Notebook

Contents Trial veteran Resistance in rivers I contain multitudes Chlamydia in heart disease Tomatoes vs. armyworms Look, Ma, no paws Peroxide damage Philip Brunell receives the first injection at NIH of the experimental shingles vaccine from nurse Patricia Hohman. TRIAL VETERAN When Philip Brunell received the first shingles vaccination in a Phase III trial June 17, it was not exactly a shot in the dark. The senior attending physician at the National Institutes of Health clinical center estimates he's been injected in the name of science 20-30 times. "Whenever we've had a vaccine trial and I've been eligible, I've taken the first dose." The National Institute of Allergy and Infectious Diseases trial tests a more potent version of the vaccine used to immunize children against the chicken pox to cause an immune response against varicella-zoster virus (VZV). VZV causes both shingles and chicken pox. The virus remains dormant in nerve cells by the spinal cord after a case of chicken pox. Reactivating it results in shingles, characterized by an outbreak of rash or blisters as well as burning, tingling, or shooting pain. The 68-year-old scientist hopes the vaccine helps him avoid shingles, which is especially prominent in people over 60. Several hundred thousand people are diagnosed with the disease each year. Although skin symptoms usually heal within weeks, the pain (called postherpetic neuralgia) sometimes lasts for years. But once people have had shingles, they seldom have a recurrence. "We believe that by boosting the body's immune response with this vaccine, mimicking a naturally occurring case of zoster, shingles and postherpetic neuralgia may be prevented," Norberto Emilio Soto, principal of the study, comments. The five-year study involves about 20 medical centers and about 37,000 volunteers. --Paul Smaglik RESISTANCE IN RIVERS A recent survey of 15 U.S. rivers at 21 different sites found widespread antibiotic-resistant bacteria, according to a study presented at the June 3 American Society for Microbiology General Meeting in Chicago. (R.J. Ash et al., "Antibiotic-resistant bacteria in U.S. rivers," American Society for Microbiology, May 30-June 3, 1999). While nearly all of the microbes cultured were common soil organisms, they may be capable of donating resistance genes to other bacteria, including human pathogens, according to lead author Ronald Ash, a professor of biology at Washburn University in Topeka, Kan. All of the rivers tested, from the Hudson River in Harlem, N.Y., to the Colorado in Glenwood Springs, Colo., contained ampicillin-resistant bacteria, some as high as 59 percent of the total population. Many of these bacteria were resistant to at least one other widely used antibiotic. Although it is possible that the bacteria picked up resistance genes from animal or human waste runoff, Ash said, "Many of the organisms we cultured were soil microbes that have developed resistance genes to naturally occurring soil antibiotics." What concerns Ash, however, is the fact that 40 percent of the multidrug-resistant bacteria isolated had plasmids that could potentially transfer resistance to human pathogens. Ash and his colleagues are characterizing the plasmids to determine whether they carry resistance genes that can be readily transferred to human pathogens or gut flora. --Sara Latta I CONTAIN MULTITUDES Walt Whitman might not have known much about microbiology, but he was right on the mark when he wrote, "I am large, I contain multitudes." Not only does the human gut contain multitudes of microbes--around 10 14, in fact--it turns out that most of them are complete strangers. Antonia Suau and her colleagues at the Institut National de la Recherche Agronomique (INRA) in Jouy-en-Josas, France, and at the University of Reading, United Kingdom, found that only 25 percent of the microorganisms in the fecal sample of a healthy 40-year-old man corresponded to previously described organisms. Suau, a graduate student at INRA, presented the results of her study at a poster session at the American Society for Microbiology General Meeting in Chicago. (A. Suau et al., "Phylogenetic analysis of 16s rRNA genes indicates that 75% of the human intestinal flora is unknown," American Society for Microbiology, May 30-June 3, 1999). Using techniques commonly employed by microbial ecologists to identify hard-to-culture organisms, Suau and her colleagues used PCR to generate 383 bacterial ribosomal RNA clones. Most fell into three known bacterial groups (Bacteriodes, Clostridium coccoides, and Clostridium leptum). Even so, the sequences of a whopping 75 percent of them diverged by greater than 2 percent from any known species. "We've missed them all along because we just didn't know how to culture them," said Suau, who says that is just what she and her colleagues intend to do. --Sara Latta CHLAMYDIA IN HEART DISEASE There's growing evidence that Chlamydia pneumoniae, a bacterium that commonly causes respiratory illness in teens and young adults, may pack a double whammy, initiating or at least contributing to heart disease. Patients with coronary artery disease are significantly more likely to have been infected with C. pneumoniae than those without, and the organism is frequently concentrated in atherosclerotic lesions. But the mechanism by which C. pneumoniae causes disease--if indeed it does--remains a mystery. Now James B. Mahony and Brian K. Coombes have found that C. pneumoniae-infected endothelial cells release a factor that causes smooth muscle cells to proliferate (B.K. Coombes, J.B. Mahony, "Chlamydia pneumoniae infection of human endothelial cells induces proliferation of smooth muscle cells via an endothelial cell-derived soluble factor(s)," Infection and Immunity, 67 [6]:2909-15, June 1999). "We know that bacterial LPS [lipopolysaccharide, a component of gram-negative bacterial cell walls] triggers