Letters

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In Defense of a Department of Geriatrics

TO THE EDITOR: Dr. Cassel writes in support of geriatric medicine
(1), which has always been subsumed as a major aspect of internal
medicine. She maintains that geriatricians . . . must have substantial
knowledge of . . . psychiatry, rehabilitation, ophthalmology, audiology, gynecology, urology, orthopedics and many other areas. I think
her patients would best be served by referral to appropriate specialists
in those fields. No evidence is provided that the elderly are better
treated by physicians with geriatric training. The conditions Dr.
Cassel considers to be geriatric, such as congestive heart failure,
osteoarthritis, and urinary incontinence, are not restricted to any age
group. Nor are preventive medicine, early diagnosis of disease, and
awareness of the advantages of shorter hospitalization specifically
geriatric subjects. In brief, I find no reason to expect better medical
care in my senior state from a geriatrician than from a competent
internist.

Saul B. Gilson, MD
New York, NY 10033
Reference
1. Cassel CK. In defense of a department of geriatrics. Ann Intern Med. 2000;133:
297-301. [PMID: 10929172]

IN RESPONSE: Dr. Gilson asserts that geriatric medicine has always

been subsumed as a major aspect of internal medicine. Although

internists see an increasingly large number of elderly patients, unfortunately that in itself does not mean that most internists are well
trained in the content and principles of geriatric medicine. Early
leaders in the field of geriatrics, such as eminent internist Paul Beeson, pointed out that the specialty of geriatric medicine as recognized
in other developed countries around the world includes a significant
body of knowledge about aging and age-related syndromes, as well as
a different approach to the patient in which functional assessment
and functional goals are coupled with diagnosis and treatment. Such
leaders as Beeson and Hazzard would argue that internal medicine
ought to incorporate this body of knowledge and approach to care,
especially in light of the aging of the population. I also share that
view and articulated it during my term as president of the American
College of Physicians. Unfortunately, however, many internists have
not had this training and are unfamiliar with functional assessment
and with recent advances in aging research. Furthermore, while this
situation is improving somewhat, there is still a great deal of room to
enrich the curriculum in medical schools and internal medicine res62 2001 American College of PhysiciansAmerican Society of Internal Medicine

idencies, making it more useful for physicians caring for patients of

advanced age. Geriatricians do not replace the other specialties in
medicine, but they must have extensive familiarity with these other
disciplines in order to effectively coordinate the care of the patient
who requires multiple referrals. Many internists have learned the
principles and content of geriatric medicine through continuing
medical education courses, reading of the literature, and relationships
with other colleagues. I suspect that Dr. Gilsons definition of a
competent internist may be very close to my definition of a good
geriatrician.
Christine K. Cassel, MD
Mount Sinai Medical Center
New York, NY 10029

Placebo-Controlled Trials
TO THE EDITOR: I was surprised that in a series of four articles
devoted to the ethics of placebo-controlled trials in the 19 September
2000 issue of Annals, including those by Temple and Ellenberg (1,
2), none referred to equipoise, a fundamental ethical and scientific
principle of human experimentation (3). This principle states that
the patient should be enrolled in a randomized, controlled trial only
if there is substantial uncertainty (equal bet) about which of the
trial treatments would benefit a patient most (3). This principle
applies to any randomized trial, regardless of whether it is placebocontrolled. However, it is in placebo-controlled trials that we should
be particularly vigilant about applying the uncertainty principle (4),
in light of recent empirical data suggesting that placebo arms may
indeed constitute inferior comparative therapy (5). Acknowledging
equipoise (that is, that true uncertainty about effects of competing
treatment alternatives exists) is the best mechanism available for
choosing an adequate control group. When the principle of equipoise is applied, patients do not lose out prospectively and are not
required to sacrifice themselves for the benefit of others (3, 4). By
amending the Declaration of Helsinki to explicitly acknowledge the
principle of equipoise, we will remain in a position both to protect
patients individual rights and autonomy and to advance science by
ensuring that the most credible results are obtained (4). In my opinion, improvement in the ethics and science of clinical research will
come with further understanding of the equipoise principlea fundamental principle on which nearly the entire system of human
experimentation is based (5). This discussion was sorely neglected in
all four Annals articles.

Letters

Benjamin Djulbegovic, MD
H. Lee Moffitt Cancer Center and Research Institute
University of South Florida
Tampa, FL 33612
References
1. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the
evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med.
2000;133:455-63. [PMID: 10975964]
2. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the
evaluation of new treatments. Part 2: practical issues and specific cases. Ann Intern
Med. 2000;133:464-70. [PMID: 10975965]
3. Edwards S, Lilford R, Braunholtz D, Jackson J, Hewison J, Thornton J. Ethical
issues in the design and conduct of randomised controlled trials. Health Technol
Assess. 1998;2:1-132. [PMID: 10194615]
4. Lilford RJ, Djulbegovic B. Declaration of Helsinki should be strengthened. Equipoise is essential principle of human experimentation [Letter]. BMJ. 2001;322:299300. [PMID: 11157551
5. Djulbegovic B, Lacevic M, Cantor A, Fields K, Bennett C, Adams J, et al. The
uncertainty principle and industry-sponsored research. Lancet. 2000;356:635-8.
[PMID: 10968436]

TO THE EDITOR: The debate over the ethics of randomized, place-

bo-controlled trials focused on clinical settings where treatment does

not affect the patients long-term health or where delay or omission
of active treatment would not increase mortality or irreversible morbidity (1). Unfortunately, this discussion ignored the issue of the use
of a placebo in randomized, controlled trials when an effective treatment known to prevent reversible but highly clinically relevant morbidity is available. A specific example graphically makes this point.
In 1993, a randomized trial comparing oral ondansetron with
placebo demonstrated that the serotonin antagonist significantly reduced emesis caused by moderately emetogenic cancer chemotherapy
(2). However, two previously published peer-reviewed randomized
trials had shown that dexamethasone resulted in a statistically significant improvement in emesis in the same general patient population,
compared with either placebo (3) or prochlorperazine (4). Thus, in
the oral ondansetron study, patients receiving placebo were exposed
to a well-defined risk for considerable short-term discomfort, solely
for the purpose of satisfying the drug approval processan inexpensive, well-tolerated, and documented effective antiemetic agent
was available at the time. Were patients entering this trial able to
provide truly informed consent?
No patient died as a result of participating in this phase III
antiemetic study, and irreversible morbidity was not observed.
However, on the basis of solid clinical data, patients entering this
study experienced a totally unnecessary risk for serious impairment in
their quality of life. Was this an ethical study design (4)?
Maurie Markman, MD
The Cleveland Clinic Foundation
Cleveland, Ohio 44195
References
1. Simon R. Are placebo-controlled clinical trials ethical or needed when alternative
treatment exists? [Editorial] Ann Intern Med. 2001;133:474-5. [PMID: 10975967]
www.annals.org

