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Editorials

I BUPROFEN AND P ATENT D UCTUS A RTERIOSUS

HE ductus arteriosus connects the pulmonary artery to the descending aorta. During fetal life it diverts most of the combined ventricular output away from the lungs toward the placenta. In full-term newborns, the ductus closes within 24 to 48 hours after delivery. However, in preterm newborns, the ductus frequently fails to close. As a result, 70 percent of preterm infants delivered before 28 weeks of gestation require either medical or surgical closure of a patent ductus arteriosus. The clinical consequences of a patent ductus arteriosus are related to the degree of left-to-right shunting through the ductus. Despite the ability of the left ventricle in preterm infants to increase its output in the face of a left-to-right shunt, blood-flow distribution is altered owing to the drop in diastolic pressure and localized vasoconstriction. The decrease in organ perfusion has an important role in some of the clinical problems caused by a patent ductus arteriosus: feeding intolerance, necrotizing enterocolitis, and decreased glomerular filtration rate. A patent ductus arteriosus also exposes the pulmonary microvasculature to systemic blood pressure and increased pulmonary blood flow. Premature infants with respiratory distress already have low plasma oncotic pressure and increased capillary permeability; therefore, the increase in microvascular pressure produces increased interstitial and alveolar edema and loss of pulmonary compliance. The increased fraction of inspired oxygen and mean airway pressures that are required to overcome these early changes in compliance may explain why a persistently patent ductus arteriosus increases the incidence of chronic lung disease in these preterm infants. In full-term infants, closure of the ductus occurs in two phases: smooth-muscle constriction produces functional closure of the lumen of the ductus within hours after birth, and anatomical occlusion of the lumen occurs over the next several days owing to extensive neointimal thickening and loss of smoothmuscle cells from the inner muscle media. The initial functional constriction of the ductus is responsible for its ultimate anatomical closure; the loss of luminal blood flow produces a zone of hypoxia in the muscle media of the ductus that appears to be the necessary signal for irreversible anatomical closure.1 This hypoxic zone is associated with local induction of cell death and local production of hypoxia-inducible growth factors, such as vascular endothelial growth factor and transforming growth factor b, which play an early
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part in the remodeling of the ductus.1 Failure of hypoxia of the muscle media to develop, despite initial constriction, leads to failure of remodeling. In preterm infants, the ductus frequently remains open for many days after birth. Even when it does constrict, profound hypoxia and anatomical remodeling frequently fail to develop; this leads to subsequent reopening of the ductus. Preterm infants seem to require greater constriction of the ductus to produce the level of vessel-wall hypoxia found in full-term infants. However, if this degree of hypoxia can be induced in the ductus, then most of the anatomical changes that occur in full-term infants will occur. The initial functional constriction of the ductus depends on an alteration in the balance between dilating and contracting forces. The ductus normally has a high level of intrinsic tone during fetal life. After delivery, an increase in arterial oxygen tension plays an additional important part in constriction of the ductus. The mechanism of action of oxygen is still unknown. The ductus also produces several vasodilator substances that inhibit the ability of the intrinsic tone and of oxygen to constrict the ductus. Vasodilator prostaglandins, especially prostaglandin E2, play a part in maintaining the patency of the ductus during fetal and neonatal life. Inhibition of prostaglandin synthesis, through inhibition of the enzyme cyclooxygenase, results in constriction of the fetal ductus. Both isoforms of cyclooxygenase (COX-1 and COX-2) are expressed in the ductus, and both nonselective cyclooxygenase inhibitors (e.g., indomethacin) and selective inhibitors constrict the ductus. The ductus also produces a nitric oxidelike vasodilator; competitive inhibitors of nitric oxide synthase constrict the ductus in newborns. After delivery, there is an increase in the partial pressure of arterial oxygen, a drop in circulating prostaglandin E2, a decrease in the number of prostaglandin E 2 receptors in the wall of the ductus, and a drop in blood pressure within the lumen of the ductus (caused by the drop in pulmonary vascular resistance). All these events promote constriction of the ductus in full-term newborns. In addition, the profound vesselwall hypoxia that accompanies constriction of the ductus inhibits endogenous prostaglandin and nitric oxide production within the wall and prevents subsequent reopening. In premature infants, the ductus is less likely to constrict after birth than in full-term infants. The intrinsic tone of the ductus in very premature infants (those born at less than 28 weeks of gestation) is lower than it is in full-term infants. In addition, the immature ductus is more sensitive to the vasodilating effects of prostaglandin E2 and nitric oxide. Although the factors that alter the sensitivity of the ductus to locally produced prostaglandin E2 and nitric oxide are unknown, we do know that prenatal administration of glucocorticoids decreases the sensitivity of the duc-

