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Archive - Oct 2011

October 26th

Advance Toward Simple Breath Test for Multiple Sclerosis

Scientists from Israel, together with collaborators, are reporting the development and successful tests in humans of a sensor array that can diagnose multiple sclerosis (MS) from exhaled breath, an advance that the researchers describe as a landmark in the long search for a fast, inexpensive, and non-invasive test for MS -- the most common neurological disease in young adults. The report was published online on September 22, 2011 in the journal ACS Chemical Neuroscience. In the article, senior author Dr. Hossam Haick and colleagues report that doctors now diagnose MS based on its characteristic symptoms, which include muscle spasms, numbness, coordination problems, and slurred speech. One common tool for confirming the diagnosis and making informed decisions on treatment is magnetic resonance imaging (MRI) of the brain. Another tool is a lumbar puncture or "spinal tap" to analyze the fluid that bathes the brain and spinal cord. MRI scans, however, are costly, and lumbar punctures are invasive. To overcome these obstacles, the researchers have identified volatile organic compounds from exhaled breath that can be associated with MS. Based on these findings, the researchers developed a new sensor array that can diagnose MS by analyzing the determined chemical compounds that appear in the breath of MS patients. Using the sensors, the researchers carried out a proof-of-concept clinical study on 34 MS patients and 17 healthy volunteers and found that the sensors are just as accurate as a spinal tap, but without the pain or the risk of side effects. "The results presented here open new frontiers in the development of fast, noninvasive, and inexpensive medical diagnosis tools for detection of chronic neurological diseases," the scientists stated.

Nature Study Identifies Genetic Basis of Human Metabolic Individuality

In what is so far the largest investigation of its kind, researchers have uncovered a wide range of new insights about common diseases and how they are affected by differences between two persons' genes. The results from this study could lead to highly targeted, individualized therapies. Led by researchers from Weill Cornell Medical College-Qatar and published in the September 1, 2011 issue of Nature, the study provides details on the genetics behind many diseases, including cardiovascular and kidney disorders, diabetes, cancer, gout, thrombosis, and Crohn's disease, and elucidates the role that individual differences in metabolism play in these disorders. Disturbances in metabolism are at the root of a variety of human afflictions and complex diseases. Although many of the genes that contribute to these conditions have been identified since the completion of the Human Genome Project in 2003, it is still not known how metabolic disorders related to these genetic aberrations disrupt cellular processes. One hundred years ago, Dr. Archibald Garrod, one of the fathers of modern biochemistry, realized that inborn errors in human metabolism are "merely extreme examples of variations of chemical behavior which are probably everywhere present in minor degrees" and that this "chemical individuality [confers] predisposition to and immunities from the various mishaps which are spoken of as diseases." Ever since, identification of the genetic basis of human chemical individuality has been elusive. Now researchers have addressed this challenge by using a new technology, called metabolomics. They measured the levels of more than 250 biochemical compounds in over 60 metabolic pathways, including lipids, sugars, vitamins, amino acids and others in blood from over 2,800 individuals.

October 25th

Protein Panel Predicts Mortality in Idiopathic Pulmonary Fibrosis

A panel of blood proteins can predict which patients with the progressive lung disease idiopathic pulmonary fibrosis (IPF) are likely to live at least five years or to die within two years, say researchers at the University of Pittsburgh School of Medicine and Centocor R&D. The findings, published online on October 20, 2011 in the American Journal of Respiratory and Critical Care Medicine, could help doctors determine those patients in imminent need of a lung transplant and those who can wait a while longer. Fifty percent of IPF patients die within three years of diagnosis, but others will do well for long periods of time, explained investigator Dr. Naftali Kaminski, professor of medicine, pathology, human genetics, and computational biology, Pitt School of Medicine, and director, The Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease at the University of Pittsburgh Medical Center (UPMC). In the disease, breathing becomes increasingly impaired as the lungs progressively scar. "It's hard to tell based on symptoms alone which patients are in the greatest danger," Dr. Kaminski said. "This biomarker panel has predictive power that can guide our treatment plan. It may also help us design more effective research trials because we'll be able to better match experimental therapies with the most appropriate patients." The research team collected blood samples from 241 IPF patients. They measured the levels of 92 candidate proteins in 140 patients and found that high concentrations of five particular proteins that are produced by the breakdown of lung tissue predicted poor survival, poor transplant-free survival, and poor progression-free survival regardless of age, sex, and baseline pulmonary function. They then confirmed the results in a second group of 101 patients.

