Johns Hopkins Magazine -- June 1999
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JUNE 1999

H E A L T H    &    M E D I C I N E

Vitamin A's dramatic impact on maternal health... cancer screening for just pennies... predisposed toward alcoholism... a nationwide nursing shortage... vive la différence... gene switches...

Vitamin A wins again

Women in the developing world are about 70 times more likely to die as a result of pregnancy than are women in industrialized nations. But School of Public Health researchers, led by Keith West, recently reported that women can dramatically reduce this risk by increasing their intake of vitamin A or beta carotene.

West, a professor of international health, studied 44,646 women of reproductive age in a poor, rural district in the southeast central plains of Nepal. Rice is the staple food, and local foods that are rich in vitamin A or beta carotene, a precursor to vitamin A--such as mango, papaya, leafy greens, butter, and liver--are in short supply or cost more than most families can afford.

Parul Christian (left) was on the Hopkins team led by Keith West that tested Vitamin A supplementation in Nepalese women.
Many people in this region are probably borderline vitamin A-deficient; pregnancy and breastfeeding push women over the brink to where they experience the full-blown symptoms. Night-blindness, for instance, is common among pregnant women in rural Nepal. Some even note the condition as confirmation of a pregnancy, says West.

The women enrolled in the study were divided into three groups. One group received weekly capsules of the recommended dietary allowance of vitamin A. The second group received weekly capsules containing beta carotene. The third group received placebo capsules.

During the three-and-a-half-year study, 20,119 of the women became pregnant a total of 22,189 times, the researchers reported in the February 27 issue of the British Medical Journal. The mortality rates for women in the placebo, vitamin A, and beta carotene groups were, respectively, 704, 426, and 361 per 100,000 pregnancies. Combined, vitamin A or beta carotene supplements reduced pregnancy-related deaths by 44 percent.

"We think the main effect vitamin A is having is an impact on infection," concludes West. Vitamin A may bolster the immune system and reduce this risk. Several previous studies have demonstrated that vitamin A supplementation improves fetal and infant health. The latest study is one of the first to examine its impact on maternal health. --Melissa Hendricks

Cancer screening for just pennies

Researchers from Hopkins and the University of Zimbabwe have found simple, inexpensive tools for screening women for cervical cancer: vinegar and a flashlight.

Washing the cervix with acetic acid (i.e., vinegar) bleaches abnormal cells that can then be seen by eye with the help of a flashlight, explains Hopkins obstetrician/gynecologist Paul Blumenthal. The white regions suggest that cells have been invaded by the human papilloma virus, and are thus pre-cancerous.

In a study in Zimbabwe of almost 11,000 women, Blumenthal and his colleagues demonstrated that the simple vinegar and flashlight technique was even more sensitive than Pap smear testing. One drawback, however, was that it yielded a higher false positive rate.

"We've been so seduced by technology that we don't realize there are low-tech ways," comments Blumenthal, who conducted the study with researchers from the University of Zimbabwe and Lynne Gaffikin, an epidemiologist at the Hopkins affiliate JHPIEGO, an international reproductive health and training organization. The team reported its findings in the March 13 Lancet.

Cervical cancer is the leading cancer killer of women in developing countries. The disease is easily prevented and cured if it is diagnosed early. But Pap smear testing, the routine method for screening women in the United States, is not widely available and is prohibitively costly in the developing world. --MH

Prewired for alcoholism?

Children of alcoholics have an unusual brain chemistry that could predispose them toward alcoholism, according to a recent Hopkins study.

Based on extensive earlier studies, scientists believe that alcohol's effects ties into the brain's reward pathway. Alcohol, according to this model, stimulates the production of endogenous opioids, which results in a surge of dopamine, which leads to pleasurable sensations. Alcoholics have a deficiency somewhere in this pathway, according to this theory. As a result, the alcoholic requires larger quantities of alcohol than the non-alcoholic to achieve the same degree of pleasure.

The recent study, which was directed by neuroendocrinologist Gary Wand, is perhaps the first to examine whether such deficiencies in opioid activity are present in the children of alcoholics as well--and whether these deficiencies predate heavy drinking, which itself could alter brain chemistry.