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ED ITOR IA LS

tus to prostaglandin E 2 and decreases the incidence er medical option for infants whose poor renal function precludes the use of indomethacin. Unfortunately, of patent ductus. Surgical ligation of a patent ductus in premature we still must wait several years for information about infants can now be performed in the neonatal inten- its potential long-term neurodevelopmental effects. Several caveats need to be raised. The infants in sive care unit with low rates of mortality and morbidity. However, respiratory compromise, blood-pres- these trials were more mature (average gestational age, sure fluctuations, intracranial hemorrhage, infection, 28 weeks) than those who are at greatest risk for chylothorax, recurrent laryngeal-nerve paralysis, and patent ductus arteriosus and its associated complicadeath are still risks associated with surgical closure tions (those born at 26 weeks or less). Whether these among infants born at less than 28 weeks of gesta- results will apply to this very immature group remains tion. Inhibition of prostaglandin synthesis with non- to be tested. Similarly, the low frequency of gastroinselective inhibitors of COX-1 and COX-2 appears to testinal and intracranial complications in these more be an effective alternative to surgery for closure of a mature study infants makes it impossible to draw any patent ductus. At this time, indomethacin is the only conclusion about safety issues regarding these organ nonselective cyclooxygenase inhibitor approved for systems in less mature infants. Finally, from a practithe treatment of patent ductus arteriosus. In most in- cal standpoint, even if long-term results demonstrate tensive care nurseries, indomethacin has replaced sur- a clear-cut benefit of ibuprofen over indomethacin, it gery as the preferred therapy for a patent ductus. Howis unclear whether the North American pharmaceuever, indomethacin has been associated with several tical industry will be interested in making it available adverse effects in newborns, including alterations in to the infants who need it. renal function, necrotizing enterocolitis, and gastrointestinal hemorrhage. RONALD I. CLYMAN, M.D. Indomethacin reduces renal and mesenteric blood University of California, San Francisco flow, which may play a part in these adverse effects. San Francisco, CA 94143-0544 It also reduces cerebral blood flow velocity2 and cerREFERENCES ebral oxygenation,2 which could lead to cerebral ischemia, although it does not have a negative effect on 1. Clyman RI, Chan CY, Mauray F, et al. Permanent anatomic closure of neurodevelopmental outcome.3 Unlike its effects on the ductus arteriosus in newborn baboons: the roles of postnatal constricthe ductus, the action of indomethacin on these other tion, hypoxia, and gestation. Pediatr Res 1999;45:19-29. Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized organ systems may not be due entirely to its inhibi- 2. double-blind controlled trial comparing the effects of ibuprofen with intion of prostaglandin synthesis.4-6 domethacin on cerebral hemodynamics in preterm infants with patent ducIbuprofen, another nonselective cyclooxygenase in- tus arteriosus. Pediatr Res 2000;47:36-42. 3. Merritt TA, White CL, Coen RW, Friedman WF, Gluck L, Rosenberg hibitor, has also been shown to close the ductus in anM. Preschool assessment of infants with patent ductus arteriosus: comparimals.7 However, ibuprofen does not appear to reduce ison of ligation and indomethacin therapy. Am J Dis Child 1982;136:507mesenteric blood flow,4,6,8 and it has a smaller effect 12. 4. Malcolm DD, Segar JL, Robillard JE, Chemtob S. Indomethacin comthan indomethacin on renal perfusion.4,6,8 Similarly, promises hemodynamics during positive-pressure ventilation, independentibuprofen does not reduce cerebral blood flow and ly of prostanoids. J Appl Physiol 1993;74:1672-8. 5. Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Differences in may even extend the range of blood pressures for the effects in the newborn piglet of various nonsteroidal antiinflammatory which cerebral blood flow is autoregulated.2,6,9,10 Stud- drugs on cerebral blood flow but not on cerebrovascular prostaglandins. ies in animals suggest that ibuprofen may even have Pediatr Res 1991;30:106-11. 6. Speziale MV, Allen RG, Henderson CR, Barrington KJ, Finer NN. Efcytoprotective effects in the intestinal tract.11 fects of ibuprofen and indomethacin on the regional circulation in newIn the early 1990s, initial attempts to evaluate the born piglets. Biol Neonate 1999;76:242-52. Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in effects of a parenteral form of ibuprofen on the duc- 7. the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can tus were thwarted by the marketing division of the J Physiol Pharmacol 1979;57:825-31. drug company that controlled the U.S. patent. Fortu- 8. Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. of indomethacin and ibuprofen on mesenteric and renal blood flow nately, investigators in Europe were more successful Effects in preterm infants with patent ductus arteriosus. J Pediatr 1999;135:733-8. in obtaining a parenteral formulation and have been 9. Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative able to examine its efficacy and potential toxicity. The evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pestudy reported in this issue of the Journal by Van diatr 1997;131:549-54. Overmeire et al.12 represents the largest trial to date. 10. Chemtob S, Laudignon N, Beharry K, et al. Effects of prostaglandins indomethacin on cerebral blood flow and cerebral oxygen consumpThe investigators found that ibuprofen was as effec- and tion of conscious newborn piglets. Dev Pharmacol Ther 1990;14:1-14. tive as indomethacin for the treatment of a patent duc11. Grosfeld JL, Kamman K, Gross K, et al. Comparative effects of intus but was associated with a significantly lower in- domethacin, prostaglandin E1, and ibuprofen on bowel ischemia. J Pediatr 1983;18:738-42. cidence of renal toxic effects. Their findings extend the Surg 12. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of iburesults of earlier but smaller trials.2,8,13,14 These encour- profen and indomethacin for closure of patent ductus arteriosus. N Engl J aging results suggest that there may be a safer means Med 2000;343:674-81. 13. Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, of treating patent ductus arteriosus than indometha- Aranda JV. Early ibuprofen administration to prevent patent ductus artericin or surgery. In addition, ibuprofen may offer anoth- osus in premature newborn infants. JAMA 1996;275:539-44.
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14. Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997;76:F179-F184. 2000, Massachusetts Medical Society.