2. Beck T, Ciociola A, Jones S, Harvey W, Tchekmedyian N, Chang A, et al. Efficacy

of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. The Ondansetron Study Group. Ann Intern Med.
1993;118:407-13. [PMID: 8439113]
3. Cassileth P, Lusk E, Torri S, DiNubile N, Gerson S. Antiemetic efficacy of dexamethasone therapy in patients receiving cancer chemotherapy. Arch Intern Med. 1983;
143:1347-9. [PMID: 6347109]
4. Markman M, Sheidler V, Ettinger D, Quaskey S, Mellits E. Antiemetic efficacy of
dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in
patients receiving cancer chemotherapy. N Engl J Med. 1984;311:549-52. [PMID:
6379459]
5. Markman M. When regulatory requirements conflict with ethical study design: the
case of oral ondansetron. Cancer Invest. 1994;12:654-6. [PMID: 7994600]

IN RESPONSE: Dr. Djulbegovic argues that the principle of equipoise

must be of particular concern in placebo-controlled trials because
placebo-treated patients may be disadvantaged and should not sacrifice themselves for the benefit of others. It seems important, as we
emphasized in our papers, to distinguish between studies of treatments for serious illness and studies of symptomatic treatments. Exposure to placebo in the former requires genuine uncertainty about
the outcome. Exposure to placebo in a trial of headache, anxiety, or
seasonal allergy, however, cannot reasonably be said to constitute
sacrifice of oneself. It is, at worst, the sort of choice to defer or
omit therapy that people with symptomatic conditions make every
day. Moreover, at least in the first trial carried out, there is, in fact,
equipoise uncertainty as to whether the drug or placebo will be
superior. There may be knowledge that some other treatment is
effective, but that is a different question. It should, however, be
appreciated that during treatment development, studies are replicated and there are often multiple placebo-controlled trials of various
doses and regimens in diverse settings and populations. These studies
help define safe and effective use of the drug, but the favorable results
of these trials are at least strongly suspect. Nonetheless, despite possible lack of equipoise, such trials have been conducted, have been
considered ethical, and are valuable. In contrast, if in the course of
drug development it becomes known that a treatment enhances survival or decreases significant morbidity, relevant equipoise no longer
exists and another placebo-controlled trial cannot be conducted.
Dr. Markman asks whether placebo controls are justified where
available therapy is known to prevent reversible but highly clinically
relevant morbidity, such as emesis caused by moderately emetogenic cancer chemotherapy. He specifically questions the conduct of
a placebo-controlled trial of ondansetron in preventing emesis after
cyclophosphamide regimeninduced emesis, since dexamethasone
had been shown to be effective in that population. He asks whether
patients in the trial gave truly informed consent and why they should
have endured emesis when an inexpensive existing treatment was
available. In this setting, Dr. Markman suggests that the appropriate
comparator was dexamethasone, not placebo, but does not state
whether these should have been noninferiority trials or superiority
trials. A superiority trial (or a trial seeking evidence of greater efficacy
when ondansetron is added to dexamethasone) would have been
informative and interpretable, perhaps particularly desirable given
3 July 2001 Annals of Internal Medicine Volume 135 Number 1 63

Letters

dexamethasones low cost. An interpretable noninferiority trial, however, would have required a full evaluation of all trials (not just one
or two) comparing dexamethasone with placebo. If dexamethasone
had consistently been shown to be effective (superior to placebo) in
decreasing emesis, an appropriately sized equivalencenoninferiority
trial could have been informative. Despite the documented effectiveness of ondansetron in the setting of highly emetogenic chemotherapy, however, there are many situations, primarily postsurgical, in
which ondansetron has not been consistently distinguishable from
placebo as an antiemetic. In these situations, a comparison with
dexamethasone would have been uninformative. To know whether
ondansetron was effective in these cases, placebo-controlled trials
would be necessary.
Whether patients or physicians accept a trial of a particular
design depends on the trials value and necessity. It may be that an
active control design is interpretable in the initial treatment of patients receiving moderately or markedly emetogenic cancer chemotherapy. This could be shown by a thorough review of experience
with placebo-controlled trials of the proposed active control. If a
consistent benefit were established, most patients and physicians
would not want to participate in a placebo-controlled trial of a new
agent, and no such trial would be needed for regulatory approval.

Centers for Disease Control and Prevention to conclude that antimicrobial use in food animals is the dominant source of antibiotic
resistance among foodborne pathogens (5). Both the Centers for
Disease Control and Prevention and the World Health Organization
have called for an end to the use of antibiotics for growth promotion
in animals. It is time for our leaders in medicine to include this
problem in discussions about antibiotic resistance.

Robert Temple, MD
Susan S. Ellenberg, PhD
U.S. Food and Drug Administration
Rockville, MD 20857

IN RESPONSE: Dr. Lodato makes a good point regarding the contribution of antibiotic abuse in animals to antibiotic resistance and
antibiotic-resistant infections in people. Agricultural antibiotic use
seems to have been particularly important in vancomycin resistance
in Europe (but not the United States), as well as fluoroquinolone
resistance in Salmonella species and Campylobacter jejuni. Nevertheless, to keep perspective, the overuse of antibiotics in patients, particularly those with viral respiratory infections, and extensive use of
broad-spectrum antibiotics in hospitals probably account for the
lions share of our current dilemma. Having said this, I acknowledge
that the publication by Mlbak and colleagues (1) should have made
my listing.

