New England Journal of Medicine

This article has no abstract; the first 100 words appear below. In clinical trials, the term “patients at risk” refers to the altruistic people who volunteer to participate in studies of novel treatments. In this issue of the Journal, three reports¹–³ provide details about patients who were participating in trials involving experimental treatment with natalizumab for either multiple sclerosis or Crohn's disease and who were affected by progressive multifocal leukoencephalopathy (PML). PML is a rapidly progressive, often fatal demyelinating brain disorder caused by infection of the central nervous system with JC virus⁴; it usually occurs in patients with diminished T-cell function. These events remind us once again of the . . . This editorial was published on June 9, 2005, at www.nejm.org.

This article has no abstract; the first 100 words appear below. THE purpose of this paper is to suggest ways by which the practicing physician may improve the medical evaluation of physical ability. With this objective in mind the basic question becomes: How can a specified person use his particular combination of physical abilities to best advantage without causing undue harm to himself or others? This question in some form has long been the daily concern of the physician in advising his patients how to live and work with their physical shortcomings. Yet many of the answers given to this question are often extremely vague, such as "Take it easy," "No . . . Source Information BOSTON *Member, World Health Organization Expert Advisory Panel on Social and Occupational Health.

This article has no abstract; the first 100 words appear below. The July 18, 1985, issue of the Journal contains five interesting articles¹²³⁴⁵ dealing with the plight of teaching hospitals and with the implications of their sale to proprietary or for-profit entities. Reflecting the rapid changes taking place in our hospitals, the articles discuss such topics as access to capital, earnings growth, conflict management, and risk sharing. It is disconcerting to note, however, that they do not address the possible effects of these changes on the adequacy of care given to the patient. These articles are not unusual; instead, they typify an apparent general lack of concern for the effects that . . . John R. Hogness, M.D. Association of Academic Health Centers Washington, DC 20036

This article has no abstract; the first 100 words appear below. SEVERAL adequate forms of therapy are available for control of thyrotoxicosis, but none are perfect. The major shortcomings of antithyroid-drug therapy are that at best half the patients on therapy for one or two years enter a permanent remission and, secondly, that the rigid schedule of drug administration is a serious impediment to the pursuit of normal activities. The instructions so frequently repeated — propylthiouracil methimazole must be taken every eight hours — are based on valid observations. The drugs are rapidly metabolized and their ability to prevent thyroidal uptake of iodide diminishes in six to twelve hours. This probably . . .

A 44-year-old man presented to the emergency department with chest pain that had started 1 hour earlier and had awakened him from sleep. The pain was severe, substernal, burning, radiating to the left arm, and accompanied by nausea and vomiting.

The rapidly increasing volume of work for the individual physician is placing inordinate demands on his time and energy. Increasing the practitioner's facility in handling competently and comfortably a much greater patient load is a critical need. The need for the community practitioner to relate to a medical center for intellectual stimulation, training and advanced technical knowledge should be met. Subsidization of the community practitioner during the period of practice, study and experimentation with new methods of delivering care would encourage change. A more efficient and satisfying method of delivery of medical care on the community level may entice younger doctors into the field.

This article has no abstract; the first 100 words appear below. I FEEL very humble in having my name added to those of the illustrious men who have preceded me as Shattuck Lecturers. It was not difficult to accept this honor, but efforts to meet its challenge have not been easy. I have given careful thought to the selection of my subject. Most of my predecessors, by virtue of their noteworthy contributions, have discussed various aspects of the scientific developments in medicine. Probably because of my inability to add to those, and since I was given complete freedom of choice, I have elected to attempt to develop this lecture around those . . . *Presented at the annual meeting of the Massachusetts Medical Society, Boston, May 22, 1957. Source Information BOSTON †Clinical professor of surgery, Harvard Medical School; consulting visiting surgeon, Massachusetts General Hospital.

