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New Drug Candidate Reduces Blood Lipids

Results of a recent clinical trial indicate that a thyroid-hormone-like substance that works specifically on the liver reduces blood cholesterol with no serious side effects. The trial was conducted by researchers from Sweden’s Karolinska Institute and collaborating institutions. Presently, high cholesterol levels in the blood are primarily treated with a group of drugs called statins, but these drugs are not always sufficiently effective and higher doses commonly cause adverse reactions. In this new clinical trial, researchers showed that a new thyroid hormone analogue called eprotirome can reduce blood cholesterol effectively in patients who have already received statins. Patients who were given supplementary medication with eprotirome demonstrated levels of harmful blood fats that were as much as 30 percent lower than those of patients who received a placebo supplementary treatment. "This drug could help patients who react adversely to statins or be used as a supplementary treatment for those who don't respond well to them," said Dr. Bo Angelin, who led the study. Eprotirome mimics the natural ability of thyroid hormone to stimulate the metabolism of cholesterol, and exerts its effects exclusively on the liver. The development of similar, non-selective drugs has previously been stopped on account of the serious adverse effects they have had on other organ systems (e.g., cardiac dilatation and osteoporosis) or on the physiological regulation of thyroid hormones. The new clinical trial results were published in the March 11, 2010 issue of the New England Journal of Medicine. [Press release] [NEJM abstract]

Familial Mutation Identified in African-Americans with Prostate Cancer

The first inherited mutation in African-American men with a family history of prostate cancer has been identified by researchers from Louisiana State University. "We detected this mutation only in African-American men with prostate cancer," noted senior author Dr. Shahriar Koochekpour. "We found it in the cell's androgen receptor (AR), a protein which interacts and responds to male sex hormones. This protein is profoundly involved in prostate cancer formation and its progression to an advanced metastatic, incurable stage. We believe that this mutation increases the risk of the development and progression of prostate cancer, in part by altering the receptor's DNA-binding ability, and by regulating the activities of other genes and proteins involved in the growth and aggressive behavior of tumors. We are hopeful that this discovery will eventually lead to a simple genetic test for prostate cancer for African-American men who are at high risk for developing prostate cancer, allowing genetic counseling and earlier, potentially life-saving treatment.” The authors noted that additional studies will be required to define the frequency and contribution of the mutation to early-onset and/or familial prostate cancer in African Americans. African-American men have a higher incidence and death rate from prostate cancer, as well as clinically more aggressive disease than Caucasians. According to the American Cancer Society's most current data for 2009-2010, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among American men. Between 2001 and 2005, the prostate cancer incidence rate was 59% higher in African-American men. African-American men also have the highest mortality rate for prostate cancer of any racial or ethnic group in the United States.

Green Tea May Help Protect Against Glaucoma and Other Eye Diseases

In a rat model, Hong Kong scientists have shown that powerful antioxidants in green tea can penetrate the eye, raising the possibility that the tea may help protect against glaucoma and other common eye diseases that may be related to oxidative stress. The authors point out that so-called green tea "catechins" have been among a number of antioxidants thought capable of protecting the eye. Until now, however, nobody knew if the catechins in green tea actually passed from the stomach and gastrointestinal tract into the tissues of the eye. In this new research, the scientists resolved this uncertainty in experiments with laboratory rats that drank green tea. Analysis of eye tissues showed beyond a doubt that eye structures absorbed significant amounts of individual catechins. The retina, for example, absorbed the highest levels of gallocatechin, while the aqueous humor tended to absorb epigallocatechin. The effects of green tea catechins in reducing harmful oxidative stress in the eye lasted for up to 20 hours. "Our results indicate that green tea consumption could benefit the eye against oxidative stress," the report concluded. This new research was published on January 19, 2010 in the Journal of Agricultural and Food Chemistry, an American Chemical Society publication. [Press release] [JAFC abstract]

New Form of Prion Disease Described

NIH scientists investigating how prion diseases destroy the brain have observed a new form of the disease in mice that does not cause the hole-filled, sponge-like brain deterioration typically seen in prion diseases. Instead, the disease resembles a form of human Alzheimer's disease, cerebral amyloid angiopathy, that damages brain arteries. The study results, reported by NIH scientists at the National Institute of Allergy and Infectious Diseases (NIAID), are similar to findings from two newly reported human cases of the prion disease Gerstmann-Straussler-Scheinker syndrome (GSS). The mouse findings represent a new mechanism of prion disease brain damage, according to study lead author Dr. Bruce Chesebro, chief of the Laboratory of Persistent Viral Diseases at the NIAID’s Rocky Mountain Laboratories in Montana. The role of a specific cell anchor for prion protein is at the crux of the NIAID study. Normal prion protein uses a specific molecule, glycophosphoinositol (GPI), to fasten to host cells in the brain and other organs. In their study, the NIAID scientists genetically removed the GPI anchor from study mice, preventing the prion protein from fastening to cells and thereby enabling it to diffuse freely in the fluid outside the cells. The scientists then exposed those mice to infectious scrapie and observed the mice for up to 500 days to see if they became sick. The researchers documented signs typical of prion disease including weight loss, lack of grooming, gait abnormalities, and inactivity. But when they examined the brain tissue, they did not observe the sponge-like holes in and around nerve cells typical of prion disease.