S EX, H ORMONES, H YSTERECTOMIES

AND

N this issue of the Journal, Shifren and coworkers1 postulate that the reduction in androgens resulting from bilateral oophorectomy is associated with sexual dysfunction in some women and that testosterone replacement can reverse this decline in sexual function and also improve psychological well-being. The potential importance of these postulates is substantial. Recent survey data suggest that the prevalence of sexual dysfunction among women in the United States is approximately 40 percent.2 Many of these women have had hysterectomies, about 600,000 of which are performed here annually.3 Bilateral oophorectomy is performed in conjunction with hysterectomy in about half of women 40 to 44 years of age who undergo the procedure and in almost 80 percent of women 45 to 54 years old.3 Many of these women ask their doctors about androgen-replacement therapy. Although the production of estrogens and oocytes is its chief function, the ovary is also an important source of androgens. In contrast to the dramatic reduction in estradiol production that occurs after menopause, the decline in testosterone production is smaller, from 250 to 180 g per day.4 Clearly, ovarian testosterone production continues in postmenopausal women. Testosterone concentrations in ovarian venous serum are almost 15 times as high as in peripheral serum,5 and serum testosterone concentrations decline by 50 percent after oophorectomy in postmenopausal women. Thus, natural menopause does not result in nearly the reduction in androgen production that occurs after oophorectomy. Surgically induced menopause can therefore serve as a useful model for studying the effects of androgen deficiency and androgen replacement, but the results may not apply to natural menopause. The theory of a relation among menopause, serum androgen concentrations, mood, and sexual function is controversial. Using age-matched, premenopausal women as controls for women undergoing menopause, Matthews and coworkers6 did not find a significant effect of menopause on mood. In an observational study of 210 women who had undergone natural menopause but who were not receiving estrogen-replacement therapy, serum testosterone concentrations did not correlate with libido or any other aspect of sexual function.7 Moreover, despite a steady decline in serum testosterone concentrations with age, such that women in their 40s have about half the serum testosterone concentration of women in their