At least two major structural criteria have emerged that delineate genes that are actively expressed from those that are inactive: the 'open'-versus-'closed' configuration of the gene in chromatin, and the degree to which the gene DNA is modified by methylation. In the nucleus, DNA exists as a nucleoprotein complex called chromatin, consisting of DNA bound tightly to histones and other proteins. Most DNA within a given cell type is rendered transcriptionally inactive by virtue of its condensation into chromatin. This inaccessible, or 'closed,' DNA is recognized experimentally by its moderate resistance to digestion by deoxyribonucleases. The small proportion of DNA that exists in a more 'open' configuration is far more readily digested; it includes the majority of genes actively expressed in that cell type. Thus, the human globin genes are in this 'open' configuration in erythroblasts but not in brain. The second criterion is related to the tendency of cellular DNA to be modified extensively by methylation. Some genes are relatively hypomethylated when actively expressed but more fully methylated in the inactive state. In model gene-expression systems, the drug 5-azacytidine, a methylation inhibitor, activates transcription of some previously inactive genes. These features of DNA physiology are germane to the treatment of patients with hemoglobinopathies. The human γ-globin gene, which controls production of fetal hemoglobin (Hb F:α2γ2), appears to be an example of a gene whose activity is enhanced in the hypomethylated state. Sickle-cell anemia and the thalassemias arise from mutations of the β-globin gene, which controls adult hemoglobin (Hb A:α2β2) production. The disastrous clinical phenotypes associated with these disorders become apparent only when fetal hemoglobin changes to adult hemoglobin during the perinatal period. Thus, reversion to the fetal mode of hemoglobin synthesis is clearly a desirably therapeutic goal. Patients with homozygous hereditary persistence of fetal hemoglobin possess no β-globin genes; yet, they live essentially normal lives, sustained by efficient production of hemoglobin F after birth. Moreover, patients with sickle-cell anemia who also have high levels of hemoglobin F tend to have milder disease because hemoglobin F retards intracellular sickling by hemoglobin S. These facts define the clinical challenge: to manipulate the perinatal switch so as to promote fetal-hemoglobin synthesis at high levels. Molecular analysis of globin genes has predicted that inhibition of DNA methylation might achieve this goal. In patients with sickle-cell anemia or thalassemia who were treated with relatively low doses of 5-azacytidine, fetal-hemoglobin synthesis increased dramatically. More important, clinical measures of their hematologic status improved. An interesting 'side effect' was a concomitant decline in β-gene activity, suggesting that a partial reversal of the change from hemoglobin F to hemoglobin A may have occurred.

This article has no abstract; the first 100 words appear below. ALL your presidents have, in addition to surgery, one thing in common — the Presidential Address. The subject finally selected will, to no small degree, reflect the varying special interests and activities of each. I have recently fulfilled my responsibilities to the Council on Medical Education and Hospitals of the American Medical Association. The eleven years as a member, five of them as chairman of this Council, have been at times exciting, always challenging and very sobering whenever I contemplated the staggering responsibilities facing medicine. The need to give this address has challenged me to review critically my own . . . *The Presidential Address, Presented to the New England Surgical Society, Portsmouth, New Hampshire, October 4, 1963. "But when His disciples saw it, they had indignation, saying, "To what purpose this waste?" St. Matthew, XXVI Chapter, 8th verse. Source Information BOSTON † Professor of clinical surgery, emeritus, Harvard Medical School.

This article has no abstract; the first 100 words appear below. CHARLES Wendell Townsend (1859–1934) was undoubtedly better known as an ornithologist and as a writer than as a physician. Until his retirement in 1917, however, he was "one of Boston's most skilled obstetricians and an authority on the nutrition of children."¹ He graduated from Harvard Medical School in 1885. He was said to have been a brilliant student, and in 1928 he was made an honorary member of Phi Beta Kappa.¹ He had a brisk practice in obstetrics (then apparently a medical specialty) and in pediatrics. He married in 1891 and in 1892 acquired a house in Ipswich, Massachusetts, where . . . Source Information NEWTON CENTER, MASSACHUSETTS *Member, Board of Consultation, Massachusetts General Hospital.

