Johns Hopkins Magazine - April 1995 Issue

Health and Medicine

Taste tests, etc.

Only the sperm knows

Why is a sperm like a nose? Because both can, in a sense, "smell," says Hopkins MD/PhD student Loren Walensky. He finds that sperm tails contain the same types of odor-binding proteins that noses do. The proteins, he suggests, "smell" odor messages from the egg, which allow the sperm to find the egg.

The finding could explain a lot about the awesome interaction of sperm meets egg. Like a tiny tadpole swimming across a murky pond in search of a speck of food, a minute sperm must blindly swim an immense distance. Sperm awaiting the appearance of an egg can remain tucked in the vaginal lining for days, says Walensky. "Upon ovulation, the sperm immediately bolts, and reaches the fertilization site within minutes," he says. How does the sperm know where to go?

Scientists theorize that the sperm navigates toward some chemical signal emitted by the egg, a reaction they call chemotaxis. But precise details are vague. In 1992, investigators at the University of Brussels spotted proteins in dog testicles like those found in odor receptors. Those results started scientists thinking that the tracking mechanism used by sperm could be similar to the pathway for smell. In the nose, airborne odor molecules, say from a pepperoni pizza, appear to bind to receptor molecules, and trigger a chain reaction that eventually tells the brain there is pepperoni nearby.

Intrigued by the finding of the Brussels group, Walensky decided to search for similar receptors in sperm. In experiments reported in the January Molecular Medicine, he used antibodies to odorant receptor proteins developed in the lab of Hopkins neuroscientist Gabriele Ronnett. The antibodies, he reports, bind to proteins in the upper tail regions of rat sperm--the regions that contain clumps of mitochondria, the powerhouses that fuel cellular activities like swimming. So the receptors could act much the way they do in the nose; they could be transmitting messages from the egg to regions of the sperm responsible for steering it to the egg, suggests Walensky.

Sperm may also have a way to tone down the reaction, posits Walensky. Such "desensitization" occurs in the nose, as when you stop smelling garlic after an hour in an Italian restaurant. Likewise, Walensky discovered that sperm appear to contain a second set of proteins that tone down the first set of receptors. These proteins might go to work when the sperm finally reaches the egg, telling it to stop swimming and start fertilizing, he says.

"Perhaps," he speculates, "evolution put the receptors on the tail." Since only a small percentage of sperm in ejaculate succeeds in getting close to the egg, and only one ultimately finishes the race, sniffing out the egg could be nature's test for the most robust sperm. Further research could lead to new methods of contraception, says Walensky. For example, by finding a way to inhibit the sperm's odor receptor proteins, scientists might devise a way to prevent fertilization. Conversely, a technique that enhances the sperm's egg-sniffing ability could help aid reproductive technology such as in vitro fertilization. --MH

Timing of immune response affects development of AIDS

Just as some people infected with HIV remain healthy for well over a decade, some progress to full-blown AIDS in less than three years. Why the difference?

Immune response to highly specific parts of the virus in the first few months after infection may be key, says Homayoon Farzadegan, an epidemiologist at the School of Public Health. In a recent study, 17 gay men developed AIDS within three years after producing few antibodies to HIV gag-gene products when newly infected. However, 43 men who initially showed strong immune response to gag-gene products remained symptom-free for at least six years.

The findings could help physicians identify which patients may need treatment soon, and which patients probably will not develop symptoms for many years, says Farzadegan. As well, treatments might be developed to target key immune defenses. --EH

Painkillers associated with some kidney failure

People who take one or more Tylenol tablets daily (or other products containing the pain reliever acetaminophen) could double their risk of kidney failure, according to a study by Hopkins epidemiologists.

"Acetaminophen could be responsible for about 10 percent of kidney failure that we see in this [mid-Atlantic] region," says Paul Whelton, director of the School of Public Health's Welch Center for Prevention, Epidemiology, and Clinical Research. People in kidney failure, or end-stage renal disease, generally require dialysis. If heavy users of acetaminophen reduced or stopped taking the drug, says Whelton, it could reduce the number of people needing dialysis by 10 percent.

The investigators caution, however, that kidney failure is relatively rare, occurring in fewer than two out of every 10,000 people each year. "So even doubling that number is still not a high risk," says Whelton. He also emphasizes that "the results have primary relevance for relatively heavy users of the drug, those who consume on average more than one pill a day. I don't believe the intermittent user should be concerned."

The investigators surveyed 716 dialysis patients about their use of acetaminophen, aspirin, and non-steroidal anti- inflammatory drugs. They compared those results to the drug use of 361 healthy people. All of those surveyed were from the mid- Atlantic states.