20s, survey data indicate a greater prevalence of sexual dysfunction among younger women.2 In a randomized, placebo-controlled trial of high doses of intramuscular testosterone enanthate in women in whom menopause had been surgically induced, the women given testosterone reported higher libido on a questionnaire than the women in the placebo group.8 However, in a study comparing estrogen and methyltestosterone with estrogen alone in postmenopausal women, neither treatment altered sexual behavior, as compared with placebo.9 In the present study by Shifren et al.,1 transdermal testosterone was used for androgen-replacement therapy in women concurrently treated with estrogen. The use of transdermal testosterone had the advantage of producing steady-state serum testosterone concentrations that did not raise serum lipid concentrations a recognized problem with orally administered testosterone. Another important feature of the study was its placebo-controlled design. Had a placebo effect not been demonstrated, the change in perceived sexual function with the lower-dose testosterone patch (150 g per day) would have seemed quite dramatic. When compared with the equally impressive change in the placebo group, however, the apparent effect of the 150-g patch on sexual functioning disappeared. Taking placebo effects into account, the only significant effects on sexual functioning occurred with the 300-g patch in older women. From the perspective of clinical utility, several issues can be raised about the use of the testosterone patch in women with impaired sexual function. First, the 300-g testosterone patch resulted in a mean serum total testosterone concentration of 102 ng per deciliter (3.5 nmol per liter), a value that is well above the upper limit of normal for menstruating women, and serum free and bioavailable testosterone concentrations were in the high-normal range. Thus, long-term daily use of the 300-g patch is likely to be associated with clinically important androgenic effects. Second, the higher dose of testosterone was effective only in women at least 48 years old who had undergone hysterectomy plus bilateral oophorectomy and reported significantly impaired sexual function at base line. Third, in clinical practice many women who report sexual dysfunction have one or more potentially confounding variables, such as use of antidepressant-drug therapy or dyspareunia, that would have excluded them from the study by Shifren and colleagues. This fact further restricts the generalizability of the results. Additional questions remain about the role of androgens in postmenopausal women. Menopause is associated with an increase in bone loss, which is diminished by estrogen therapy. In a two-year study of women with surgically induced menopause who did not have established osteoporosis, those receiving an estrogenandrogen combination had significantly higher vertebral bone density than those receiving

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estrogen alone.10 A possible role for androgen therapy in women with osteoporosis remains to be clearly defined. The possibility of a relation between sexual function and the decline in androgen production that occurs after menopause (especially after menopause induced by prophylactic oophorectomy) is a potentially important issue worthy of further study. If such a relation is consistently demonstrated, and if a testosterone dose is found that can reverse sexual impairment and improve psychological well-being without exerting unwanted androgenic effects on a long-term basis, transdermal testosterone may prove to be a useful treatment.
DAVID S. GUZICK, M.D., PH.D. KATHLEEN HOEGER, M.D.
University of Rochester Medical Center Rochester, NY 14642

REFERENCES
1. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-8.

2. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44. [Erratum, JAMA 1999;281:1174.] 3. Lepine LA, Hillis SD, Marchbanks PA, et al. Hysterectomy surveillance United States: 19801993. MMWR CDC Surveill Summ 1997;46(SS4):1-15. 4. Adashi EY. The climacteric ovary: a viable endocrine organ. Semin Reprod Endocrinol 1991;9:200-5. 5. Judd HL, Lucas WE, Yen SSC. Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 1974;118:793-8. 6. Matthews KA, Wing RR, Kuller LH, et al. Influences of natural menopause on psychological characteristics and symptoms of middle-aged healthy women. J Consult Clin Psychol 1990;58:345-51. 7. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones and the menopausal transition. Maturitas 1997;26:83-93. 8. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in surgical menopause. Psychosom Med 1985;47:339-51. 9. Myers LS, Dixen J, Morrissette D, Carmichael M, Davidson JM. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J Clin Endocrinol Metab 1990;70:112431. 10. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995;85:529-37. [Erratum, Obstet Gynecol 1995;85:668.] 2000, Massachusetts Medical Society.

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Clinical Implications of Basic Research

T HE R OLE OF THE I NTERLEUKIN-1 R ECEPTOR A NTAGONIST IN B LOCKING I NFLAMMATION M EDIATED BY I NTERLEUKIN-1

PPROACHES involving the blockade of inflammatory cytokines such as interleukin-1 and tumor necrosis factor a (TNF-a) are entering mainstream clinical medicine: antibodies against TNF-a and soluble receptors for TNF-a are being used to treat rheumatoid arthritis and Crohns disease. A large number of preclinical studies form the scientific basis for these anticytokine-based therapies. In experiments in animals in which a disease involving several cytokines has been induced, administration of neutralizing antibodies or the use of other means to block the biologic activity of a specific cytokine attenuates the effects of the disease or halts its progression. A novel approach to unraveling the role of a particular cytokine in a disease comes from studies of genetically altered mice in which the production of a specific cytokine is prevented by the targeted deletion of its gene. These so-called knockout mice lack the ability to synthesize a specific cytokine and can be phenotypically normal or unusually susceptible to an experimentally induced disease. Of considerable interest is the fact that certain diseases develop spontaneously in some cytokine-knockout mice. For example, inflammatory bowel disease develops spontaneously in interleukin-10knockout mice, perhaps because this cytokine has an essential role in regulating the immune responses to the microbial flora of the gastrointestinal tract. In two recent publications, researchers reported that inflammatory autoimmune diseases developed spontaneously in mice that were genetically manipulated to prevent the production of the interleukin-1receptor antagonist.1,2 Interleukin-1receptor antagonist is a naturally occurring cytokine and a member of the interleukin-1 family whose only function is to prevent a biologic response to interleukin-1. As shown in Figure 1, when interleukin-1 occupies its receptor, various proinflammatory events are initiated, but when interleukin-1receptor antagonist occupies the receptor, no such events are initiated, because interleukin-1 cannot bind to the cells. Receptors for interleukin-1 are found on cells with various functions, and when activated by this cytokine, they release secondary substances that mediate inflammation and tissue remodeling. Interleukin-1 is a very active cytokine that stimulates the production of pros-