This article has no abstract; the first 100 words appear below. In this issue of the Journal is a report of a study showing that if women take vitamins around the time of conception, it has no effect on the incidence of neural-tube defects in the newborn.¹ This is a large, carefully designed and analyzed case–control study with negative results — that is, the exposure, in this case vitamins, was not found to be effective. The results are in contrast to those of earlier studies that did find an association between vitamin use in pregnant women and a lower incidence of neural-tube defects in their offspring.²³⁴⁵ It is widely believed that . . . Marcia Angell, M.D.

This article has no abstract; the first 100 words appear below. THERE is little doubt that there are important differences in the biologic behavior of tumor cells and normal cells that can be correlated with altered surface properties. Thus, the uncontrolled growth and invasiveness of cancers is accompanied in vivo by loss of contact inhibition of cell movement and cell division, decreased surface adhesiveness and altered membrane transport of various nutrients. This correspondence between in vivo and in vitro observations has stimulated considerable interest in the underlying molecular events that control cell surface properties. Two major themes, which are probably not mutually exclusive, have been developed to explain how membrane function . . . Source Information From the Department of Physiology, University of Connecticut Health Center, Farmington, CT 06032, where reprint requests should be addressed to Dr. Berlin.

On the basis of evidence from multiple clinical trials, it is recommended that antihypertensive therapy be instituted for patients with confirmed hypertension — that is, when the systolic blood pressure exceeds 140 mm Hg or the diastolic blood pressure exceeds 90 mm Hg.1 However, many patients who have a myocardial infarction, stroke, or other cardiovascular event have blood pressures below these thresholds. In fact, it is recognized that cardiovascular risk increases linearly at blood-pressure levels lower than those that usually trigger the use of antihypertensive therapy — specifically at a systolic pressure of 130 to 135 mm Hg and a . . .

This article has no abstract; the first 100 words appear below. To the Editor: We read with interest the letter on I-cell disease by Luchsinger et al.¹ This nosologic entity was first recognized as a result of fibroblast culture studies.² It was named I-cell disease, or inclusion-cell disease, because all fibroblasts grown in culture from skin biopsies of the patients contain large quantities of peculiar cytoplasmic inclusions. This is particularly evident with the phase-contrast microscope (Fig. 1). More recently, the disease has also been called mucolipidosis II.³ We concur with the authors' statement that the presence of the I-cell culture phenotype in itself does not yet allow a diagnosis of I-cell . . .

Francis Galton was sheltering from a brief summer shower in the grounds of Naworth Castle when suddenly the true nature of correlation flashed into his mind, and for a moment he forgot everything else in his "great delight."1 Thus was the correlation coefficient, r, conceived, its public birth being before the Royal Society in December of that year, 1888.2 Few researchers have shared in the mathematical ecstasy of this inventive statistician, but most of us have, with differing degrees of reluctance, buckled down to learning about α, β, P, F, z, t, and the like, recognizing . . .

THE minimum daily adult requirement for vitamin B12 has not been established.1 Shortly after the isolation of crystalline vitamin B12 in 1948 by Rickes et al.,2 West and Reisner3 reported that the minimum effective parenterally administered dose for patients with pernicious anemia was 1 microgm. daily. Noting that these investigators had not obtained a reticulocyte response to 0.1 microgm. of cyanocobalamin daily in the only patient given this dose, Darby and his associates4 found that parenteral administration of cyanocobalamin, in doses of 0.25 to 1.0 microgm. daily, to patients with pernicious anemia in relapse resulted in reticulocyte responses . . .

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).

Because of the great fragility of the outer laminated membrane of a hydatid cyst, conventional methods of evacuating these cysts usually result in their uncontrolled rupture. An apparatus has been designed that creates a rigid frozen ring on the surface of the cyst or the organ containing it. Through the isolated central portion the cyst contents can be evacuated without risk of rupture. The device has been used successfully in the treatment of 53 large hydatid cysts. As an adjunctive solution for sterilizations of any residual larvae in the emptied exocyst space, 0.5 per cent silver nitrate solution is suggested. The efficacy of this agent against the parasites was demonstrated in the laboratory, and it was used in the surgical treatment of 28 intact hydatid cysts.

