred personal distance can vary depending on our situation, making us far more willing to accept less space in a crowded subway car than we would be at the office.)

One explanation for this variation, Kennedy says, is that cultural preferences and experiences affect the brain over time and how it responds in particular situations. “If you’re in a culture where standing close to someone is the norm, you’d learn that was acceptable and your personal space would vary accordingly,” he says. “Even then, if you violate the accepted cultural distance, it will make people uncomfortable, and the amygdala will drive that feeling.”

The findings may have relevance to studies of autism, a complex neurodevelopmental disorder that affects an individual’s ability to interact socially and communicate with others. “We are really interested in looking at personal space in people with autism, especially given findings of amygdala dysfunction in autism. We know that some people with autism do have problems with personal space and have to be taught what it is and why it’s important,” Kennedy says.

He also adds a word of caution: “It’s clear that amygdala dysfunction cannot account for all the social impairments in autism, but likely contributes to some of them and is definitely something that needs to be studied further.”

Other coauthors of the paper, “Personal Space Regulation by the Human Amygdala,” are postdoctoral scholar Jan Gläscher and J. Michael Tyszka, the associate director of the Caltech Brain Imaging Center and director of Magnetic Resonance Physics. The work was funded by the National Institute of Mental Health, the Simons Foundation, the Della Martin Foundation, and a global Center of Excellence grant from Japan.

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Image Caption: Patient SM, a woman with complete bilateral amygdala lesions (red), preferred to stand close to the experimenter (black). On average, control participants (blue) preferred to stand nearly twice as far away from the same experimenter. Images drawn to scale. Credit: Nature Neuroscience/Dan Kennedy (Caltech)

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On the Net:

• California Institute of Technology
• Nature Neuroscience

Patients should forgo prolonged dental heroics — root canals — and replace bad teeth with dental implants, dentists say.

There really is no justification for undergoing multiple endodontic or periodontic procedures, and enduring the pain and financial burden, to save a diseased tooth, John Minichetti, a dentist with the American Academy of Implant Dentistry.

The days are over for saving teeth till they fall out. Preserving questionable teeth is not the best option from both oral health and cosmetic perspectives.

Even though patients often resist losing natural teeth, in many cases the best outcomes occur after extraction and inserting implants, Minichetti said.

Root canals can fail because abscesses occur and oral surgery is required to clean out the infected area, Minichetti said.

Minichetti said a recent study published in the Journal of Oral Implantology showed single-tooth dental implants are 98.5 percent successful after seven years, while the American Academy of General Dentistry found first-time root canals fail 5 percent of the time and at much higher rates in repeat procedures.

A new study has found that friends have a strong influence over whether teenagers move from merely experimenting with cigarettes to becoming full-fledged smokers.

The study showed that 58 percent of the 270 teenagers who had become occasional smokers made it a daily habit by 12th grade.

According to a study published in the journal Pediatrics, the likelihood of that happening depended partly on friends and parents.

Teens were also more likely to become smokers when friends or parents smoked.  However, they were less likely to become habitual smokers if their parents had a “positive family management” style, such as monitoring their comings and goings, doling out reasonable punishments for rule-breaking and rewarding good behavior.

Teens that had non-smoking parents who kept tabs on them were at a 31 percent risk of becoming daily smokers.  Teens that had parents who smoked and were also more lax in managing their kids’ behavior had a 71 percent chance of smoking.

“We found that parents play an important role in preventing teens’ smoking escalation from experimental to daily smoking,” lead researcher Dr. Min Jung Kim, a research associate at the University of Washington in Seattle, told Reuters Health in an email.

According to Kim, there are several ways parents can make a difference.

She said that if they smoke they should quit.  Also, she said parents should aim for “effective supervision and appropriate punishment or rewards for children’s behavior.”

Kim said this includes knowing your children’s friends and laying out rules for their behavior, like smoking.

“Parents need to make sure they establish clear guidelines in their families about smoking and discuss these with school-aged children,” Kim said.

Previous studies have shown that friends’ smoking habits are the best indicator on whether a teenager will become a regular smoker.  However, some researchers say that parents have relatively little influence once their kids hit adolescence.

According to the researchers, the current study suggests otherwise.  This study indicates that parents seem to have an important role in counteracting peer pressure.

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On the Net:

• Pediatrics

There are an estimated 7.6 million alcohol-related emergency department (ED) visits each year in the country. A first step in identifying an alcohol problem is screening all ED patients utilizing two well-researched screening tests. Once identified, one technique that has proven successful is motivationally-based brief interviews focused on reducing alcohol use. The research to date, however, has been focused on an academic medical environment and not within the more common environment of the community hospital ED, where 56 percent of all ED visits occur.