Update in Infectious Diseases

TO THE EDITOR: Dr. Bartletts update on infectious diseases (1) was

very much appreciated, but I was troubled by its omission of any

mention of the link between antibiotic resistance and the widespread
use of antibiotics to promote growth in livestock. Roughly one third
of all antibiotics produced in the United States are fed to animals
solely to enhance weight gain (2). A September 1999 advertisement
in Swine Practitioner boasted about a product containing a tetracycline, a sulfonamide, and penicillin to enhance growth and feed
efficiencyavailable without a prescription. Since 1998, the European Union has prohibited for use in animal growth promotion all
antibiotics used in human medicine (3). The United States, by contrast, allows 19 different antibiotics to be used for growth promotion, and of these, 7 are from classes used in human medicine (3).
The economic use of antibiotics, not to cure sick animals but to
promote weight gain, is especially problematic in an age of unprecedented antibiotic resistance. Although this practice translates into
cheaper meat prices, the economic advantage seems to be minimal.
Denmark has banned the use of human antibiotics for growth promotion for 5 years and has seen productivity actually increase (3). A
National Research Council study (4) estimated that a similar ban in
the United States would increase per capita costs by $5 to $10 per
year. Use of antibiotics as growth promoters in livestock has been
linked to the emergence of antibiotic-resistant diseases, helping the
64 3 July 2001 Annals of Internal Medicine Volume 135 Number 1

Robert J. Lodato, MD
Dexter Internal Medicine
Dover-Foxcroft, ME 04426
References
1. Bartlett J. Update in infectious diseases. Ann Intern Med. 2000;133:285-92.
[PMID: 10929170]
2. Mellon M. Antibiotic resistance: causes and cures. From a press briefing at the
National Press Club, 4 June 1999. Available at www.ucsusa.org/food/brf.cause.html.
3. Mellon M. Europe says no to using antibiotics to promote livestock growth.
Nucleus. 19992000;22:6-8.
4. The use of drugs in food animals: benefits and risks. National Research Council.
Washington, DC: National Academy Pr; 1998.
5. Mlbak K, Baggesen D, Aarestrup F, Ebbesen J, Engberg J, Frydendahl K, et al. An
outbreak of multidrug-resistant, quinolone-resistant Salmonella enterica serotype typhimurium DT104. N Engl J Med. 1999;341:1420-5. [PMID: 10547404]

John G. Bartlett, MD
Johns Hopkins University
Baltimore, MD 21287-0003
Reference
1. Mlbak K, Baggesen D, Aarestrup F, Ebbesen J, Engberg J, Frydendahl K, et al. An
outbreak of multidrug-resistant, quinolone-resistant Salmonella enterica serotype typhimurium DT104. N Engl J Med. 1999;341:1420-5. [PMID: 10547404]

Testosterone and Resistance Training in AIDS

TO THE EDITOR: There are two points of interest in the article by

Grinspoon and colleagues (1), which examined the effects of testosterone supplementation on muscle mass and strength in patients
with AIDS cachexia. First, all patients had normal free testosterone
levels (that is, they were eugonadal). Second, the dosage of testosterone enanthate used (200 mg/wk) was twice the physiologic replacement dosage.
www.annals.org

Letters

Eight published randomized, controlled trials have examined

testosterone supplementation in men at doses that produced physiologic serum concentrations and assessed the effects of such supplementation on muscle mass and strength. Results from these trials
suggest that testosterone supplementation at these doses increased
muscle mass and strength in hypogonadal but not eugonadal patients. Testosterone doses that produced supraphysiologic concentrations of testosterone in eugonadal patients had inconsistent effects on
muscle. Earlier studies had several shortcomings and produced inconclusive results (2, 3). In 1996, Bhasin and coworkers (4), in a
well-designed study, reported that a supraphysiologic dosage of testosterone enanthate (600 mg/wk for 10 weeks) increased muscle size
and strength in a group of eugonadal normal men. The study by
Grinspoon and colleagues reports similar findings in a group of
eugonadal men with AIDS wasting. The short-term administration
of these supraphysiologic dosages of testosterone did not cause adverse events in either study sample.
These two studies suggest that short-term administration of supraphysiologic doses of testosterone may have beneficial effects in
eugonadal men with wasting caused by such conditions as cancer,
AIDS, or age-related sarcopenia. The safety of long-term administration, however, is not known. Potential side effects include increased
hematocrit levels, stimulation of benign prostatic hypertrophy, and
prostate carcinoma, as well as angry behavior.
Hosam K. Kamel, MD
Saint Louis University School of Medicine
St. Louis, MO 63104
References
1. Grinspoon S, Corcoran C, Parlman K, Costello M, Rosenthal D, Anderson E, et al.
Effects of testosterone and progressive resistance training in eugonadal men with AIDS
wasting. A randomized, controlled trial. Ann Intern Med. 2000;133:348-55. [PMID:
0010979879]
2. Young NR, Baker HW, Liu G, Seeman E. Body composition and muscle strength
in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol
Metab. 1993;77:1028-32. [PMID: 0008408450]
3. Friedl KE, Dettori JR, Hannan CJ Jr, Patience TH, Plymate SR. Comparison of the
effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men. J Steroid Biochem Mol
Biol. 1991;40:607-12. [PMID: 0001958561]
4. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, et al. The
effects of supraphysiologic doses of testosterone on muscle size and strength in normal
men. N Engl J Med. 1996;335:1-7. [PMID: 0008637535]

IN RESPONSE: We agree with Dr. Kamel that our data demonstrate

a significant effect of supraphysiologic testosterone on muscle mass

and strength in eugonadal men with AIDS wasting. The use of testosterone may therefore be considered to reverse sarcopenia in this
population. However, we also agree that the long-term safety of
supraphysiologic testosterone is unknown in this population. Although our data do not show adverse effects on prostate-specific
antigen and hematocrit levels, the study was short and the longerterm safety effects remain unknown. Furthermore, our data do suggest a decrease in high-density lipoprotein cholesterol level, which
www.annals.org

may adversely affect such patients. In addition, long-term use of

high-dose testosterone may result in suppression of gonadal function.
In contrast, we have shown that progressive resistance training increases muscle mass and improves levels of high-density lipoprotein
cholesterol. How these strategies will be best used in long-term clinical care remains to be determined.
Steven K. Grinspoon, MD
Harvard Medical School
Boston, MA 02108

Garlic for Total Cholesterol Reduction

TO THE EDITOR: To investigate the effect of garlic on total choles-

terol level in persons with elevated levels, Stevinson and colleagues

(1) performed a thorough meta-analysis of trials conducted with
garlic supplements. Such an undertaking assumes that consumption
of garlic supplements and consumption of garlic cloves result in
similar levels of active compounds in the body. However, no clinical
trial has yet used a garlic supplement that has demonstrated bioavailability of the probable active compounds of garlic. This is a crucial
point because considerable evidence indicates that most of garlics
effect on cholesterol reduction is due to allicin (2), a compound that
is readily present when garlic is chopped or crushed but that must be
enzymatically formed in the body from alliin when dried garlic is
consumed in supplement form. This transformation by alliinase cannot be assumed to take place without bioavailability studies, since
alliinase is inactivated immediately by gastric acid and in 1 hour by
intestinal proteases (3). Unlike many other brands, the brand used in
10 of the 13 trials that qualified for inclusion in this meta-analysis
does not use a coating that protects alliinase from exposure to gastric
acid. Because of this, in vivo allicin formation depends on gastric pH
and gastric emptying time and is therefore in considerable doubt.
The second powder supplement included in the analysis was prepared by spray-drying, a process that results in loss of most of the
alliin. Of the two studies that used allicin-derived garlic oils, the one
that showed no effect (4) used an unusual solid form of the oil that
has since been demonstrated to have low bioavailability in a 48-hour
breath test (5). The conclusions derived from this meta-analysis can
be applied only to the particular supplement brands used in the
studies and not to garlic itself.
Larry D. Lawson, PhD
Plant Bioactives Research Institute
Orem, UT 84058
References
1. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. A metaanalysis of randomized clinical trials. Ann Intern Med. 2000;133:420-9. [PMID:
0010992573]
2. Lawson LD. Garlic: a review of its medicinal effects and indicated active compounds. In: Lawson LD, Bauer R, eds. Phytomedicines of Europe: Chemistry and
Biological Activity. American Chemical Society Symposium Series 691. Washington,
DC: American Chemical Soc; 1998:176-209.
3 July 2001 Annals of Internal Medicine Volume 135 Number 1 65