Desert Ant Uses Stereo Odor “Landscape” Detection in Navigation

The desert ant Cataglyphis fortis, which is native to the inhospitable salt-pans of Tunisia, is already well-known for its remarkable navigational abilities. It uses a sun compass along with a step counter and visible landmarks to locate its nest (a tiny hole in the desert ground) after foraging for food. Now, researchers at the Max-Planck Institute for Chemical Ecology in Germany have shown that these ants have another tool in their navigational toolbox. After the scientists recently discovered that these ants also use olfactory cues to pinpoint their nests, they conducted new experiments that revealed that the ants cannot only locate an odor source, but they also use the distribution of different odors in the vicinity of their nests in a map-like manner. The scientists found that the ants need both their antennae for this odor-guided navigation, that is, they smell the landscape scenery in stereo. "We conducted two key experiments," said Kathrin Steck, a Ph.D. student at the Institute. "First we marked four odor sources surrounding the nest entrance with the substances methyl salicylate, decanal, nonanal, and indole, and got the ants trained on them. If these four odor points were shifted away from the nest in the original arrangement, the ants repeatedly headed for the odors, even though the nest wasn't there anymore. If we rearranged the odor sources relative to each other, the ants were completely confused." Therefore the researchers assumed that ants do not "think" one-dimensionally--i.e., they do not associate the nest with only one smell--but multi-dimensionally, i.e., they relate an odor “landscape” to their nest. Spatial perception can easily be acquired if two separate sensory organs are available, such as two eyes for visual orientation. In the case of the ants, this would be their two antennae.

Blindness Gene Therapy in Second Eye Shown Safe in Animal Studies

Gene therapy for a severe inherited blindness disorder (Leber's congenital amaurosis or LCA), which produced dramatic improvements last year in twelve children and young adults who received the treatment in a clinical trial, has cleared another hurdle. The same research team that conducted the human trial has now reported that a study in large animals has shown that a second injection of the normal gene (RPE65) into the opposite, previously untreated, eye is safe and effective, with no signs of interference from unwanted immune reactions following the earlier injection. LCA is an autosomal recessive retinal disease that progresses to total blindness by adulthood and that can be caused by mutation in any one of a variety of different genes, including the RPE65 gene. Approximately 3,000 people in the United States are estimated to have the disease. In the current study, the research team found no evidence of toxic side effects in the blood or the eyes of the ten animals—six dogs and four monkeys—that received the gene therapy (with the normal RPE65 gene). Each animal received an injection first in the right eye, then in the left eye 14 days later. All six dogs, which had been specially bred to have congenital blindness, had improved vision, in addition to showing no toxic effects from the gene therapy. The monkeys, which were not blind, also showed no toxic effects from the therapy. These new findings suggest that LCA patients who benefit from gene therapy in one eye may experience similar benefits from treatment in the other eye. Researchers had exercised caution by treating only one eye in the human trial. "We designed this study to investigate the immunological consequences of administering the gene therapy injection to the second eye after treating the first one," said senior author Dr.

Two Dopamine Receptors Are Key to Ritalin Activity

Research reported by scientists from the University of California-San Francisco (UCSF) has shown that, in a rat model, Ritalin (methylphenidate) boosts both the ability to focus on tasks and the speed of learning by increasing the activity of the neurotransmitter dopamine through mechanisms involving two distinct dopamine receptors in the amygdala region of the brain. "We found that a dopamine receptor, known as the D2 receptor, controls the ability to stay focused on a task--the well-known benefit of Ritalin," said Dr. Patricia Janak, co-senior author of the paper. "But we also discovered that another dopamine receptor, D1, underlies learning efficiency." "Since we now know that Ritalin improves behavior through two specific types of neurotransmitter receptors, the finding could help in the development of better targeted drugs, with fewer side effects, to increase focus and learning," said Dr. Antonello Bonci, the other co-senior author of the article. The research assessed the ability of rats to learn that they could get a sugar water reward when they received a signal--a flash of light and a sound. The scientists compared the behavior of animals receiving Ritalin with those that did not receive it, and found those receiving Ritalin learned much better. However, they also found that if they blocked the dopamine D1 receptors with drugs, Ritalin was unable to enhance learning. And if they blocked D2 receptors, Ritalin failed to improve focus. The experiments established the distinct role of each of the dopamine receptors in enabling Ritalin to enhance cognitive performance.