Junk DNA May Underlie Major Differences Between Humans and Chimps

For years, scientists believed the vast phenotypic differences between humans and chimpanzees would be easily explained – the two species must have significantly different genetic makeups. However, when their genomes were later sequenced, researchers were surprised to learn that the DNA sequences of human and chimpanzee genes are nearly identical. What then is responsible for the many morphological and behavioral differences between the two species? Researchers at the Georgia Institute of Technology (Georgia Tech) have now determined that the insertion and deletion of large pieces of DNA near genes are highly variable between humans and chimpanzees and may account for major differences between the two species. The research team led by Georgia Tech Professor of Biology John McDonald has verified that while the DNA sequence of genes between humans and chimpanzees is nearly identical, there are large genomic “gaps” in areas adjacent to genes that can affect the extent to which genes are “turned on” and “turned off.” The research shows that these genomic “gaps” between the two species are predominantly due to the insertion or deletion (INDEL) of viral-like sequences called retrotransposons that are known to comprise about half of the genomes of both species. The findings were published October 25, 2011, in the online, open-access journal Mobile DNA. “These genetic gaps have primarily been caused by the activity of retroviral-like transposable element sequences,” said Dr. McDonald. “Transposable elements were once considered ‘junk DNA’ with little or no function. Now it appears that they may be one of the major reasons why we are so different from chimpanzees.” Dr.

Transcription Factor SP4 Found Reduced in Bipolar Disorder

Low levels of a brain protein that regulates gene expression may play a role in the origin of bipolar disorder, a complex and sometimes disabling psychiatric disease. As reported in the August-September 2011 issue of Bipolar Disorders, the journal of The International Society for Bipolar Disorders, levels of SP4 (specificity protein 4) were lower in two specific regions of the brain in postmortem samples from patients with bipolar disorder. The study suggests that normalization of SP4 levels could be a relevant pharmacological strategy for the treatment of mood disorders. "We found that levels of SP4 protein in the brain's prefrontal cortex and the cerebellum were lower in postmortem samples from patients with bipolar disorder, compared with samples from control subjects who did not have the disease," said co-senior author Dr. Grace Gill, an associate professor in the department of anatomy and cellular biology at Tufts University School of Medicine and a member of the neuroscience; genetics; and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts. Dr. Gill's laboratory team at Tufts collaborated with researchers from Spain and used postmortem samples from Spain's University of the Basque Country brain collection program to examine SP4 protein levels in samples from 10 bipolar subjects and 10 control subjects matched for gender, age, and time since death. The team focused on the prefrontal cortex and the cerebellum because brain imaging studies suggest that bipolar disorder is associated with changes in the structure of these brain regions. Little is known about the cellular and molecular changes that occur in bipolar disorder, especially in the cerebellum.

October 24th

Rare Gene Mutation Associated with High Risk of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of severe visual loss among the elderly. Researchers had previously identified several relatively common genetic variants which together predict a person's increased risk for AMD, but a significant number of persons without the disease also have these variants. Now, for the first time, investigators have been able to clearly show a specific rare mutation called CFH R1210C that predicts a very high risk of AMD and is extremely uncommon among individuals who do not have the disease. Although it is a rare variant, accounting for about 1% of the total cases, it is highly related to familial disease and earlier age of onset. This research was published online on October 23, 2011 in Nature Genetics. The paper is a collaborative effort among investigators from Tufts Medical Center, Tufts University School of Medicine; Brigham and Women's Hospital; Massachusetts General Hospital; Duke University; and Johns Hopkins University. "Our paper shows that there is a genetic variant that confers high risk of the development of AMD; this finding not only clearly links CFH gene dysfunction to disease, but also might help to identify people who need to be screened more closely," said first author, Dr. Soumya Raychaudhuri, a researcher in the Divisions of Genetics and Rheumatology at Brigham and Women's Hospital and an Assistant Professor of Medicine at the Harvard Medical School. Prior to this publication, it was known that genetic variation within the CFH gene influenced risk of AMD in individuals. In the current study, researchers conducted sequencing and genotyping of CFH in 2,423 AMD cases and 1,122 controls in the laboratory of senior author Dr. Johanna M.

Nature Study Illuminates DNA Repar in Cancer Cells

An international team of scientists led by University of California (UC) Davis researchers has discovered that DNA repair in cancer cells is not a one-way street as previously believed. Their findings show instead that recombination, an important DNA repair process, has a self-correcting mechanism that allows DNA to make a virtual u-turn and start over. The study's findings, which appeared online on October 23, 2011 in Nature, not only contribute new understanding to the field of basic cancer biology, but also have important implications for potentially improving the efficacy of cancer treatments. "What we discovered is that the DNA repair pathway called recombination is able to reverse itself," said Dr. Wolf-Dietrich Heyer, UC Davis professor of microbiology and of molecular and cellular biology and co-leader of Molecular Oncology at the UC Davis Cancer Center. "That makes it a very robust process, allowing cancer cells to deal with DNA damage in many different ways. This repair mechanism may have something to do with why some cancer cells become resistant to radiation and chemotherapy treatments that work by inducing DNA damage." Dr. Heyer likens this self-correcting ability of the DNA repair system to driving in a modern city where u-turns and two-way streets make it easy to rectify a wrong turn. "How much harder would it be to re-trace your path if you were in a medieval Italian city with only one-way streets," he said. In the current study, Dr. Heyer and his colleagues used yeast as a model system to elucidate the mechanisms of DNA repair. They expect their findings, like most that come out of work on yeast, will be confirmed in humans. "Whether in yeast or humans, the pathways that repair DNA are the same," Dr. Heyer said. The research team used electron microscopy to observe repair proteins in action on strands of DNA.