Kidney failure rose in a dose-dependent fashion, the scientists report in the December 22, 1994, New England Journal of Medicine. People who took acetaminophen between two and seven times a week had a 1.4 times greater risk than normal. People who took the drug one or more times a day had a 2.1 times greater risk.

The study also showed that people who used relatively large amounts of nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen, or indomethacin also appeared to increase their risk of kidney failure. Aspirin, however, did not appear to increase the chances of kidney damage.

"We need additional research to be sure this is a truly causal relationship," says Whelton. Until then, he advises people to use "good common sense. Do not use medications unless there's a reason. If you use a lot of pain reliever, consult with a doctor." People who need a lot of pain medication or those at risk of kidney failure might want to use aspirin, he says. --MH

Battling anemia in Sri Lanka

In Sri Lanka, hundreds of residents are taking an unusual taste test. They're sampling a variety of local breads and bread products to see whether they can detect anything unusual in any of the items. Do the testers notice a flavor of rusty nails in a sample of flat bread, for instance? Do they smell anything peculiar in a particular cookie?

Though the test may seem like a challenge for epicures, its ultimate goal is to conquer anemia among Sri Lanka's 18 million residents. Estimates indicate that half the women in Sri Lanka and throughout Southeast Asia have the disorder, the most common nutritional disorder in the world, says Rebecca Stoltzfus, assistant professor of nutrition at the School of Public Health. "Southeast Asia is probably the worst area in the world for iron deficiency," she says.

Anemia lowers a person's ability to think, decreases productivity, and increases the risk of infection. Pregnant women with anemia have a greater risk of dying in pregnancy or childbirth. In children, anemia can retard growth and mental development. "As countries develop and get rid of other nutritional problems, anemia hangs on," says Stoltzfus, particularly in places where people consume few animal products, which supply iron. Parasites like hookworm also contribute to anemia by eating blood, which stores most of the body's iron.

With the United States Agency for International Development and the Sri Lankan government, Stoltzfus is developing a program to reduce anemia by fortifying all Sri Lanka's wheat flour with iron. Step one are the taste tests, to see whether volunteers can taste or smell iron in various breads, pastas, crackers, and cookies prepared with iron-fortified flour.

"Food fortification is a good intervention," says Stoltzfus. "It's extremely inexpensive. The cost-benefit analysis becomes meaningless." Furthermore, wheat is a prime food to fortify in Sri Lanka, she says, since it comprises about 40 percent of the nation's staple calories. All the country's wheat is imported from the U.S. and processed at one mill. Adding iron to the nation's wheat would be relatively simple.

So why hasn't it been done already? One stumbling block is that scientists first need to find out how much iron and what type of iron should be used. "We'd like to pack in as much iron as we can without it tasting like rust," says Stoltzfus. Bread with too much iron won't be palatable, and consumers won't buy it. So the products in the taste test contain varying amounts.

The bread products also contain five different forms of iron, ranging from ones that are highly bioavailable (more likely to be absorbed by the blood supply) to those that are of low bioavailability (thus more likely to be excreted). Ideally, says Stolzfus, "we'd like to pick the highest level of bioavail- ability. But when you use iron that is more bioavailable it can react with the fats in the bread," she says. "The bread ends up tasting like nails, or the color changes to green, or the bread doesn't rise as well."

For phase two of the project, Stoltzfus and her colleagues are designing a study to monitor the levels of hemoglobin (the iron-carrying molecule found in red blood cells) and rates of anemia in people who are eating fortified flour. The study seeks to make sure that fortification really does increase their blood iron levels.--MH

Whipple at Hopkins is safer and cheaper

Health insurance companies often steer patients requiring specialty care to hospitals they think provide the cheapest service. But those companies may be doing themselves a disservice, says a team of Hopkins investigators. Academic medical centers can be more successful and less costly, at least for a complicated, risky operation for pancreatic cancer known as the Whipple procedure, they report.

The scientists found that 2.2 percent of inpatients for the procedure died at Hopkins as compared to an average of 13.5 percent at 38 other hospitals surveyed. Further, the cost of the procedure at Hopkins was $26,204 as com- pared to $31,659 at the other hospitals. The authors of the study, which appeared in the January Annals of Internal Medicine, surveyed the records of all patients who underwent the Whipple procedure in Maryland from 1988 through the first half of 1993. Hopkins performed half of the total 501 procedures during that time, and 38 lower volume hospitals performed the rest.