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3. Jansen H, Muller B, Knobloch K. Characterization of an alliin lyase preparation

from garlic (Allium sativum). Planta Med. 1989;55:434-9.
4. Berthold HK, Sudhop T, von Bergmann K. Effect of a garlic oil preparation on
serum lipoproteins and cholesterol metabolism: a randomized controlled trial. JAMA.
1998;279:1900-2. [PMID: 0009634262]
5. Lawson LD. Effect of garlic on serum lipids [Letter]. JAMA. 1998;280:1568.
[PMID: 0009820256]

IN RESPONSE: Dr. Lawson rightly points out that the results of our
meta-analysis refer only to the use of garlic supplements and not the
consumption of garlic per se. The question of interest was whether
garlic supplements reduce cholesterol levels in patients with elevated
levels to the extent that these supplements might be considered a
treatment option for hypercholesterolemia, as suggested by previous
data (1). This question is a pertinent one, given that garlic supplements are marketed for that purpose. Our results indicated that supplements probably do not reduce total cholesterol levels to a clinically meaningful degree, but clearly this does not imply that eating
garlic does not have health benefits. As discussed in our paper, systematic reviews of herbal medicines invariably combine data derived
from different preparations. This can be problematic, not least because of the lack of bioavailability data for the possible active compounds of garlic. Dr. Lawson has presented interesting data to suggest that the conflicting results of clinical trials may be related to the
quality and coating of the tablets (2). Although he points out that
unlike other brands, the tablets used in most of the trials included in
our analysis were not enteric-coated, it is worth noting that the
efficacy of these other brands has not been demonstrated in rigorous
clinical trials. It could also be mentioned that unlike other research,
our work in this area is independent of commercial interests.

Clare Stevinson, BSc, MSc

Max H. Pittler, MD
Edzard Ernst, MD, PhD, FRCP(Edin)
University of Exeter
Exeter EX2 4NT, United Kingdom
References
1. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A
meta-analysis. Ann Intern Med. 1993;119:599-605. [PMID: 0008363171]
2. Lawson L. Tablet quality: a major problem in clinical trials with garlic supplements
[Abstract]. Forsch Komplementarmed Klass Naturheilkd. 2000;7:45.

Wine and Mortality

TO THE EDITOR: If wine drinkers experience lower mortality rates

than drinkers of beer and spirits (1), it may be because these beverages affect body tissue distribution differently. Two cross-sectional
studies in the United States have reported that beer and spirit consumption was positively associated but wine consumption was inversely (or nonsignificantly) associated with the waist-to-hip ratio
among men and women in young adulthood (2) and middle age (3).
These beverage-specific associations persisted after adjustments for
several factors, including age, education, smoking, and body mass
index. An elevated waist-to-hip ratio might be the result of relative
66 3 July 2001 Annals of Internal Medicine Volume 135 Number 1

enlargement of the upper body (waist) or relative reduction in the

size of the lower body.
Our 10-year follow-up of 44 080 middle-aged healthy white
women (4) explored how regular consumption (5 days per week
reported across a 10-year interval) of these three alcohol types was
associated with risk for weight gain in the waist and in the periphery
(predominantly hips and thighs). Compared with nonconsumers,
regular drinkers of wine, beer, and spirits had similar, nonsignificant
likelihoods of weight gain in the waist, with odds ratios of approximately 1.0, but the beverage-specific groups differed notably in the
likelihood of weight gain in the periphery. Regular wine drinking
was not associated with peripheral weight gain. However, women
who regularly drank beer or spirits had a reduced likelihood of peripheral weight gain (odds ratios, 0.59 [95% CI, 0.43 to 0.81] and
0.54 [CI, 0.44 to 0.65], respectively).
These consistent findings suggest that the apparent advantage of
wine drinking might be related to the preservation of muscle or
adipose tissue in the lower extremities. Large hips and thighs may be
protective (5). Whether these differential effects are related to the
alcoholic beverage itself or to behaviors associated with its consumption remains to be determined.
Henry S. Kahn, MD
National Center for Chronic Disease Prevention
and Health Promotion
Atlanta, GA 30341-3717
References
1. Grnbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein H, et al. Type
of alcohol consumed and mortality from all causes, coronary heart disease, and cancer.
Ann Intern Med. 2000;133:411-9. [PMID: 10975958]
2. Slattery M, McDonald A, Bild D, Caan B, Hilner J, Jacobs D, et al. Associations of
body fat and its distribution with dietary intake, physical activity, alcohol, and smoking
in blacks and whites. Am J Clin Nutr. 1992;55:943-9. [PMID: 1570801]
3. Duncan B, Chambless L, Schmidt M, Folsom A, Szklo M, Crouse J, et al. Association of the waist-to-hip ratio is different with wine than with beer or hard liquor
consumption. Atherosclerosis Risk in Communities Study Investigators. Am J Epidemiol. 1995;142:1034-8. [PMID: 7485048]
4. Kahn H, Tatham L, Heath C. Contrasting factors associated with abdominal and
peripheral weight gain among adult women. Int J Obes Relat Metab Disord. 1997;21:
903-11. [PMID: 9347409]
5. Kahn H. Why are large legs protective? [Letter] Am J Clin Nutr. 1997;66:712-3.
[PMID: 9280198]