As a result, physicians and researchers at Rhode Island Hospital’s Injury Prevention Center set out to identify a model that could integrate screening and brief interventions (SBI) for alcohol misuse into a community hospital environment. The study was published in the August 2009 issue of the journal Substance Abuse. Their goal was to develop, implement and evaluate the adoption of a model of SBI, using feedback from the community hospital ED. This would then allow them to create a delivery method for the toolkit for SBI developed by the American College of Emergency Physicians (ACEP) and the National Highway Traffic Safety Administration.

Under the direction of lead author Michael Mello, MD, MPH, director of the Injury Prevention Center and an emergency medicine physician at Rhode Island and The Miriam hospitals, the researchers worked with Robert Dinwoodie, DO, MBA, an emergency medicine physician at Kent Hospital as a pilot site.

The project was divided into two phases over a year. The first phase involved meeting with key stakeholders to gather information and feedback on the SBI delivery model design and implementation. The feedback was then used to adapt the proposed SBI model design for the community hospital and train the staff. Phase two focused on the implementation and adoption of the SBI into the ED setting in the community hospital over a 6-month period. The research study design team included ED physicians, a clinical psychologist, experimental psychologist and project coordinator, along with a research assistant who was present in the ED to record the extent of adoption into the ED’s practice.

Mello says, “Our research identified numerous barriers, with key stakeholders expressing concern over potential disruption to the clinical practice and patient flow; the burden of SBI on staff time, particularly nurses; the willingness of nursing and physician staff to accept the SBI; and staff reluctance to speak to patients about alcohol-related issues when not directly related to a patient’s chief complaint. These are all understandable concerns.”

As a result, the SBI model was modified to address the concerns. The implementation was limited to an area of the ED for non-critical patients, active participation was limited to physicians only who would evaluate using the screening tool and then refer patients screening positive to a research assistant who would then perform the 5- to 10-minute brief intervention.

Prior to the adoption of the SBI model in the community hospital ED, a medical record review revealed that alcohol screening only occurred in 50 percent of patients, and of those, only 23 percent of the positive screens were referred for an alcohol intervention. In the study, during the time period when the research assistant was present in the ED, 90 percent of eligible patients were screened, and 71 percent of those patients were then evaluated by ED staff. Further, 38 percent of screened patients met the screening criteria, with 77 percent of the patients who met the criteria being correctly identified by ED staff and referred to the research assistant for the brief intervention. One month after the research assistant was no longer present in the ED, a repeat medical record review found documented alcohol screening had returned to the 50 percent level.

Dinwoodie, of Kent Hospital, says, “The research was done to look at the feasibility and impact of implementing an alcohol abuse screening and brief intervention program into a community hospital emergency department setting. The results of the study suggest that implementing such a program is possible by training staff such as emergency department nursing personnel, however, implementation will potentially be more successful if additional staff trained to conduct the screening and intervention are utilized.”

Mello and the researchers comment that the return of the alcohol screenings to the 50 percent level when the research assistant was no longer in the ED suggests that the program did not create a sustainable change. Mello says, “Our study shows, however, that with the appropriate training and tools, combined with additional resources devoted to this effort, SBI can be successfully transitioned and integrated into community hospital EDs. Additional research would help to further refine the SBI model so that it would work in different types of community hospitals.”

Mello concludes, “In the end, if the identified barriers can be overcome, we believe that a refined model will result in higher levels of screening for alcohol problems and appropriate referrals for help with many patients.”

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Lifespan

Resolvyx Pharmaceuticals, Inc., the leading resolvin therapeutics company, today announced positive data from a Phase 2 clinical study evaluating RX-10045, a resolvin administered as a topical eye drop for the treatment of patients with chronic dry eye syndrome. In this 28-day, randomized, placebo-controlled, 232-patient trial, RX-10045 produced dose-dependent, statistically significant improvement on the primary endpoints for both the signs and symptoms of dry eye, and was generally shown to be safe and well tolerated. These Phase 2 results represent the first demonstration of clinical efficacy for the novel class of resolvin compounds and suggest that resolvins have the potential to treat a broad range of inflammatory diseases.

“There is an urgent need for new treatment options in dry eye and the results of this Phase 2 study are as strong as any I have seen,” said Stephen Pflugfelder, MD, an expert in dry eye at Baylor College of Medicine. “Based both on these clinical results and on its unique mode of action, I am confident that RX-10045 can be an important new treatment modality for these patients.”

The 28-day, randomized, multi-center, placebo-controlled study in 232 patients with moderate dry eye patients was designed to evaluate the safety, tolerability and efficacy of RX-10045 administered twice daily. The Phase 2 study examined three doses of RX-10045 and utilized a controlled adverse environment (CAE) to measure corneal staining in a stressful drying environment, as well as daily patient diaries using a standard visual analog scale to assess symptom improvement over the course of the study.