taglandins and nitric oxide, both of which are highly inflammatory. In addition, interleukin-1 induces the synthesis of chemokines, small proteins that facilitate the entry of neutrophils, macrophages, and lymphocytes into tissues. Interleukin-1 is a potential target of therapeutic intervention in a variety of inflammatory and autoimmune conditions.3 In double-blind, placebo-controlled trials, administration of interleukin-1receptor antagonist significantly reduced local inflammation of joints and bone erosions in patients with moderately severe rheumatoid arthritis.4,5 The cytokine is being evaluated in clinical trials as a treatment for graft-versus-host disease and multiple sclerosis. Therefore, the finding that in mice that lacked the ability to produce interleukin-1receptor antagonist an inflammatory disease developed spontaneously was of considerable importance. The implication of these studies is that there is a natural balance between the proinflammatory activities of interleukin-1 and the ability of interleukin1receptor antagonist to keep those activities in check by occupying interleukin-1 receptors. In mice in which the gene for interleukin-1receptor antagonist had been knocked out, two distinct diseases developed spontaneously that were similar to rheumatoid arthritis and arteritis in humans. One group of investigators reported that inflammatory arthropathy began to appear in these mice at 5 weeks of age and that by 13 weeks, all the mice had deformed joints with bone erosions, infiltrating neutrophils, and other histologic changes similar to those in the joints of patients with rheumatoid arthritis.1 No such disease developed in the control mice, which had normal amounts of interleukin-1receptor antagonist. The knockout mice also produced antibodies against double-stranded DNA, antibodies to type II collagen, and excessive amounts of immunoglobulins. Levels of interleukin-1 messenger RNA in the joints of these mice were 10 times as high as the levels in control mice. Another group observed that a lethal arterial inflammation characterized by transmural infiltration of neutrophils, macrophages, and T lymphocytes developed in mice in which the gene for interleukin-1 receptor antagonist had been knocked out.2 The lesions were commonly seen at branch points and flexures, which in humans are sites of high turbulence and of atherosclerotic-plaque formation. The arteritis in these mice caused arterial stenosis that was accompanied by infarction of organs and hemorrhage from aneurysmal rupture, which was the probable cause of death. The inflammatory nature of the lesions is consistent with the biologic effects of interleukin1 on endothelial cells and smooth-muscle cells (Fig. 1). In heterozygous mice the offspring of one parent with normal amounts of interleukin-1receptor antagonist and one parent incapable of producing interleukin-1receptor antagonist arterial lesions also developed, but these were less inflammatory than

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CL INICAL IMPLICA TIONS OF BA S IC RES EA R C H

Adhesion molecules, PAF, nitric oxide, PGE, chemokines Endothelium

Adhesion molecules, PGE, chemokines

IL-1 receptor

IL-1 IL-1Ra

Fibroblasts

Macrophage

Lymphocyte
Lymphocyte growth factors

Adhesion molecules, PAF, PGE, chemokines, osteoclast precursors

Collagenases

Chondrocyte Proliferation Vascular smooth muscle

Figure 1. The Actions of Interleukin-1 (IL-1) and Interleukin-1Receptor Antagonist (IL-1Ra). Interleukin-1 activates its receptor on cells with various functions, which results in the production of secondary substances that mediate inflammatory events as well as tissue remodeling. In endothelial cells, interleukin-1 induces the release of platelet-activating factor (PAF), nitric oxide, and prostaglandin E (PGE), which reduce vascular resistance. Chemokines and the expression of adhesion molecules on the endothelial surface facilitate the emigration of circulating leukocytes into the tissues. Lymphocytes stimulated by interleukin-1 release lymphocyte growth factors that activate lymphocytes and promote expansion. Chondrocytes respond to interleukin-1 by producing collagenases that contribute to the breakdown of cartilage. The action of interleukin-1 on smooth muscle results in the production of growth factors. Interleukin-1stimulated macrophages lead to the activation of osteoclast precursor cells and result in increased bone resorption. Fibroblasts activated by interleukin-1 release inflammatory mediators. When interleukin-1 receptors are occupied by the interleukin-1receptor antagonist, interleukin-1 cannot bind and thus cannot elicit a biologic response. There is a natural balance between the proinflammatory activities of interleukin-1 and the ability of interleukin-1receptor antagonist to keep those activities in check by occupying interleukin-1 receptors.

those in homozygous mice and were not lethal. The knockout mice with spontaneous arteritis did not have the rheumatoid-arthritislike disease. The two distinct patterns of disease observed in the two studies may be explained by differences in the normal flora in Japan and the United Kingdom, where the studies were conducted, or by differences in the genetic backgrounds of the two colonies of knockout mice. The knockout mice, like their normal littermates,

lived in relatively clean but not sterile facilities and were free of obvious and detectable infections. Neither arthritis nor arteritis developed in the control mice. One conclusion that can be drawn from these studies is that the interleukin-1receptor antagonist produced in healthy mice protects them from the effects of interleukin-1, which is also produced in healthy animals under normal conditions. These results are also consistent with the concept that the increased producVol ume 343 Numb e r 10