The emergence of resistance to treatment complicates the public health problem of head-louse infestations and drives the need for continuing development of new treatments. There are limited data on the activity of ivermectin as a topical lousicide. In two multisite, randomized, double-blind studies, we compared a single application of 0.5% ivermectin lotion with vehicle control for the elimination of infestations without nit combing in patients 6 months of age or older. A tube of topical ivermectin or vehicle control was dispensed on day 1, to be applied to dry hair, left for 10 minutes, then rinsed with water. The primary end point was the percentage of index patients (youngest household member with ≥3 live lice) in the intention-to-treat population who were louse-free 1 day after treatment (day 2) and remained so through days 8 and 15. A total of 765 patients completed the studies. In the intention-to-treat population, significantly more patients receiving ivermectin than patients receiving vehicle control were louse-free on day 2 (94.9% vs. 31.3%), day 8 (85.2% vs. 20.8%), and day 15 (73.8% vs. 17.6%) (P<0.001 for each comparison). The frequency and severity of adverse events were similar in the two groups. A single, 10-minute, at-home application of ivermectin was more effective than vehicle control in eliminating head-louse infestations at 1, 7, and 14 days after treatment. (Funded by Topaz Pharmaceuticals [now Sanofi Pasteur]; ClinicalTrials.gov numbers, NCT01066585 and NCT01068158.).

In patients with the acquired immunodeficiency syndrome (AIDS), toxoplasmic encephalitis is usually a presumptive diagnosis based on the clinical manifestations, a positive antitoxoplasma-antibody titer, and characteristic neuroradiologic abnormalities. A response to specific therapy helps to confirm the diagnosis, but it is unclear how rapid the response should be. We studied the course of patients treated for acute toxoplasmic encephalitis and evaluated objective clinical criteria for this empirical diagnosis. A quantifiable neurologic assessment was used prospectively to evaluate the clinical outcome of patients with AIDS and toxoplasmic encephalitis who were treated with oral clindamycin (600 mg four times a day) and pyrimethamine (75 mg every day) for six weeks. Thirty-five of 49 patients (71 percent) responded to therapy, and 30 of these (86 percent) had improvement by day 7. Thirty-two of those with a response (91 percent) improved with respect to at least half of their base-line abnormalities by day 14. Improvement in neurologic abnormalities within 7 to 14 days after the start of therapy was strongly associated with the neurologic response at 6 weeks. The four patients in whom treatment failed and the two patients with lymphoma had progressing neurologic abnormalities or new abnormalities during the first 12 days of therapy. Nonlocalizing abnormalities (headache and seizure) improved regardless of the clinical outcome. Oral clindamycin and pyrimethamine are an effective treatment for toxoplasmic encephalitis. Patients who have early neurologic deterioration despite treatment or who do not improve neurologically after 10 to 14 days of appropriate antitoxoplasma therapy should be considered candidates for brain biopsy.

Psoriasis is a common chronic, inflammatory skin disease that affects approximately 6 million people in the United States, crossing the boundaries of sex, age, and race. For most patients, the diagnosis of psoriasis marks the beginning of a lifelong struggle, with cycles of remission and exacerbation. Although psoriasis is rarely life threatening, it is frequently associated with stigmatizing chronic lesions that can cause considerable physical and psychological morbidity. Because of its seemingly benign nature, the psychological and economic effects of psoriasis are often underestimated by physicians and other health care professionals. The past decade has seen monumental advances in the . . .

This book, whose editor is from the Riyadh Armed Forces Hospital in Saudi Arabia, concentrates mainly on the clinical aspects and treatment of tuberculosis. Of its 64 contributing authors, 29 are from Saudi Arabia; others, some of whom are well-known tuberculosis experts, are from Europe, North America, Asia, and Africa. The international orientation of the book gives it an interesting point of view in the discussion of the historical aspects of tuberculosis. Most textbooks about the disease mention the evidence of phthisis in the remains of Egyptian mummies but then race centuries ahead to the dark, airless, overcrowded mills of . . .

This well-organized and clearly written book provides a fascinating inside look at the development of Deaf culture. As noted in the introduction to the book, the authors use the convention of capitalizing Deaf when referring to members of a distinct culture - people who share features of a community within a community, most notably their fluency in sign language. When the word "deaf" is used more broadly to denote the condition of hearing loss, it is lowercased. This history of the development of the language and mores of Deaf people provides a basis for understanding the current climate in the . . .