IN RESPONSE: Dr. Kahn adds to the long list of possible explanations for the apparent beneficial effect of wine compared with beer
and spirits on morbidity and mortality. His opinions are of great
interest. However, I doubt that the beverage-specific differences in
waist-to-hip ratio can explain some, if any, of this effect. First, although there truly do seem to be differences, as found in the two
studies mentioned by Dr. Kahn, they would need to be quite large
(larger than those reported) to be able to explain our findings. Second, we did consider body weight in the analyses, but since participants who did not drink wine had a mean body mass index of 26
kg/m2 and those who did had a body mass index of 25 kg/m2, it had
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Letters

no effect on mortality, as can be seen in our Table 1. Third, the

apparent added beneficial effect of wine in our study seemed to apply
mainly to death from cancer and not to death from coronary heart
disease, which is much more strongly associated with increases in
waist-to-hip ratio.
Morten Grnbaek, MD, DrMedSci, PhD
Copenhagen University Hospital
DK-1399 Copenhagen K, Denmark

3. Meigs J, Singer D, Sullivan L, Dukes K, DAgostino R, Nathan D, et al. Metabolic

control and prevalent cardiovascular disease in non-insulin-dependent diabetes mellitus
(NIDDM): The NIDDM Patient Outcome Research Team. Am J Med. 1997;102:
38-47. [PMID: 9209199]
4. Mehler P, Jeffers B, Biggerstaff S, Schrier R. Smoking as a risk factor for nephropathy in non-insulin-dependent diabetics. J Gen Intern Med. 1998;13:842-5. [PMID:
9844083]
5. Bakris G, Williams M, Dworkin L, Elliott W, Epstein M, Toto R, et al. Preserving
renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working
Group. Am J Kidney Dis. 2000;36:646-61. [PMID: 10977801]

Smoking and Abnormalities in Renal Function

TO THE EDITOR: Pinto-Sietsma and colleagues recently reported

that cigarette smoking is associated with albuminuria in nondiabetic

persons (1). They refer to the known adverse effects of smoking in
diabetic patients that were previously reported in the literature. Their
references, however, are entirely to studies of patients with type 1
diabetes mellitus. Smoking has not consistently been found to be an
important risk factor for nephropathy in patients with type 2 diabetes mellitus, which accounts for 90% of the 16 million cases of
diabetes in the United States (2, 3).
We would also like to comment on the association between
smoking and nephropathy in type 2 diabetes mellitus, which we have
reported in a recent article (4). In our study, the multivariate odds
ratio for nephropathy was 1.61 (95% CI, 1.01 to 2.58) in smokers
with type 2 diabetes mellitus who were enrolled in the Appropriate
Blood Pressure Control in Diabetes trial.
Diabetic nephropathy continues to be the leading cause of endstage renal disease. In patients with diabetes, aggressive blood pressure control, newly defined as a value less than 130/80 mm Hg, is an
important cornerstone of any successful program to prevent diabetesrelated complications (5). Impressive evidence continues to mount
from several clinical trials that show marked benefits from aggressive
blood pressure reduction. In addition, since approximately 25% of
all diabetic patients smoke, finding another potential hazard associated with smoking gives physicians further impetus to strongly encourage smoking cessation in order to attenuate the rate of decline in
renal function. The exact pathophysiologic basis for this association
is currently unknown. Smoking may contribute to decline in renal
function through its effect on cytokine-transforming growth factor
and renal hypertrophy or through an effect on glomerular ischemia
and elevations of plasma endothelin-1 levels.
Philip S. Mehler, MD
Raymond Estacio, MD
Denver Health
Denver, CO 80204

TO THE EDITOR: Pinto-Sietsma and colleagues (1) found that smok-

ing was associated with albuminuria and abnormal renal function in

nondiabetic patients. This fine report adds to a body of evidence
showing that tobacco smoking causes structural and functional abnormalities in the kidneys, increases the risks for primary and secondary renal disease, hastens end-stage renal failure, and worsens the
outcome for patients receiving dialysis and for recipients of kidney
transplants (2). However, neither Pinto-Sietsma and colleagues nor
other recent authors have cited early studies that strongly suggested
that the kidneys were a target for the adverse effects of tobacco smoking.
Researchers in the 1800s observed effects of tobacco and nicotine on renal structure and function. By the early 1900s, reviews of
tobacco-related diseases included information that linked cigarette
smoking and renal dysfunction (3, 4). In the famous 1964 Report of
the Surgeon Generals Advisory Committee on Smoking and Health
(5), among prospective studies in which mortality ratios (MRs) for
nephritis were analyzed, the median MRs among smokers and
former smokers were 1.5 and 1.1, respectively. These MRs, although
unadjusted for passive smoking, were similar to median MRs for
coronary artery disease (MR, 1.7), cancer of the kidney (MR, 1.4),
and cerebrovascular disease (MR, 1.3). The relationships between
tobacco smoking and these vascular and neoplastic diseases have been
studied extensively over the past 35 years; however, despite 100
years worth of evidence about the adverse effects of tobacco smoke
and nicotine on the kidneys, the findings in the 1964 report were
largely ignored.
One can only speculate why researchers failed to investigate the
renal effects of smoking until recently. The good news is that active
research into basic mechanisms and therapeutic interventions related
to tobacco smoking and kidney disease has finally begun (2).
Stephen J. Jay, MD
Indiana University School of Medicine
Indianapolis, IN 46202
References

References
1. Pinto-Sietsma S, Mulder J, Janssen W, Hillege H, de Zeeuw D, de Jong P. Smoking
is related to albuminuria and abnormal renal function in nondiabetic persons. Ann
Intern Med. 2000;133:585-91. [PMID: 11033585]
2. Lee E, Lee V, Lu M, Lee J, Russell D, Yeh J. Incidence of renal failure in NIDDM.
The Oklahoma Indian Diabetes Study. Diabetes. 1994;43:572-9. [PMID: 8138063]
www.annals.org

1. Pinto-Sietsma S, Mulder J, Janssen W, Hillege H, de Zeeuw D, de Jong P. Smoking

is related to albuminuria and abnormal renal function in nondiabetic persons. Ann
Intern Med. 2000;133:585-91. [PMID: 11033585]
2. Sessa A, Conte F, Meroni M, Battini G, eds. Cigarette Smoking and the Kidney.
Series: Contributions to Nephrology, vol. 130. New York: Karger; 2000.
3. Kellogg JH. Tobaccoism. Battle Creek, MI: Modern Medicine Publishing; 1922.
3 July 2001 Annals of Internal Medicine Volume 135 Number 1 67

Letters

4. Lickint F. Tabak und Organismus; Handbuch der gesamten Tabakkunde. Stuttgart:

Hippokrates; 1939.
5. Summary of the Report of the Surgeon Generals Advisory Committee on Smoking
and Health. U.S. Surgeon Generals Advisory Committee on Smoking and Health.
Washington, DC: U.S. Department of Health, Education, and Welfare; 1964.