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tion of interleukin-1 during an inflammatory disease in humans contributes to the pathologic process by binding to and triggering its receptor (Fig. 1). Normally, enough interleukin-1receptor antagonist is produced to hold interleukin-1mediated inflammation at bay. In cases of runaway inflammation, there is an insufficient amount of interleukin-1receptor antagonist to control the activity of interleukin-1. Hence, the administration of exogenous interleukin-1receptor antagonist or other agents that reduce the effects of interleukin-1 should ameliorate inflammatory diseases.
CHARLES A. DINARELLO, M.D.
University of Colorado Health Sciences Center Denver, CO 80262

Supported by a grant (AI-15614) from the National Institutes of Health.

REFERENCES
1. Horai R, Saijo S, Tanioka H, et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 2000;191:313-20. 2. Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 2000;191:303-12. 3. Dinarello CA. Biological basis for interleukin-1 in disease. Blood 1996; 87:2095-147. 4. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196-204. 5. Cohen S, Hurd E, Cush JJ, et al. Treatment of interleukin-1 receptor antagonist in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients. Arthritis Rheum 1999;42:Suppl:S273. abstract.

2000, Massachusetts Medical Society.

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INFOR MA TION FOR A UTH ORS

INFORMATION FOR AUTHORS

These guidelines are in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. (The complete document appears at www.icmje.org.) MANUSCRIPTS Manuscripts containing original material are accepted for consideration if neither the article nor any part of its essential substance, tables, or figures has been or will be published or submitted elsewhere before appearing in the Journal. This restriction does not apply to abstracts or press reports published in connection with scientific meetings. Authors should submit to the Editor copies of any published papers or other manuscripts in preparation or submitted elsewhere that are related to the manuscript to be considered by the Journal. The Journal discourages the submission of more than one article dealing with related aspects of the same study. Submit an original manuscript with one set of original figures and two copies of the complete manuscript. Manuscripts must be no longer than 2700 words. Please supply a word count (not including abstract or references). Use standard-sized paper, and triple-space throughout. Address all submissions to the Editor, New England Journal of Medicine, 10 Shattuck St., Boston, MA 02115-6094. A covering letter signed by all authors should identify the person (with the address, telephone num ber, and e-mail address) responsible for negotiations concerning the manuscript; the letter should make it clear that the final manuscript has been seen and approved by all authors and that they have taken due care to ensure the integrity of the work. At least one persons name must accompany a group name e.g., Thelma J. Smith, for the Boston Porphyria Group. As stated in the Uniform Requirements (see above), credit for authorship requires substantial contributions to: (a) conception and design, or analysis and interpretation of data; and (b) the drafting of the article or critical revision for important intellectual content. If more than 12 authors are listed for a multicenter trial, or more than 8 for a study from a single institution, each author must sign a statement attesting that he or she fulfills the authorship criteria of the Uniform Requirements. No more than 12 names will be listed under the title; other names will appear in a footnote. Acknowledgments will be limited to a column of Journal space, and those acknowledged will be listed only once. (See editorial, Nov. 21, 1991, issue.) LETTERS TO THE EDITOR See the Journal correspondence section. CONFLICT OF INTEREST Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript or with a company making a competing product. Such information will be held in confidence while the paper is under review and will not influence the editorial decision, but if the article is accepted for publication, the editors will usually discuss with the authors the manner in which such information is to be communicated to the reader. Because the essence of reviews and editorials is selection and interpretation of the literature, the Journal expects that authors of such articles will not have any financial interest in a company (or its competitor) that makes a product discussed in the article. COPYRIGHT Authors agree to execute copyright transfer forms as requested. Copyright in any contribution is owned by the Massachusetts Medical Society. The Society and its licensees have the right to use, reproduce, transmit, derivate, publish, and distribute the contribution, in the Journal or otherwise, in any form or medium. Authors will not use or authorize the use of the contribution without the Societys written consent, except as may be allowed by U.S. fair use law. UNITS OF MEASUREMENT Authors should express all measurements in conventional units, with Systme International (SI) units given in parentheses throughout the text. Figures and tables should use conventional units, with conversion factors given in legends or footnotes. In accordance with the Uniform Requirements, however, manuscripts containing only SI units will not be returned for that reason. TITLES AND AUTHORS NAMES With the manuscript, provide a page giving the title of the paper; titles should be concise and descrip-