This Seminar was organized in 1983 to examine the provision of primary health care in Boston. Its report is a later outgrowth of the Seminar. The group was charged with clarifying the issue of access and providing a method for identifying and solving problems within the context of primary health care. Using the epidemiologic concept of risk as an organizing principle, the group synthesized both local and national information to address several questions: What segments of the Boston population are at risk of inadequate and inappropriate primary health care? Who are the uninsured, and how does the lack of sufficient . . .

The term "cardiogenic embolism" refers to embolization from a cardiac source to a target organ. Cardiogenic Embolism is an excellent compendium of all proven, probable, or possible cardiac conditions that predispose patients to systemic emboli, but it tells us very little about the consequences of these emboli. There is not a single chapter on the effects of emboli of the lower limbs or viscera, and there is only one five-page chapter on the neurologic aspects of cardiogenic embolism. There are chapters on the epidemiology of stroke and neuroradiology, but silent brain infarcts, vascular dementia as a result of multiple embolic . . .

Self-mutilation, most commonly by cutting or burning, frequently begins in adolescence and may continue for a lifetime if the behavior is left untreated. It can cause permanent scarring, blood loss, infection (including human immunodeficiency virus infection), and even death. It is also psychologically dangerous. Self-mutilation can be visually shocking - imagine a crosshatching of ugly red gashes on an adolescent's arms and legs - and eerily silent, a dramatic symbol that takes the place of words. It has the power to move not only psychiatrists and other mental health workers, but also the members of the emergency room staff, who . . .

It is difficult not to feel sympathy for (or fearful identification with) David Baltimore, who endured an ordeal of epic proportions over more than a decade because he objected to the tactics of his inquisitors. After all, it is hard to feel good about a governmental process that takes 10 years to grind to its conclusion, sullies all the participants along the way, and ends with a verdict that excoriates the competence of the prosecutors while damning with faint praise the quality of the science. On the other hand, that the process was horrific is not a defense of conduct. . . .

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.

There is debate about whether the initial treatment for patients with Parkinson's disease should be levodopa or a dopamine agonist. In this prospective, randomized, double-blind study, we compared the safety and efficacy of the dopamine D2-receptor agonist ropinirole with that of levodopa over a period of five years in 268 patients with early Parkinson's disease. If symptoms were not adequately controlled by the assigned study medication, patients could receive supplementary levodopa, administered in an open-label fashion. The primary outcome measure was the occurrence of dyskinesia. Eighty-five of the 179 patients in the ropinirole group (47 percent) and 45 of the 89 patients in the levodopa group (51 percent) completed all five years of the study. In the ropinirole group 29 of the 85 patients (34 percent) received no levodopa supplementation. The analysis of the time to dyskinesia showed a significant difference in favor of ropinirole (hazard ratio for remaining free of dyskinesia, 2.82; 95 percent confidence interval, 1.78 to 4.44; P<0.001). At five years, the cumulative incidence of dyskinesia (excluding the three patients who had dyskinesia at base line), regardless of levodopa supplementation, was 20 percent (36 of 177 patients) in the ropinirole group and 45 percent (40 of 88 patients) in the levodopa group. There was no significant difference between the two groups in the mean change in scores for activities of daily living among those who completed the study. Adverse events led to the early withdrawal from the study of 48 of 179 patients in the ropinirole group (27 percent) and 29 of 89 patients in the levodopa group (33 percent). The mean (+/-SD) daily doses given by the end of the study were 16.5+/-6.6 mg of ropinirole (plus 427+/-221 mg of levodopa in patients who received supplementation) and 753+/-398 mg of levodopa (including supplements). Early Parkinson's disease can be managed successfully for up to five years with a reduced risk of dyskinesia by initiating treatment with ropinirole alone and supplementing it with levodopa if necessary.