IN RESPONSE: We appreciate the interest in our recent article on

smoking and renal abnormalities in nondiabetic persons. As Drs.

Mehler and Estacio point out, smoking has been found to have
adverse effects on renal function not only in patients with type 1
diabetes mellitus but also in those with type 2 diabetes mellitus (1).
We agree with their plea that physicians should strongly encourage
cessation of smoking in patients with type 2 diabetes mellitus. Our
finding that smoking is also associated with both albuminuria and
renal function changes in patients without diabetes argues that smoking has renal effects independent of the diabetic setting. It adds to
our knowledge about the mechanism of albuminuria. Increased urinary albumin excretion seems to be a phenomenon related not only
to diabetes and hypertension but also to smoking, central obesity
(Pinto-Sietsma SJ, Navis G, Janssen WM, de Zeeuw D, Gans RO,
de Jong PE. A central body fat distribution is related to renal abnormalities. Unpublished data), and the use of oral contraceptives and
hormone replacement therapy (2). This may partly explain why microalbuminuria may also be found in 5% to 6% of nondiabetic and
nonhypertensive persons.
We thank Dr. Jay for drawing attention to the medical literature as early as 1922. At that time, it indeed was already reported
that smoking could cause Bright disease, known in those days as
congestion, degeneration, and damage of the kidney. Furthermore, it
was described that tobacco induced a pronounced contraction of the
vessels of the kidney (3). These and other historical data, as pointed
out by Dr. Jay, underline the importance and difficulties of the
struggle for smoking cessation. Microalbuminuria is thought to be an
early marker for worsened renal and cardiovascular prognosis. Therefore, our finding that patients who stopped smoking no longer had
an increased risk for microalbuminuria argues for a more aggressive
and intensive approach to encourage smoking cessation in patients
with microalbuminuria, both those with diabetes and those without.

Kava Hepatotoxicity
TO THE EDITOR: Phytotherapeutic preparations for sleep and anxiety disorders that contain kava-lactones are available over the counter
in many countries. A 33-year-old woman took the drug Laitan
(Schwabe Pharma AG, Kuessnacht, Switzerland) (210 mg of kavalactones daily) for 3 weeks. The patient reported intake of no other
drugs except the homeopathic medication Exsepta (Tentan AG, Rothrist, Switzerland). Two months later, she restarted use of the kava
preparation. After another 3 weeks, 1 day after intake of 60 g of
alcohol, she developed malaise, loss of appetite, and jaundice. Levels
of aminotransferases, bilirubin, and alkaline phosphatase were elevated 60-, 15- and 3-fold, respectively (aspartate aminotransferase,
40.8 kat/L [2450 U/L]; alanine aminotransferase, 40.5 nkat/L
[2430 U/L]; total bilirubin, 399 mol/L [23 mg/dL]; alkaline phosphatase, 4.98 kat/L [299 U/L]). Prothrombin time was normal.
Tests for autoantibodies and results of viral serologic tests were negative, except for low titers of EpsteinBarr virus IgM. Liver biopsy
showed infiltrated portal tracts, bridging necroses, destruction of interlobular bile ducts, and canalicular cholestasis (Figure). Liver enzyme levels returned to normal within 8 weeks after withdrawal of
Laitan. A lymphocyte transformation test (1) performed after recovery indicated strong and concentration-dependent T-cell reactivity to
Laitan (stimulation index, 13.2) but not Exsepta. Phenotyping of
cytochrome P4502D6 activity with debrisoquine showed that the
patient was a poor metabolizer. We also performed phenotyping in a
patient who had had positive results on a rechallenge test (3) and
found that she was a poor metabolizer of debrisoquine. Since the
local prevalence of CYP2D6 deficiency is 9% (4), the probability
that two consecutive patients are deficient is less than 0.01%.

Figure. Liver biopsy specimen showing an inflamed

portal tract.

Sara-Joan Pinto-Sietsma, MD
Wilbert M.T. Janssen, MD, PhD
Paul E. de Jong, MD, PhD
University Hospital Groningen
9713 GZ Groningen, the Netherlands
References
1. Mehler P, Jeffers B, Biggerstaff S, Schrier R. Smoking as a risk factor for nephropathy in non-insulin-dependent diabetics. J Gen Intern Med. 1998;13:842-5. [PMID:
9844083]
2. Monster TBM, Janssen WMT, de Jong PE, de Jong-den Berg LTW. Oral contraceptives and hormone replacement therapy are associated with microalbuminuria. Arch
Intern Med. [In press]
3. Kellogg JH. Tobaccoism. Battle Creek, MI: Modern Medicine Publishing; 1922.
68 3 July 2001 Annals of Internal Medicine Volume 135 Number 1

A mixed cellular infiltrate is dominated by lymphocytes, exhibits eosinophil granulocytes and activated macrophages, and involves an interlobular bile duct (hematoxylin eosin stain; original magnification, 175).
www.annals.org

Letters

The histologic findings and the results of the lymphocyte transformation test are compatible with an immune-mediated reaction,
possibly mediated through a reactive metabolite. In humans, kavalactones are metabolized through hydroxylation (2), but the involved
enzymes have not been identified. The present data strongly suggest
that kava preparations may be hepatotoxic and that CYP2D6 deficiency is a risk factor, as is the antianginal agent perhexiline (5).
Stefan Russmann, MD
Bernhard H. Lauterburg, MD
University of Bern
3010 Bern, Switzerland
Arthur Helbling, MD
Inselspital
3010 Bern, Switzerland
References
1. Nyfeler B, Pichler WJ. The lymphocyte transformation test for the diagnosis of
drug allergy: sensitivity and specificity. Clin Exp Allergy. 1997;27:175-81. [PMID:
0009061217]
2. Duffield AM, Jamieson DD, Lidgard RO, Duffield PH, Bourne DJ. Identification
of some human urinary metabolites of the intoxicating beverage kava. J Chromatogr.
1989;475:273-81. [PMID: 0002777959]
3. Strahl S, Ehret V, Dahm HH, Maier KP. [Necrotizing hepatitis after taking herbal
remedies]. Dtsch Med Wochenschr. 1998;123:1410-4. [PMID: 0009856112]
4. Schmid B, Bircher J, Preisig R, Kupfer A. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.
Clin Pharmacol Ther. 1985;38:618-24. [PMID: 0004064464]
5. Morgan MY, Reshef R, Shah RR, Oates NS, Smith RL, Sherlock S. Impaired
oxidation of debrisoquine in patients with perhexiline liver injury. Gut. 1984;25:105764. [PMID: 0006479680]