More practice--on the part of the surgeons, nurses in the operating room, and staff on the hospital floors--accounts for part of the higher success rate, says Toby Gordon, vice president for planning and marketing at Hopkins Hospital, who conducted the study with director of surgery John Cameron and others. A more experienced team of people reduces complications like infections that can follow the Whipple procedure. Also, experienced staff order fewer lab tests and radiological services, and their patients are less likely to need long stays in intensive care, says Gordon. At Hopkins, patients spent an average of two days in the ICU following the Whipple procedure, as compared to four days for patients at the other 38 hospitals. "Gains in efficiency allow us to save costs for the patient," says Gordon. --MH

Drug helps prevent sickle cell crises

A Hopkins-led national study has revealed the first drug that helps stave off the excruciatingly painful attacks of sickle cell disease. The data are so clear that officials stopped the clinical trial in January, four months before the study was scheduled to end, and asked that volunteers who had been receiving placebo be given the medication. The drug, hydroxyurea, cuts in half the number of painful episodes in sickle cell anemia patients.

Sickle cell disease, which afflicts about 150 out of every 100,000 African Americans, stems from a defect in hemoglobin, the oxygen-carrying molecule of red blood cells. In people with the disease, hemoglobin molecules can clump into rigid polymers, causing the red blood cells to stiffen into sickles that stick together and clog blood vessels, which prevents oxygen from reaching organs. Results include infections, strokes, blindness, and a life-threatening condition called acute chest syndrome involving severe chest pain and fever. Sickle cell patients have equated attacks of the disease with the pain of childbirth. On average, people with the disease die in their 40s.

Until now, the best help for sickle cell anemia patients was pain relief through painkiller drugs or blood transfusions. Hydroxyurea is the first drug that actually prevents some of the painful attacks.

Scientists propose that the drug triggers the production of fetal hemoglobin, a form normally produced only in the fetus and newborn. Fetal hemoglobin may not cause cell sickling in patients with sickle cell disease.

Hopkins professor of medicine Samuel Charache notes, however, that hydroxyurea is not a cure. To continue to reap its benefits, patients need to take the medication daily. He also says that hydroxyurea should not be offered to children or to pregnant women until further studies are conducted. The drug also has the potential to cause a drastic and potentially fatal reduction in blood cells.

Charache and Michael Terrin, vice president of the Maryland Medical Research Institute in Baltimore, led the investigation, which followed 299 adult patients at 21 clinical centers around the United States. Half the patients took daily doses of hydroxyurea and half took placebo capsules. Those taking hydroxyurea were seen at hospitals for crises half as often as patients taking placebo, and also required fewer blood transfusions. --MH

Screening for suicide

Each year, about 30,000 Americans kill themselves, and most have seen their physicians during the previous year, says Lisa Cooper- Patrick, a Hopkins specialist in internal medicine. Typically, these patients complain about stress-related physical ailments: headaches, trouble sleeping, feeling vaguely terrible.

But only some of them seem depressed, so their doctors don't tend to ask about suicidal thoughts. In most cases, the risk of suicide is missed.

Now, using more than 6,000 interviews from a massive earlier study by the National Institute of Mental Health, Cooper-Patrick and colleagues have isolated traits shared by many people with suicidal thoughts: sleep disturbance, intense guilt, depressed mood, and feelings of hopelessness. More than 90 percent of those who expressed feelings of either worthlessness or despair also had suicidal ideation, says Cooper-Patrick.

The team suggests that doctors should routinely inquire about these four symptoms, then probe for suicidal thoughts if they get even one positive answer. Such screening, the study found, would identify 84 percent of patients who are thinking about suicide.

People can then be referred for help, to prevent the downward slide from suicidal "ideation" to contemplation, threats, attempts, and finally completion. "If you only ask patients who have already been diagnosed with psychiatric disorders," says Cooper-Patrick, "you'll miss two-thirds of the ones who are thinking about suicide."

The data draw from 6,041 adults who were interviewed as part of an NIMH study to assess rates of psychiatric illness in the general population. All had told trained interviewers that they had received care in a general medical setting within the previous year, and all said that at some time within the last year they had felt so low they thought of committing suicide.

To screen general medical patients, Cooper-Patrick advises beginning with the least threatening question: "Have you ever had a period of two weeks or more when you had trouble falling asleep, staying asleep, waking up too early, or sleeping too much?" Of general medical patients, 18 percent will say yes. Of suicidal patients, two-thirds will say yes.

The study was published in December 1994 in the Journal of the American Medical Association. --EH

Written by Elise Hancock and Melissa Hendricks.

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