tive (not declarative). Also include a running head of fewer than 40 letter spaces; the name(s) of the author(s), including the first name(s) and no more than two graduate degrees; the name of the department and institution in which the work was done; the institutional affiliation of each author; and the name and address of the author to whom reprint requests should be addressed. Any grant support that requires acknowledgment should be mentioned on this page. ABSTRACTS Provide on a separate page an abstract of not more than 250 words. This abstract should consist of four paragraphs, labeled Background, Methods, Results, and Conclusions. They should briefly describe, respectively, the problem being addressed in the study, how the study was performed, the salient results, and what the authors conclude from the results. KEY WORDS Three to 10 key words or short phrases should be added to the bottom of the abstract page; these will help us index the article and may be published with the Abstract. Use terms from the Medical Subject Headings from Index Medicus. REFERENCES References must be triple-spaced and numbered consecutively as they are cited. References first cited in tables or figure legends must be numbered so that they will be in sequence with references cited in the text. The style of references is that of Index Medicus. List all authors when there are six or fewer; when there are seven or more, list the first three, then et al. The following is a sample reference: 1. Lahita R, Kluger J, Drayer DE, Koffler D, Reidenberg MM. Antibodies to nuclear antigens in patients treated with procainamide or acetylprocainamide. N Engl J Med 1979;301:1382-5. Numbered references to personal communications, unpublished data, and manuscripts either in preparation or submitted for publication are unacceptable (see Permissions). If essential, such material may be incorporated in the appropriate place in the text. TABLES Double-space tables and provide a title for each. If an article is accepted, the Journal will arrange to deposit extensive tables of important data with the National Auxiliary Publications Service (NAPS); we will pay for the deposit and add an appropriate footnote to the text. This service makes available microfiche or photocopies of tables at moderate charges to those who request them. ILLUSTRATIONS Figures should be professionally designed. Symbols, lettering, and numbering should be clear and large enough to remain legible after the figure has been reduced to fit the width of a single column. The back of each figure should include the sequence number, the name of the author, and the proper orientation (e.g., top). Do not mount the figure on cardboard. Photomicrographs should be cropped to a width of 8 cm, and electron photomicrographs should have internal scale markers. If photographs of patients are used, either the subjects should not be identifiable or their pictures must be accompanied by written permission to use the figure. Permission forms are available from the Editor. Legends for illustrations should be triple-spaced on a separate sheet and should not appear on the illustrations. Color illustrations are encouraged. Send both transparencies and prints for this purpose. ABBREVIATIONS Except for units of measurement, abbreviations are discouraged. Consult Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers (Sixth edition. New York: Cambridge University Press, 1994) for lists of standard abbreviations. The first time an abbreviation appears it should be preceded by the words for which it stands. DRUG NAMES Generic names should generally be used. When proprietary brands are used in research, include the brand name in parentheses in the Methods section. PERMISSIONS Materials taken from other sources must be accompanied by a written statement from both author and publisher giving permission to the Journal for reproduction. Obtain permission in writing from at least one author of papers still in press, unpublished data, and personal communications. REVIEW AND ACTION Manuscripts are examined by the editorial staff and are usually sent to outside reviewers. We encourage authors to suggest the names of possible reviewers, but we reserve the right of final selection. Only one copy of rejected manuscripts will be returned, usually within six weeks. Decisions about potentially acceptable manuscripts may take longer.

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