Medication Assistance Programs

TO THE EDITOR: Prescription medications are the most rapidly expanding component of national health care expenses. Ninety billion
dollars were spent on prescription drugs in 1998, and this number is
projected to increase to $171 billion by 2007, representing 8% of
total national health care expenditures (1). Approximately 16% of
the U.S. population does not have health insurance, and a greater
percentage has health insurance that does not include a prescription
medication benefit (2). Therefore, it is becoming increasingly difficult for some segments of the population to purchase the prescription drugs that they need.
Many pharmaceutical companies offer assistance by providing
free or reduced-cost medications to patients who meet specific financial criteria. A wide range of medications for many indications are
provided in these programs. Drugs may be provided free, or patients
may be required to pay a fee or shipment charge. Medications are
supplied by direct delivery to the patient or physician, or the patient
may be issued a benefit card or voucher that must be presented at a
pharmacy. The amount of medications given and the length of time
that a patient may be enrolled vary.
Physician involvement is necessary for patient enrollment in
www.annals.org

these programs, so clinicians must be informed about them to increase patient access to medications. Information concerning medication assistance programs sponsored by pharmaceutical companies
can be obtained from a variety of sources, including Pharmaceutical
Research and Manufacturers of America, such publications as Reimbursement Assistance Programs Sponsored by the Pharmaceutical Industry and the Directory of Prescription Drug Patient Assistance Programs,
and various Internet sites (3, 4). However, the best source of information about assistance programs and specific details concerning
patient eligibility and program enrollment is the manufacturer of the
medication.
Of course, these programs are not the solution to this universal
problem of medication access, and it is important to note that they
operate at the discretion of the pharmaceutical company and may therefore be terminated at any time. Nonetheless, it is equally important
to be aware of their existence as a possible source for medications.
The Appendix Table, available on the Annals Web site (www.annals
.org), provides an extensive listing of many medications whose manufacturers offer medication assistance programs (5).
Marie A. Chisholm, PharmD
Joseph T. DiPiro, PharmD
University of Georgia College of Pharmacy
Athens, GA 31062
Medical College of Georgia
Augusta, GA 30912-2450
References
1. Smith S, Freeland M, Heffler S, McKusick D. The next ten years of health spending: what does the future hold? The Health Expenditures Projection Team. Health Aff
(Millwood). 1998;17:128-40. [PMID: 0009769576]
2. Current population reports. Health insurance coverage, 1998. Bureau of the Census.
Washington, DC: Government Printing Office; 1999.
3. Windisch P, Webb J. Reimbursement assistance programs sponsored by the pharmaceutical industry. Chicago: University Health System Consortium Services Corporation; 1997.
4. Directory of Prescription Drug Patient Assistance Programs 19992000. Washington, DC: Pharmaceutical Research and Manufacturers of America; 1999.
5. The top 200 prescriptions for 1998 by number of US prescriptions dispensed.
Available at http://www.rxlist.com/98top.htm.

Acute Renal Failure Related to High-Dose Celecoxib

TO THE EDITOR: A 57-year-old woman developed acute renal failure
on 6 July 2000. She had been prescribed celecoxib, 200 mg/d, 10
months earlier for symptomatic osteoarthritis and had been followed
with bimonthly visits thereafter. Her baseline creatinine and blood
urea nitrogen (BUN) levels were normal at 88 mol/L (1.0 mg/dL)
and 3.9 mmol/L (11 mg/dL), respectively. In the last half of June
2000, her orthopedist doubled the daily celecoxib dose to 400 mg.
Two weeks later, on 6 July 2000, she presented with marked dependent edema and markedly elevated blood pressure (160/110 mm
Hg). Creatinine and BUN levels were elevated at 265 mol/L (3.0
mg/dL) and 15.4 mmol/L (43 mg/dL), respectively. Celecoxib ther3 July 2001 Annals of Internal Medicine Volume 135 Number 1 69

Letters

apy was discontinued on 7 July 2000, and a complete work-up for

acute renal failure was begun on 14 July 2000. Results of the
work-up were negative, and renal function returned to normal;
creatinine and BUN levels decreased to 88 mol/L (1.0 mg/dL) and
6.8 mmol/L (19 mg/dL), respectively. Edema and hypertension also
resolved.
A MEDLINE search for celecoxib and acute renal failure revealed only two cases, reported by Perazella and Eras in May 2000
(1). This is the second report and the third case involving this serious
problem with a widely used drug. In February 1999, Moreland and
St. Clair (2) reviewed the use of analgesics, including the new cyclooxygenase-2 inhibitors, for pain management in patients with rheumatic diseases; the notorious renal side effects of nonsteroidal antiinflammatory drugs (NSAIDs) were also reviewed. In December
1999, Brater (3) reviewed the effects of NSAIDs on renal function,
with a focus on cyclooxygenase-2 inhibitors. All NSAIDs seem to
share nephrotoxic side effects, including decreased sodium excretion,
decreased potassium secretion, and decreases in renal perfusion. Preliminary data suggest that cyclooxygenase-2 inhibitors also affect renal prostaglandins. It now seems that these shared renal effects also
include acute renal failure and that they are dose related.

thromboembolic events, including deep venous thromboses, atriovenous graft thromboses, and pulmonary emboli, that were due to
protein C deficiency. Of note, several of the patients family members are also deaf and mute. Aware that protein C deficiency was
associated with a single gene defect, we used the OMIM gene map to
ascertain the location of this gene and to determine whether possible
defects in neighboring loci were associated with the other disease
entities present in our patient. The search revealed that the long arm
of chromosome 2 (2q) includes loci associated with protein C deficiency (2q13-14); type 1 primary hyperoxaluria (2q36-37); type 16
autosomal dominant deafness (2q23-24.3); congenital hypothyroidism due to thyroid dysgenesis or hypoplasia (2q12-14); and dilated
cardiomyopathy types 1H, 1G, and 1I (2q14-22, q31, and q35,
respectively) (1). A defect affecting 2q may have accounted for the
complex clinical picture in our patient.
Electronic genetic databases are a valuable diagnostic tool for
the clinician and may suggest appropriate follow-up for patients and
families.