Wand and his colleagues studied 26 young adults who had at least a father who was alcoholic, and 22 young adults whose families did not have a history of alcoholism. None of the volunteers was alcoholic.

The researchers administered a drug called naloxone to block the opioid pathway; the blocking process causes the body to produce a stress hormone called cortisol. "Children of alcoholics are much more sensitive to this blocking effect," Wand found. That is, their bodies produced more cortisol at lower amounts of naloxone.

"They probably have less opioid activity," says Wand. "Their opioid system is deranged in some way."

Next on the researchers' slate: refining a PET scanning technique that highlights opioid receptors in the brain--providing a more direct method of measurement. They also plan to study whether either the direct or indirect measurements of opioid activity can predict future alcoholism. --MH

A nationwide nursing crunch

The nation's demand for nurses is escalating at a time when nursing schools are producing fewer graduates. Hospitals like Johns Hopkins are struggling to cope with the resulting nursing shortage.

"We're not just competing with other hospitals," says the hospital's vice president for nursing, Karen Haller. Ambulatory care, home health care, nursing homes, and other out-of-hospital healthcare providers have increased dramatically. "So the demand for nurses is tremendous," she says.

"The nursing crunch does not mean that Johns Hopkins Hospital has fewer nurses available for patients," notes Haller. Hopkins fills staffing holes with per diem nurses, who work on a daily basis, and traveling nurses, who generally work on 13-week contracts.

This arrangement means that full-time nurses need to devote considerable time and energy to training their temporary counterparts. These additional demands strain the staff, says Kelly Caslin, a senior charge nurse and 10-year veteran of the Medical Intensive Care Unit. "There's frustration among senior staff who have to train new nurses, [be responsible for a unit], and oversee the temps," says Caslin. "It takes three months to train a new nurse and a year [for them] to feel comfortable."

Another item that rankles is salary differences. Permanent staff nurses at Hopkins Hospital earn an average base rate of $22 per hour. Hopkins pays the agencies that provide temporary nurses about twice that rate. (Just how much of that money ends up in the hands of the temporary nurses is not clear.)

Several factors are contributing to the nursing shortage, says Haller. Nursing school enrollments are falling; new enrollments to baccalaureate nursing programs fell 5.5 percent between 1997 and 1998, according to the American Association of Colleges of Nursing. (The Hopkins School of Nursing is an exception. This year's enrollment--514 students--is the second highest in the history of the school.)

And many veteran hospital nurses are attracted to the easier physical demands of outpatient and ambulatory care nursing. "Hospital nursing is hard work, tiring work," and nurses are often required to work irregular hours, nights, or weekends, says Haller. In managed care and many other outpatient settings, nurses can work Monday through Friday, 9 to 5.

Not surprisingly, hospitals like Hopkins are having a harder time recruiting experienced nurses. In fiscal year 1996, Hopkins administrators interviewed 400 experienced nurses for job openings; two years later, that figure had dropped to 193.

In an effort to attract and retain nursing staff, Hopkins Hospital has begun offering bonuses for signing and working the night shift, and new promotion opportunities for nurses with associate-level degrees. The hospital is also running more job advertisements and doing more to court students at area nursing schools--including paid summer internships for nursing students.

Sue Donaldson, dean of the Hopkins School of Nursing, says that numbers aren't everything. "What's needed in the new environment of the hospital is a nurse who can handle [patients who are sicker]. That translates to RNs with baccalaureate degrees and higher degrees. The real finessing in the midst of this shortage is to look at the long term for incentives that push the educational programs." --MH

Illustration by
Kevin O'Malley
Vive la différence!

Differences between American and French culture don't stop at Budweiser versus burgundy. Culture's reach also extends to medical practice, suggests Gail Geller, an associate professor of health policy and management at the Johns Hopkins Genetics and Public Policy Studies Unit.

In a viewpoint piece in the March 13 Lancet, Geller and her French and American co-authors probe cultural differences that may account for disparities between recommendations for the medical care of women who have an inherited risk of breast and ovarian cancers.

A task force in each nation recently issued the recommendations, which pertain largely to women who have a mutation in genes BRCA1 or BRCA2, mutations that increase their risk of breast and ovarian cancer.

