Research Notes

Editor's Note: This is an extended version of the Research Notes that appeared in the print edition of The Scientist. A CF-Sinusitis Connection Some sufferers of chronic sinusitis can attribute their debilitating headaches to carrying a mutation in the cystic fibrosis (CF) gene, according to striking results from a study at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine (XinJing Wang et al., "Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population," Journal of the American Medical Association, 284[14]:1814-9, Oct. 11, 2000). CF is a disruption in the chloride channel protein CFTR, resulting in the buildup of secretions in the lungs, pancreas, and elsewhere. The clue to a link between the inherited illness and the much more common sinusitis came from 15 years of observations on people with mild cases of CF. "Just about every patient with CF has severe sinus disease. As we began to study patients with milder 'flavors' of CF-those who do not require supplemental pancreatic enzymes, or those with less prominent chloride elevations in their sweat, or patients with very mild lung disease-we found that even with increasing levels of functional CFTR protein, the patients still have sinus disease," explains professor of pediatrics and medicine Garry Cutting. If CF patients universally have sinusitis, he and his co-workers hypothesized, might carriers of CF, with just one mutant copy of the gene, perhaps also suffer from sinusitis? To find out, they tested patients from an otolaryngology clinic for CF status. The speed with which the link emerged surprised the researchers-7 percent of the first 147 patients carried a mutant CF gene variant. Identifying the connection between CF carrier status and sinusitis may have repercussions for many. "Drugs developed to augment CFTR function might be useful against sinusitis, in carriers and possibly others as well. And vice versa, drugs that treat sinusitis in the general population might be helpful in treating CF. It is a two-way street," says Cutting. The study also suggests that standard approaches to treating sinusitis may be inappropriate for CF carriers, with their distinctive disruptions in electrolyte secretion. At least one patient so far has avoided unnecessary surgery, thanks to this new way of looking at a common condition. "We had one patient who was about to undergo his twelfth surgery. He had always felt that there was something more wrong with him than abnormal sinus anatomy. I was able to consult the protocol, and found out that he indeed had a mutation for the CF gene," Cutting relates. Although routine gene screening of the hordes with painful sinuses is a long way from economic reality, eventually this approach could help tailor treatments. In a broader sense, the work may catalyze further investigation into other common conditions that might result from heterozygosity for a particular gene. -Ricki Lewis Is Marijuana Addictive? Studying the biological basis of marijuana addiction has typically proven to be a tricky prospect. A recent study from the National Institute on Drug Abuse might help elucidate the biological factors of marijuana dependence by demonstrating that monkeys with access to the drug tend to go back for more (G. Tanda et al., "Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys," Nature Neuroscience, 3:1073-4, November 2000). Researchers showed that four monkeys-each with THC available intravenously-consistently and repeatedly pressed a lever to self-administer the drug. According to senior author Steven Goldberg, chief of preclinical pharmacology at NIDA, both the speed with which the animals pressed the levers and the number of injections they took per session were on a par with similar cocaine-abuse experiments. The results suggest that THC, like cocaine or heroin, triggers reward mechanisms in the brain to maintain drug-seeking and taking behavior. However, similar, previous THC self-administration experiments by other groups in monkeys did not demonstrate monkey-cravings for the drug. Goldberg suspects that the discrepancy may be due to his group's use of lower doses comparable to those used by people, and their ability to put the THC into solution, thus allowing it to reach the brain faster and boost the level of "reward." Because monkeys are in limited supply, Goldberg used animals that had been previously used in cocaine experiments. He controlled for this by first putting a saline solution in the IV syringe, waiting until cocaine-induced lever-pressing disappeared, then replacing the saline with THC. Goldberg's group is currently following up the experiment with a study involving drug-naive monkeys. "Up until now there's been no animal model to explore the way [marijuana] functions as a reward to make people continue smoking," says Goldberg. "We now have a way that we can explore these biological mechanisms." -Eugene Russo Seeing a Solution The discovery that 14 genes are differentially expressed in the extraocular muscles and limb muscles in rats may offer a route to better understanding of and possible treatment for Duchene's muscular dystrophy and diseases affecting the extraocular muscles (C. Niemann, et al., Journal of the Neurological Sciences, 179:76-84, October 2000). Because the extraocular muscles are spared in muscular dystrophy, researchers regard them as different from other voluntary muscles, which are destroyed by this disorder. "This is the first sort of evidence that the transcriptional or expression profile of the extraocular muscles is different," says senior author Tejvir Khurana, assistant professor of physiology at the University of Pennsylvania and Pennsylvania Muscle Institute. There are likely more genes differentially expressed than 14, he says. The researchers verified that number from 100 genes they cloned after screening all genes expressed in these muscles. Khurana says that one long-term therapeutic approach to treating muscular dystrophy might involve, in effect, converting limb muscles to eye muscles by up-regulating the genes expressed in extraocular muscles but not in limb muscles. That strategy might entail using proteins that would turn on the promoters of the extraocular muscle genes, which are not expressed in the limbs. Khurana notes the research also has implications for better understanding diseases affecting the extraocular muscles, such as double vision and strabismus. These conditions, he says, result from the six pairs of extraocular muscles not contracting synchronously. The finding that the gene for the protein, embryonic myosin heavy chain is expressed more in extraocular muscles than in limbs "would be very important for addressing diseases such as strabismus, in which nothing is really wrong except the eye muscles are contracting out of synch," he says. -Harvey Black

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Ricki Lewis

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November 2000

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