The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. We sought confirmation of efficacy in a second, larger trial. We enrolled 3306 patients with acute ischemic stroke in a randomized, double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms. Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days. We examined scores on neurologic and activities-of-daily-living scales as secondary end points. We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages. The efficacy analysis was based on 3195 patients. Prognostic factors were well balanced between the treatment groups. Mortality was equal in the two groups, and adverse-event rates were similar. The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 (1588 patients) and the placebo group (1607 patients; P=0.33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94; 95% confidence interval [CI], 0.83 to 1.06). Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit: the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was no evidence of efficacy for any of the secondary end points. Among patients treated with alteplase, there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage. NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms. (ClinicalTrials.gov number, NCT00061022 [ClinicalTrials.gov].)

The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06, a clinical trial sponsored by the National Cancer Institute (NCI), has provided evidence of the value of lumpectomy and breast irradiation for treating women with breast cancer in an early stage. Publicity generated by the discovery that the study included fraudulent data on patients enrolled by St. Luc Hospital in Montreal aroused concern about the overall accuracy of the data and conclusions. To address this concern, the NCI conducted an audit of other participating institutions. In 1994, data on 1554 of the 1809 randomized patients (85.9 percent) enrolled by centers other than St. Luc Hospital were audited at 37 clinical sites in North America. The audit included data on eligibility, survival, disease-free survival, the length of time to a recurrence of cancer in the ipsilateral breast, and documentation of signed informed consent. End points were assessed for all 1554 patients, and eligibility was assessed for 1507 patients; 47 patients were excluded because their forms were not complete or not returned. A total of 1429 patients had their eligibility status verified. Of a total of 7770 data points examined with respect to the number of positive nodes at base line, treatment characteristics, first events (excluding death), recurrence of cancer in the ipsilateral breast, and survival, 7577 (97.5 percent) were verified, 123 (1.6 percent) could not be verified, and 70 (0.9 percent) were discrepant with the NSABP file. Of the 1554 patients, 1340 (86.2 percent) had all audited items (including eligibility) verified, 69 (4.4 percent) had at least one discrepant item, and 113 (7.3 percent) had at least one unverified item (as a result of missing or incomplete data); 32 (2.1 percent) were not assessed for eligibility but had no other discrepant or unverifiable items. Written informed consent was documented for 1098 patients before surgery and 210 after surgery; no date appeared on the signed form for 137. The informed-consent status was not verified for 71 patients and could not be determined for 38. The rates of verification of end-point data and documentation of written informed consent were similar among the total-mastectomy group, the lumpectomy group, and the group treated by lumpectomy and breast irradiation. The audit confirms the adequacy of the data on which the reanalysis of Protocol B-06 and the results after 12 years of follow-up are based.

The promise of clinical privacy that is part of the Hippocratic Oath contains an escape clause. "All that may come to my knowledge in the exercise of my profession . . . which ought not to be spread abroad," takers of the oath affirm, "I will keep secret and will never reveal." But what things "ought not to be spread abroad," and who is to judge? American medicine increasingly faces such questions, and psychiatrists (and other mental health professionals) are often on the front lines. Third parties want to know what people tell their psychotherapists - and what therapists think . . .

There are few diseases as easy to recognize as classic gouty podagra (from the Greek word meaning "foot seizure"). A gluttonous, bibulous, upper-class man suddenly notices a severely painful, swollen great toe. The attack passes after several days to several weeks, even without therapy. Hippocrates referred to gout (from the Latin gutta - a drop) as the arthritis of the rich, as opposed to rheumatism, the arthritis of the poor. The list of sufferers throughout history includes important persons of power, prestige, and artistic accomplishment. Roy Porter and G.S. Rousseau are professors of history and English, respectively. Their talents have . . .

Many developmental biologists and geneticists have enjoyed reading the literature on the work of Walter Gehring's laboratory. It was thus a great pleasure to peruse a book detailing the behind-the-scenes story of Gehring's seminal contributions to our understanding of homeobox proteins. The most fascinating aspect of Master Control Genes in Development and Evolution is Gehring's genuine amusement with science, embellished by intriguing stories about his colleagues. The scientific information is plainly presented and basic, so that even those who are unfamiliar with developmental genetics can understand it. There is a long history of studies of homeotic transformation in drosophila, dating . . .