October 23rd

Evolutionary Computing Used to Identify Potentially Effective Drug Combinations

University of Manchester researchers and colleagues have found a way to identify potentially ideal drug combinations (from billions of others) that would prevent inflammation from occurring. The findings, published online on October 23, 2011 in Nature Chemical Biology, could be the first step in the development of new drug combinations to combat severe diseases and conditions. Most non-infectious disease, such as cancer, stroke, and Alzheimer's are worsened by inflammation, which is the body's natural defense mechanism. Inflammation has evolved to help fight infection but can also be very damaging in long-term disease, prolonging suffering and ultimately possibly contributing to premature death. After a stroke, the body reacts to the injury as if it were an infection, causing further damage. By blocking the inflammation, the chances of survival or higher quality of life following a stroke are greatly enhanced. This can be achieved by quickly and effectively identifying combinations of drugs that can be used together. Existing 'clot-busting' stroke drugs are only effective if administered within three hours after the stroke – often very difficult to achieve as people are often unaware they are having a stroke – and even then do not completely solve the problem, often leaving sufferers with serious disabilities. However, using ideal drug combinations the researchers suggest they can block inflammation and therefore greatly reduce the damage caused by non-communicable diseases such as stroke. Although the researchers have initially concentrated on stroke, they believe the process can be applied to all drugs and for a huge variety of diseases.

Femtosecond Laser Could Revolutionize Cataract Surgery

Two new studies add to the growing body of evidence that a new approach to cataract surgery may be safer and more efficient than today's standard procedure. The new approach, using a special femtosecond laser, is FDA-approved, but not yet widely available in the United States. It's one of the hottest topics at the 115th Annual Meeting of the American Academy of Ophthalmology. Research reported on October 23, 2011, by Dr. William W. Culbertson, of the Bascom Palmer Eye Institute at the University of Miami School of Medicine, and by Dr. Mark Packer, of Oregon Health and Sciences University, confirms several advantages of laser cataract surgery. Dr. Culbertson's team studied how pre-treating cataracts with the femtosecond laser affected the level of ultrasound energy needed to soften the cataracts. This emulsification is performed so that the cataracts can be easily suctioned out. Surgeons want to use the lowest possible level of ultrasound energy, since in a small percentage of patients it is associated with slower recovery of good vision after surgery and/or problems with the cornea, which is the clear outer layer of the eye. Ideally, in appropriate cases, ultrasound use would be eliminated altogether. In Dr. Culbertson's prospective, randomized study, 29 patients had laser cataract surgery with a femtosecond laser in one eye and the standard cataract procedure, called phacoemulsification, in the other. Laser surgery included: a laser capsulotomy, which is a circular incision in the lens capsule, followed by laser lens fragmentation, then ultrasound emulsification and aspiration. Lens fragmentation involved using the laser to split the lens into sections and then soften it by etching cross-hatch patterns on its surface.

Engineered Protein Shows Promise As Therapy for Hemophilia

A genetically engineered clotting factor that controlled hemophilia in an animal study offers a novel potential treatment for human hemophilia and a broad range of other bleeding problems. The researchers took the naturally occurring coagulation factor Xa (FXa), a protein active in blood clotting, and engineered it into a novel variant that safely controlled bleeding in mouse models of hemophilia. "Our designed variant alters the shape of FXa to make it safer and efficacious compared to the wild-type factor, but much longer-lasting in blood circulation," said study leader Dr. Rodney A. Camire, a hematology researcher at The Children's Hospital of Philadelphia. "The shape of the variant FXa changes when it interacts with another clotting factor made available following an injury," added Dr. Camire. "This increases the functioning of the protein which helps stop bleeding." Dr. Camire is an associate professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania. The study appeared online on October 23, 2011 in Nature Biotechnology, and will be published in the journal's November 2011 print issue. In hemophilia, an inherited single-gene mutation impairs a patient's ability to produce a blood-clotting protein, leading to spontaneous, sometimes life-threatening bleeding episodes. The two major forms of the disease, which occurs almost solely in males, are hemophilia A and hemophilia B, characterized by which specific clotting factor is deficient. Patients are treated with frequent infusions of clotting proteins, which are expensive and sometimes stimulate the body to produce antibodies that negate the benefits of treatment. Roughly 20 to 30 percent of patients with hemophilia A and 5 percent of hemophilia B patients develop these inhibiting antibodies.