macrophages to take up oxidized LDL [low-density lipoprotein] and form foam cells--so called because they swell up and look, well, foamy," says Mahony. Smooth muscle cells become foamy, too, although the trigger is not as well understood. Given that even dead Chlamydia can induce endothelial cells to release the factor or factors, LPS might be a good bet. "We're going to see if Chlamydia lipopolysaccharide induces smooth muscle cells to become foam cells, activated, and to migrate." --Sara Latta TOMATOES VS. ARMYWORMS Tomato plants fight back against leaf-munching caterpillars by producing jasmonic acid, a hormone that stimulates production of protease inhibitors, which dismantle herbivores' digestive enzymes. Jennifer Thaler, a postdoctoral fellow at the University of California, Davis, has learned that the plant also takes a more subtle tack against the insect--calling in the caterpillars' natural enemy, the parasitic wasp (J.S. Thaler, "Jasmonate-inducible plant defences cause increased parasitism of herbivores," Nature, 399:686-8, June 17, 1999). In initial experiments, she monitored 103 field plots of tomato plants, half sprayed with jasmonic acid, half with water. Armyworms arrived on the scene. Three weeks later, the treated plants had twice as many wasps as did the untreated plants. But to show that the plants had actively beckoned the wasps, as opposed to the wasps being more successful at parasitizing armyworms weakened by protease inhibitors, Thaler needed another test. In the next experiments, the caterpillars were fed an artificial diet in the lab and then placed in plastic cups in the field so they had no contact with the plant or the nasty chemicals in the plant. A day after the cups were set out, "sentinel caterpillars" beneath the jasmonic acid-treated tomato plants had 37 percent more visits by parasitic wasps seeking bodies to deposit their eggs in than did caterpillars near untreated plants. "Differences in [the number of wasps on] induced and control plants were due to differences in the plants themselves, not due to differences in the quantity or quality of the herbivores feeding on these plants," Thaler explains. --Ricki Lewis LOOK, MA, NO PAWS A recent demonstration of rat brainpower may be an important early step toward the development of more advanced prosthetic devices for victims of paralysis. Researchers at Duke University and MCP Hahnemann University in Philadelphia have for the first time used simultaneously recorded neurons to control a simple robotic device in real time (J.K. Chapin et al., "Real-time control of a robot arm using simultaneously recorded neurons in the motor cortex," Nature Neuroscience, 2 :664-70, July 1999). Although similar previous studies employed electroencephalogram recordings to control robotic devices, this is the first to use the intrinsic brain circuits responsible for the desired task. Six rats were first trained to obtain water by pressing a lever. Scientists then recorded neuronal activity in the rat brains using electrodes. In the rats with the highest numbers of recorded neurons, researchers were able to reconstruct a neural population code for the animals' normal learned movement. Investigators then essentially flipped a switch so that the robot arm was controlled via the rat brain rather than the animal's arm. Four of the six rats were able to control the device with enough accuracy to regularly obtain water using their brains alone. "What we would like to do [eventually] ... is to allow a paralyzed person to reach out [an] arm and grasp something, manipulate it," says lead author John Chapin, a professor of neurobiology at Hahnemann. "But that's a long way off." Investigators will next attempt similar experiments in monkeys; they'll also try to improve the technology so that they're able to record the activity of enough neurons to facilitate robotic movement in three dimensions. --Eugene Russo PEROXIDE DAMAGE Scientists at Harvard Medical School have added a new piece to the Alzheimer's disease puzzle. ß-amyloid protein plaques are found in the brains of Alzheimer's patients upon autopsy. However, how the plaques are related to the neural degeneration associated with the disease is still a mystery. Ashley I. Bush, director of the Laboratory for Oxidation Biology, and his colleagues suggest a new mechanism for explaining how Alzheimer's disease damages the brain (X. Huang et al., "The Aßpeptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction," Biochemistry, 38 :7609-16, June 15, 1999). Previous research found that zinc, copper, and iron ion concentrations are elevated in the gray matter of Alzheimer's-affected brains and specifically in the amyloid deposits. Bush explains, "Since the Aßpeptide, the subunit that makes up amyloid, recruits metal ions, [we saw the potential] for a number of reduction-oxidation reactions to occur. The neurotoxic properties of Aßpeptides might be mediated by [their] interaction with metal ions." The paper shows synthetic Aßpeptide has the ability to bind copper or iron ions and synthesize hydrogen peroxide out of oxygen. Hydrogen peroxide has previously been detected in laboratory cell cultures exposed to synthetic amyloid plaques, but researchers assumed some reaction within the dying cells produced the substance. This is the first indication that the plaques may make hydrogen peroxide, which could cause oxidative brain injury. The Harvard researchers went on to show chemicals interrupting metal ion binding with Aßpeptides inhibit hydrogen peroxide production, suggesting a new therapeutic approach to Alzheimer's disease. Experiments on hydrogen peroxide production are now being done in cell cultures and animal models. --Nadia S. Halim

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Paul Smaglik

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July 1999

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