Both the French and American groups concluded that prophylactic mastectomy (removal of the breasts) or oophorectomy (removal of the ovaries) may reduce the disease risk for these women. They also both acknowledged that physicians have not reached a consensus on the degree of risk reduction these procedures afford. But the two reports diverge from there.

The American statement says a patient's informed consent is sufficient for proceeding with these prophylactic procedures.

The French panel concludes that a patient's informed consent is not sufficient. Further, it advises doctors to perform the procedures only when the risk of breast cancer is more than 60 percent, or the risk of ovarian cancer exceeds 20 percent. Doctors, it states, should oppose prophylactic mastectomy in women younger than 30 and prophylactic oophorectomy in women younger than 35.

The two groups also differ in their recommendations for breast self-exam. Both papers acknowledge the uncertain medical benefits of breast self-exam. But the American team recommends that women perform the exams monthly beginning in early adulthood. It also advises that women exercise, follow a low-fat diet, and avoid smoking. The French group, stating that the self-exam "may also induce anxiety in some women," does not recommend it. Instead, French doctors are advised to conduct breast exams of each patient two to three times per year.

What might explain these differences? Geller and her colleagues suggest that an American tradition of autonomy and individualism, and a French tradition of paternalism, may have played a role.

Americans, say the authors, have taken disease prevention into their own hands. Jogging, fat-free foods, and smoke-free workplaces are integral to American life. Affording women the final say over having a medical procedure follows this tradition. In France, doctors have more control over their patients' clinical management.

Differences in the aesthetic value of breasts may have also come into play, suggests Geller. "The French refer to mastectomy as mutilation," she says, and rarely undertake the procedure for any reason. Though American women may share this view, they might be more inclined to say, "I'd rather live than have my breasts."

"There is a powerful aesthetic attached to women's breasts both in France and the U.S.," remarks Geller. "But here the aesthetic value is to attract someone else. In France, they are more part of a woman's sense of self." The French are also more fatalistic, says Geller, and so might be more inclined to reject a procedure that could reduce their risk of death, if it impairs their joie de vivre.

Geller's co-authors were Neil Holtzman, director of the Genetic Studies Unit; French physician Fran¨ois Eisinger; and University of Washington geneticist Wylie Burke.

"It is important to study cultural differences because we'll find--in the face of the same evidence--differences in the recommendations that can emerge," says Geller. "Unless we come to terms with these uncertainties, we'll do patients a disservice because we'll continue to create certainties out of uncertainties." --MH

Hope for "switching off" prostate cancer

Hopkins pathologists at the School of Medicine have discovered a novel genetic process linked to prostate cancer. It involves flipping off and on the equivalent of molecular switches, a process that appears to contribute to the growth of prostate tumors.

Until now, genetic changes implicated in cancer have involved structural changes--such as a deletion or mutation of some part of a gene. Gene switching, however, does not alter structure. "The important implication [of this mechanism] is that it's reversible," says Gary Pasternack, the lead author of a study reported in the March 1 Nature Medicine. The research was funded by the National Cancer Institute.

It may be possible to use drugs to reinduce or repress the molecular switches that have gone awry, and thus slow or halt the progression of prostate cancer, which is the second leading cause of death among men in Western countries. Pasternack and his colleagues are now developing an assay for screening thousands of compounds to look for such candidate drugs.

One of the genes in question is called pp32. Based on the most recent study and earlier work, the researchers conclude that pp32 is switched on in normal prostate tissue and turned off in cancerous tissue. They also discovered that two genes, pp32r1 and pp32r2, appear to be turned on in the vast majority of prostate cancers but turned off in normal prostate tissue. The findings suggest that pp32 might keep cell growth in check, while pp32r1 and pp32r2 stimulate tumor growth.

What switches the various genes off and on? Those questions remain unanswered, says Pasternack, though his team is exploring a "laundry list of possibilities." The team also has uncovered evidence of a similar switching mechanism in breast cancer, and are preparing to publish those results, adds Pasternack. His collaborators are Jonathan Brody, Jining Bai, and Jonathan Pevsner. --MH