Mark G. Graham, MD
Jefferson Medical College
Philadelphia, PA 19107

Brian S. Andrews, MD, PhD

University of California, Irvine, Medical Center
Orange, CA 92868

References

References

1. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis.
2000;35:937-40. [PMID: 0010793030]
2. Moreland LW, St Clair EW. The use of analgesics in the management of pain in
rheumatic diseases. Rheum Dis Clin North Am. 1999;25:153-91, vii. [PMID:
0010083963]
3. Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus
on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-71S. [PMID:
0010628595]

1. Online Mendelian Inheritance in Man (OMIM). McKusick-Nathans Institute for

Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center
for Biotechnology Information, National Library of Medicine (Bethesda, MD). 2000.
Available at www.ncbi.nlm.nih.gov/omim/.
2. Hamosh A, Scott AF, Amberger J, Valle D, McKusick VA. Online Mendelian
Inheritance in Man (OMIM). Hum Mutat. 2000;15:57-61. [PMID: 0010612823]

Usefulness of Online Mendelian Inheritance in Man in

Clinical Practice
TO THE EDITOR: The concomitant growth of genetic research and

information technology has given birth to electronic genetic databases, the utility of which should not go unnoticed by medical practitioners. Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic diseases maintained by Johns
Hopkins School of Medicine, is freely accessible on the Internet
(1, 2). The OMIM gene map is a table of loci of inherited disorders
arranged in order. We report a case illustrating the usefulness of
OMIM in clinical practice.
A 37-year-old congenitally deaf and mute man presented to our
service with bacterial pneumonia. His history was significant for
chronic renal failure secondary to primary hyperoxaluria, which was
diagnosed when he was 26 years of age. Initial work-up also revealed
dilated cardiomyopathy and severe hypothyroidism of uncertain
cause. In addition, over an 11-year period, the patient had multiple
70 3 July 2001 Annals of Internal Medicine Volume 135 Number 1

Bara Mouradi, BS
University of California, Irvine, Medical Center
Huntington Beach, CA 92646

Idiopathic Thrombocytopenic Purpura in a 101-Year-Old

Woman
TO THE EDITOR: A 101-year-old woman, born on 25 December

1898, presented to our institution with a 2-day history of general

weakness and presyncope. The platelet count was 0.0014 109
cells/L, hemoglobin and leukocyte counts were normal, and review
of the peripheral smear revealed no clumping or schistocytes. Five
months before admission, the patient had a normal platelet count.
Her medical history was significant only for hypertension and glaucoma. She was taking calcium carbonate, hydrochlorothiazide, lisinopril, docusate, doxazosin, and acetaminophen and had not received
any recent transfusions or intravenous fluids. Physical examination
revealed several areas of ecchymoses and petechia on her trunk and
upper extremities; lymphadenopathy and hepatosplenomegaly were
not present. Findings on computed tomography of the head, serum
chemistry tests, and coagulation studies were normal. A presumptive
diagnosis of immune thrombocytopenia was made.
The patient received one six-pack of multidonor platelets and
1 g of intravenous methylprednisolone, and her platelet count inwww.annals.org

Letters

creased to 0.011 109 cells/L. She was hospitalized and treated with
methylprednisolone and intravenous immunoglobulin (2 g/kg of
body weight over 5 days). On the fourth hospital day, her platelet
count increased to 0.115 109 cells/L. She was discharged on the
fifth hospital day with a prednisone taper. At her 3-month follow-up
visit, the platelet count was 0.209 109 cells/L. After 1 year of
follow-up, the patient remains healthy with a normal complete blood
count and no other medical problems.
The annual incidence of idiopathic thrombocytopenic purpura
ranges from 1 to 13 per 100 000 persons (1). It usually occurs in
women in their second and third decades of life (2). To our knowledge, our patient is the oldest described patient with this disorder.
Previously, the oldest described patient was 89 years of age (3). A
recent observational study (4) suggests that the incidence of the disorder in adults increases with age. As patients live longer, our patient
may be the first of many presenting with idiopathic thrombocytopenic purpura in the second century of life.
Kevin K. Chung, MD
Louis R. Macareo, MD
Teresa A. Coleman, MD
Dwight D. Eisenhower Army Medical Center
Augusta, GA 30905
References
1. Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology
ITP Practice Guideline Panel. Ann Intern Med. 1997;126:319-26. [PMID:
0009036806]
2. Mueller-Eckhardt C. Idiopathic thrombocytopenic purpura (ITP): clinical and
immunologic considerations. Semin Thromb Hemost. 1977;3:125-59. [PMID:
0000322289]
3. Weiss GB, Klock JC, Richardson HB. Idiopathic thrombocytopenic purpura in the
elderly [Letter]. Lancet. 1975;1:411-2. [PMID: 0000046576]
4. Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura
in adults increases with age. Blood. 1999;94:909-13. [PMID: 0010419881]

Correction: Physicians and Joint Negotiation

In the position paper Physicians and Joint Negotiations (1), the
third position contained an inadvertent error regarding collective
negotiations by residents. The correct policy position that was approved by the Board of Regents of the American College of PhysiciansAmerican Society of Internal Medicine on 17 July 1999 is
provided below and should be substituted for the position in italics
that appeared on the top of page 790. Both the abstract and the
conclusion of the paper should also be modified accordingly.

Physicians-in-training should have means available to

communicate with their program directors and supervisors

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to address and resolve concerns about patient care, stipends, hours, and other working conditions. Educational
content should remain the purview of the appropriate Residency Review Committee (RRC) and program directors,
and should not be subject to negotiations.
The second paragraph of the abstract should be corrected to
omit the phrase collective bargaining is not appropriate for resident
physicians and should read as follows:

The College states that employed physicians should

continue to have negotiating rights. It maintains, despite a
recent decision by the National Labor Relations Board,
that physicians in residency training are protected by accreditation requirements for programs of graduate medical
education, and educational content should not be subject
to negotiations.
The following revision is also necessary in the conclusion. The
sentence Residents have other mechanisms available to them that
are more appropriate than collective bargaining in the educational
environment should read as follows:

Residents have other mechanisms available to them to

resolve disputes in the educational environment.
These changes do not represent a change in American College
of PhysiciansAmerican Society of Internal Medicine policy.
Jack Ginsburg, MPE
American College of PhysiciansAmerican Society of Internal Medicine
Philadelphia, PA 19106
Reference
1. Physicians and joint negotiations. American College of PhysiciansAmerican Society
of Internal Medicine. Ann Intern Med. 2001;134(9 Pt 1):780-2. [PMID: 11329239]

Correction: Risk Factors for Coronary Heart Disease in Men

18 to 39 Years of Age
In a recent article on risk factors for coronary heart disease in 18- to
39-year-old men (1), the first line of the figure legend should read
Receiver-operating characteristic curves for prediction of fatal coronary heart disease in young men over 20 years, not Receiver-operating characteristic curves . . . in young men older than 20 years of age.
Reference
1. Navas-Nacher EL, Colangelo L, Beam C, Greenland P. Risk factors for coronary
heart disease in men 18 to 39 years of age. Ann Intern Med. 2001;134:433-9. [PMID:
11255518]

3 July 2001 Annals of Internal Medicine Volume 135 Number 1 71