RX-10045 produced a significant dose-dependent improvement from baseline in symptoms recorded in daily patient diaries. The improvement was observed across all symptoms evaluated in the study, including dryness, stinging, burning, grittiness, ocular discomfort and the composite of each patient’s most severe symptom (Worst Symptom Score). RX-10045 was superior to placebo on the primary symptomatic endpoint of Worst Symptom Score (p < 0.02), as well as on several individual symptoms. The onset of symptom relief occurred within the first week of treatment, and symptoms continued to improve over the course of the 28-day study, suggesting the potential for even greater benefit with longer treatment durations.

“I am very encouraged by the symptom relief achieved with RX-10045,” said Ira Udell, M.D., Chairman of the Department of Ophthalmology at the North Shore-Long Island Jewish Health System and Professor of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine. “Symptomatic improvement is what really matters to patients.”

RX-10045 also produced a 75% reduction from baseline in CAE-induced staining of the central cornea (p < 0.00001), the primary sign endpoint in the study. This improvement was greater than that observed for placebo, the difference approaching statistical significance (p = 0.11). RX-10045 also produced a significant improvement in CAE-induced staining in the inferior cornea and in the composite of central and inferior cornea, which also approached statistical significance over placebo (p = 0.09).

“We are very enthusiastic about the results of this Phase 2 study both as a demonstration of the potential of RX-10045 to treat dry eye patients and as the potential of the entire resolvin class to treat a range of inflammatory diseases,” said Greg Weinhoff, Executive Chairman of Resolvyx. “The results of this study will help Resolvyx design the pivotal trials for RX-10045, which are currently targeted to begin in the first half of 2010.”

Resolvyx is also currently conducting a Phase 1 study with a second resolvin, RX-10001, an orally-administered drug candidate for the treatment of systemic inflammatory diseases such as asthma, inflammatory bowel disease and other inflammatory diseases.

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Yates Public Relations

An indigenous family living in a mountainous area of Malaysian Borneo helped Van Andel Research Institute (VARI) researchers to discover information about genetic mutations associated with acromegaly, a form of gigantism that often results in enlarged hands, feet, and facial features.  
 
The information could lead to better screening for the disease, which most often results from a benign pituitary gland tumor that can be deadly if left untreated, but which is difficult to detect until later stages when features become pronounced.
 
Researchers located a 31-member aboriginal family that included individuals with acromegaly living in a mountainous region of Borneo, Malaysia when the effects of the family patriarch’s growing pituitary tumor necessitated medical treatment.  A medical team including VARI Distinguished Scientific Investigator Bin Tean Teh, M.D., Ph.D., and staff from the Department of Medicine at the University of Malaya Medical Centre and the Department of Medicine at the Queen Elizabeth Hospital in Malaysia subsequently traveled to the family’s village several times to collect blood samples for testing.
 
“Researchers had recently found a mutation in the AIP gene associated with acromegaly,” said Dr. Teh, “but we found that several family members who didn’t have visible symptoms of acromegaly had this mutation as well. This increases the importance of screening for families with cases of acromegaly since anyone could be a carrier.  On one side of the family, at least two generations carried the gene before someone showed any symptoms.”
 
The later stages of acromegaly often produce enlarged hands and feet, protruding brows and lower jaws, thick voice and slowed speech from swelling of vocal cords, and other symptoms.  When diagnosed, the tumor and entire pituitary gland are usually removed, followed by hormone therapy for the rest of the patient’s life.  However, because the progression of the disease is so gradual, it is difficult to detect.  If left unchecked, patients can die from complications such as heart or kidney failure. Well-known acromegalics include wrestler-actor Andr© the Giant and motivational speaker Tony Robbins. 
 
VARI Research Scientist and lead author of the study Sok Kean Khoo, Ph.D., led researchers in scanning DNA in the family’s blood to find other factors that might explain why only some family members with the genetic mutation had visible symptoms of the disease.  They found regions on a few chromosomes that might lead to further insight; these findings were published this week in the journal Endocrine-Related Cancer.
 
The prevalence of acromegaly is approximately 4,676 cases per million population, and the incidence is approximately 117 new cases per million per year.  However, Dr. Khoo said that the recent findings may mean that the prevalence is higher since carriers of the genetic mutation who do not have symptoms are not included.
 
“The sooner we know how and why people are affected differently by this disease, the sooner we can help families who have it,” said Dr. Teh.  “One of the women in this family was only 19 and probably thought that since her grandfather had lived so long with the disease, she would too.  She chose not to go to the hospital for treatment and, sadly, died two years after our last visit.”

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BCM