Vaccine Protects Monkeys Against Chicamanguya Virus

Chicamanguya virus (CHIKV) is an insect-borne infectious agent that can cause severe disease in humans and against which there is presently no vaccine. This alphavirus has infected millions of people in Africa, Europe, and Asia since it reemerged in Kenya in 2004. The severity of the disease and the epidemic spread of the virus present a serious public health threat in the absence of vaccines or antiviral therapies. Although seldom fatal, infection with the virus causes highly painful arthritis-like symptoms that can linger for months or even years. CHIKV is capable of adapting to spread through a mosquito species common in much of North America. The virus has been the focus of intense scientific interest ever since a 2006 outbreak on the island of La Reunion in the Indian Ocean infected approximately 266,000 people, killing 260 of them. The name “chicamanguya” comes from an East African tribal word describing the contorted postures of the virus’s pain-wracked victims. Now, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and collaborators have reported development of a virus-like particle (VLP) vaccine that protects rhesus macaques against infection by CHIKV. "This vaccine did an excellent job of protecting the macaques from chikungunya," said Dr. Stephen Higgs, one of the paper's authors.

MicroRNA Binds Protein to Help Prevent Leukemia Progression

In an international study, researchers have discovered that loss of a particular microRNA (miR-328) appears to be a key factor in causing the progression of the more treatable chronic phase of chronic myelogenous leukemia (CML) to its life-threatening phase known as the “blast crisis” stage. The study indicates that CML progresses when immature white blood cells lose miR-328, trapping the cells in their rapidly growing, immature state. The cells soon fill the bone marrow and spill into the bloodstream, a tell-tale sign that the disease has advanced to the blast crisis stage. "These findings indicate that the loss of miR-328 is probably essential for progression from the chronic phase of the disease to the blast crisis stage," said principal investigator and senior author Dr. Danilo Perrotti of Ohio State University. "Our findings also suggest that maintaining the level of this microRNA might represent a new therapeutic strategy for CML blast crisis patients who do not benefit from targeted agents such as imatinib (Gleevec) and dasatinib (Sprycel)," Dr. Perrotti continued. The study also revealed a new function for microRNAs. Researchers have known for some time that microRNAs help regulate the kinds of proteins that cells produce by base-pairing with mRNA targets. But this study shows, reportedly for the first time, that microRNAs can also attach directly to proteins and alter their function. In this case, miR-328 binds to a protein (hnRNP E2) that normally prevents immature blood cells from maturing. "We believe that it [miR-328] normally acts as a decoy molecule, tying up the protein [hnRNP E2] and enabling the white blood cells to mature as they should," Dr. Perrotti said "These findings may help unravel novel pathways responsible for the initiation and progression of leukemia generally," Dr. Perrotti asserted.

Polar Bear Fossil Sequencing Yields Evolutionary History

In the complete sequencing of the mitochondrial genome of a rare ancient polar bear fossil, scientists have gained an understanding of the animal’s evolutionary history and its ability to adapt to changing environments. "Our results confirm that the polar bear is an evolutionarily young species that split off from brown bears some 150,000 years ago and evolved extremely rapidly during the late Pleistocene, perhaps adapting to the opening of new habitats and food sources in response to climate changes just before the last interglacial period," said Dr. Charlotte Lindqvist, research assistant professor in the Department of Biological Sciences at the University of Buffalo and co-lead author of the report. "We have found that polar bears actually survived the interglacial warming period, which was generally warmer than the current one," Dr. Lindqvist said, "but it's possible that Svalbard [the region in Norway in which the fossil was found] might have served as a refugium for bears, providing them with a habitat where they could survive. However, climate change now may be occurring at such an accelerated pace that we do not know if polar bears will be able to keep up. The polar bear may be more evolutionarily constrained because it is today very specialized; morphologically, physiologically, and behaviorally well-adapted to living on the edge of the Arctic ice, subsisting on a few species of seals." At an estimated 110,000 to 130,000 years old, "this is, by far, the oldest mammal mitochondrial genome to be sequenced," said Dr. Stephan Schuster, from Penn State's Center for Comparative Genomics and Bioinformatics and co-lead author of the report. "It's about twice the age of the oldest mammoth genome that has, to date, been sequenced."

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