Showing papers in "The New England Journal of Medicine in 1985"

Oxygen-derived free radicals in postischemic tissue injury.

Abstract: It is now clear that oxygen-derived free radicals play an important part in several models of experimentally induced reperfusion injury. Although there are certainly multiple components to clinical ischemic and reperfusion injury, it appears likely that free-radical production may make a major contribution at certain stages in the progression of the injury. The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase. Reperfused tissues are protected in a variety of laboratory models by scavengers of superoxide radicals or hydroxyl radicals or by allopurinol or other inhibitors of xanthine oxidase. Dysfunction induced by free radicals may thus be a major component of ischemic diseases of the heart, bowel, liver, kidney, and brain.

Observations on the Systemic Administration of Autologous Lymphokine-Activated Killer Cells and Recombinant Interleukin-2 to Patients with Metastatic Cancer

Abstract: We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice We treated 25 patients with metastatic cancer in whom standard therapy had failed Patients received both 18 to 184 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2 Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn

The inverse relation between fish consumption and 20-year mortality from coronary heart disease.

Abstract: The low death rate from coronary heart disease among the Greenland Eskimos has been ascribed to their high fish consumption. We therefore decided to investigate the relation between fish consumption and coronary heart disease in a group of men in the town of Zutphen, the Netherlands. Information about the fish consumption of 852 middle-aged men without coronary heart disease was collected in 1960 by a careful dietary history obtained from the participants and their wives. During 20 years of follow-up 78 men died from coronary heart disease. An inverse dose-response relation was observed between fish consumption in 1960 and death from coronary heart disease during 20 years of follow-up. This relation persisted after multiple logistic-regression analyses. Mortality from coronary heart disease was more than 50 per cent lower among those who consumed at least 30 g of fish per day than among those who did not eat fish. We conclude that the consumption of as little as one or two fish dishes per week may be of preventive value in relation to coronary heart disease.

The contribution of low birth weight to infant mortality and childhood morbidity.

Abstract: The low-birth-weight infant remains at much higher risk of mortality than the infant with normal weight at birth. In the neonatal period, when most infant deaths occur, the proportion of low-birth-weight infants, especially those with very low weight, is the major determinant of the magnitude of the mortality rates. Furthermore, differences in low-birth-weight rates account for the higher neonatal mortality rates observed in some groups, particularly those characterized by socioeconomic disadvantages. Much of the recent decline in neonatal mortality can be attributed to increased survival among low-birth-weight infants, apparently as a result of hospital-based services. The application of these services is currently considered cost-effective, although whether this will continue to be true in the future is unclear because of the increased survival of very tiny infants. Although low-birth-weight infants remain at increased risk of both postneonatal mortality and morbidity in infancy and early childhood, the risk is substantially smaller than that of neonatal death. In addition, these adverse later outcomes have not offset the gains achieved in the neonatal period. Nonetheless, the increased survival of high-risk infants raises concern about their future requirements for special medical and educational services and about the stress on their families. Despite increased access to antenatal services, only moderate declines in the proportion of low-birth-weight infants has been observed, and almost no change has occurred in the proportion of those with very low weight at birth. In addition, in many areas of the country the birth-weight-specific neonatal mortality rates are similar for groups at high and low risk of neonatal death. In view of these findings, continuation of the current decline in neonatal mortality and reduction of the mortality differentials between high- and low-risk groups require the identification and more effective implementation of strategies for the prevention of low-weight births.

Five-Year Results of a Randomized Clinical Trial Comparing Total Mastectomy and Segmental Mastectomy with or without Radiation in the Treatment of Breast Cancer

Abstract: In 1976 we began a randomized trial to evaluate breast conservation by a segmental mastectomy in the treatment of Stage I and II breast tumors less than or equal to 4 cm in size. The operation removes only sufficient tissue to ensure that margins of resected specimens are free of tumor. Women were randomly assigned to total mastectomy, segmental mastectomy alone, or segmental mastectomy followed by breast irradiation. All patients had axillary dissections, and patients with positive nodes received chemotherapy. Life-table estimates based on data from 1843 women indicated that treatment by segmental mastectomy, with or without breast irradiation, resulted in disease-free, distant-disease-free, and overall survival at five years that was no worse than that after total breast removal. In fact, disease-free survival after segmental mastectomy plus radiation was better than disease-free survival after total mastectomy (P = 0.04), and overall survival after segmental mastectomy, with or without radiation, was better than overall survival after total mastectomy (P = 0.07, and 0.06, respectively). A total of 92.3 per cent of women treated with radiation remained free of breast tumor at five years, as compared with 72.1 per cent of those receiving no radiation (P less than 0.001). Among patients with positive nodes 97.9 per cent of women treated with radiation and 63.8 per cent of those receiving no radiation remained tumor-free (P less than 0.001), although both groups received chemotherapy. We conclude that segmental mastectomy, followed by breast irradiation in all patients and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for Stage I and II breast tumors less than or equal to 4 cm, provided that margins of resected specimens are free of tumor.

Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas.

Abstract: Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to 300 copies) of N-myc was detected in 2 of 16 tumors in Stage II, 13 of 20 in Stage III, and 19 of 40 in Stage IV; in contrast, 8 Stage I and 5 Stage IV-S tumors all had 1 copy of the gene (P less than 0.01). Analysis of progression-free survival in all patients revealed that amplification of N-myc was associated with the worst prognosis (P less than 0.0001); the estimated progression-free survival at 18 months was 70 per cent, 30 per cent, and 5 per cent for patients whose tumors had 1, 3 to 10, or more than 10 N-myc copies, respectively. Of 16 Stage II tumors, 2 with amplification metastasized, whereas only 1 of 14 without amplification did so (P = 0.03). Stage IV tumors with amplification progressed most rapidly: nine months after diagnosis the estimated progression-free survival was 61 per cent, 47 per cent, and 0 per cent in patients whose tumors had 1, 3 to 10, or more than 10 copies, respectively (P less than 0.0001). These results suggest that genomic amplification of N-myc may have a key role in determining the aggressiveness of neuroblastomas.

Circadian variation in the frequency of onset of acute myocardial infarction

Abstract: To determine whether the onset of myocardial infarction occurs randomly throughout the day, we analyzed the time of onset of pain in 2999 patients admitted with myocardial infarction. A marked circadian rhythm in the frequency of onset was detected, with a peak from 6 a.m. to noon (P<0.01). In 703 of the patients, the time of the first elevation in the plasma creatine kinase MB (CK-MB) level could be used to time the onset of myocardial infarction objectively. CK-MB—estimated timing confirmed the existence of a circadian rhythm, with a threefold increase in the frequency of onset of myocardial infarction at peak (9 a.m.) as compared with trough (11 p.m.) periods. The circadian rhythm was not detected in patients receiving beta-adrenergic blocking agents before myocardial infarction but was present in those not receiving such therapy. If coronary arteries become vulnerable to occlusion when the intima covering an atherosclerotic plaque is disrupted, the circadian timing of myocardial infarction ma...

Risk Factors for Breast Cancer in Women with Proliferative Breast Disease

Abstract: To assess the importance of various risk factors for breast cancer in women with benign proliferative breast lesions, we reevaluated 10,366 consecutive breast biopsies performed in women who had presented at three Nashville hospitals. The median duration of follow-up was 17 years for 3303 women, 1925 of whom had proliferative disease. This sample contained 84.4 per cent of the patients originally selected for follow-up. Women having proliferative disease without atypical hyperplasia had a risk of cancer that was 1.9 times the risk in women with nonproliferative lesions (95 per cent confidence interval, 1.2 to 2.9). The risk in women with atypical hyperplasia (atypia) was 5.3 times that in women with nonproliferative lesions (95 per cent confidence interval, 3.1 to 8.8). A family history of breast cancer had little effect on the risk in women with nonproliferative lesions. However, the risk in women with atypia and a family history of breast cancer was 11 times that in women who had nonproliferative lesions without a family history (95 per cent confidence interval, 5.5 to 24). Calcification elevated the cancer risk in patients with proliferative disease. Although cysts alone did not substantially elevate the risk, women with both cysts and a family history of breast cancer had a risk 2.7 times higher than that for women without either of these risk factors (95 per cent confidence interval, 1.5 to 4.6). This study demonstrates that the majority of women (70 per cent) who undergo breast biopsy for benign disease are not at increased risk of cancer. However, patients with a clinically meaningful elevation in cancer risk can be identified on the basis of atypical hyperplasia and a family history of breast cancer.

Retinoic Acid Embryopathy

Abstract: Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.

Abstract: We found that a cohort of patients with lung cancer first treated in 1977 had higher six-month survival rates for the total group and for subgroups in each of the three main TNM stages (tumor, nodes, and metastases) than a cohort treated between 1953 and 1964 at the same institutions. The more recent cohort, however, had undergone many new diagnostic imaging procedures. According to the "old" diagnostic data for both cohorts, the recent cohort had a prognostically favorable "zero-time shift." In addition, by demonstrating metastases that had formerly been silent and unidentified, the new technological data resulted in a stage migration. Many patients who previously would have been classified in a "good" stage were assigned to a "bad" stage. Because the prognosis of those who migrated, although worse than that for other members of the good-stage group, was better than that for other members of the bad-stage group, survival rates rose in each group without any change in individual outcomes. When cl...

Clinical prediction rules. Applications and methodological standards.

Abstract: The objective of clinical prediction rules is to reduce the uncertainty inherent in medical practice by defining how to use clinical findings to make predictions. Clinical prediction rules are derived from systematic clinical observations. They can help physicians identify patients who require diagnostic tests, treatment, or hospitalization. Before adopting a prediction rule, clinicians must evaluate its applicability to their patients. We describe methodological standards that can be used to decide whether a prediction rule is suitable for adoption in a clinician's practice. We applied these standards to 33 reports of prediction rules; 42 per cent of the reports contained an adequate description of the prediction rules, the patients, and the clinical setting. The misclassification rate of the rule was measured in only 34 per cent of reports, and the effects of the rule on patient care were described in only 6 per cent of reports. If the objectives of clinical prediction rules are to be fully achieved, authors and readers need to pay close attention to basic principles of study design.

Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction

Abstract: Certain risk factors for myocardial infarction have been linked with disturbances in fibrinolytic activity. The recent development in our laboratory of new sensitive and specific methods for determination of tissue plasminogen activator (t-PA) activity and antigen, as well as the discovery of a new rapid inhibitor of this enzyme, enabled us to study fibrinolytic function in detail in a representative population of postinfarction patients. Seventy-one patients (62 men and 9 women) who had survived a myocardial infarction before the age of 45 were compared with 50 healthy subjects of similar age, three years after the infarction. Low t-PA activity after venous occlusion, mostly explained by high plasma levels of the t-PA inhibitor and to some extent by impaired release of t-PA from the vessel wall, was a frequent finding in the patients. The level of t-PA inhibitor was positively and significantly correlated with levels of serum triglycerides. Our data suggest that reduced fibrinolytic capacity due to increased plasma levels of a rapid inhibitor of t-PA may have pathogenetic importance in myocardial infarction, particularly in patients with hypertriglyceridemia.

Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation

Abstract: In 1971 we began a randomized trial to compare alternative local and regional treatments of breast cancer, all of which employ breast removal. Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months. There were no significant differences among three groups of patients with clinically negative axillary nodes, with respect to disease-free survival, distant-disease--free survival, or overall survival (about 57 per cent) at 10 years. The patients were treated by radical mastectomy, total ("simple") mastectomy without axillary dissection but with regional irradiation, or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive. Similarly, no differences were observed between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation. Survival at 10 years was about 38 per cent in both groups. Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival. The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years. We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer.

Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function

Abstract: The effects of dietary fish-oil fatty acids on the function of the 5-lipoxygenase pathway of peripheral-blood polymorphonuclear leukocytes and monocytes were determined in seven normal subjects who supplemented their usual diet for six weeks with daily doses of triglycerides containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid. The diet increased the eicosapentaenoic acid content in neutrophils and monocytes more than sevenfold, without changing the quantities of arachidonic acid and docosahexaenoic acid. When the neutrophils were activated, the release of [3H]arachidonic acid and its labeled metabolites was reduced by a mean of 37 per cent, and the maximum generation of three products of the 5-lipoxygenase pathway was reduced by more than 48 per cent. The ionophore-induced release of [3H]arachidonic acid and its labeled metabolites from monocytes in monolayers was reduced by a mean of 39 per cent, and the generation of leukotriene B4 by 58 per cent. The adherence of neutrophils to bovine endothelial-cell monolayers pretreated with leukotriene B4 was inhibited completely, and their average chemotactic response to leukotriene B4 was inhibited by 70 per cent, as compared with values determined before the diet was begun and six weeks after its discontinuation. We conclude that diets enriched with fish-oil-derived fatty acids may have antiinflammatory effects by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4-mediated functions of neutrophils.

The Quality of Life of Patients with End-Stage Renal Disease

Abstract: We assessed the quality of life of 859 patients undergoing dialysis or transplantation, with the goal of ascertaining whether objective and subjective measures of the quality of life were influenced by case mix or treatment. We found that 79.1 per cent of the transplant recipients were able to function at nearly normal levels, as compared with between 47.5 and 59.1 per cent of the patients treated with dialysis (depending on the type). Nearly 75 per cent of the transplant recipients were able to work, as compared with between 24.7 and 59.3 per cent of the patients undergoing dialysis. On three subjective measures (life satisfaction, well-being, and psychological affect) transplant recipients had a higher quality of life than patients on dialysis. Among the patients treated with dialysis, those undergoing treatment at home had the highest quality of life. All quality-of-life differences were found to persist even after the patient case mix had been controlled statistically. Finally, the quality of life of transplant recipients compared well with that of the general population, but despite favorable subjective assessments, patients undergoing dialysis did not work or function at the same level as people in the general population.

Pasteurized milk as a vehicle of infection in an outbreak of listeriosis.

Abstract: Between June 30th and August 30th, 1983, 49 patients in Massachusetts acquired listeriosis. Seven cases occurred in fetuses or infants and 42 in immunosuppressed adults; 14 patients (29 per cent) died. Of 40 Listeria monocytogenes isolates available for testing, 32 were serotype 4b. Two case-control studies, one matching for neighborhood of residence and the other for underlying disease, revealed that the illness was strongly associated with drinking a specific brand of pasteurized whole or 2 per cent milk (odds ratio = 9, P less than 0.01 for the neighborhood-matched study; odds ratio = 11.5, P less than 0.001 for the illness-matched study). The association with milk was further substantiated by four additional analyses that suggested the presence of a dose-response effect, demonstrated a protective effect of skim milk, associated cases with the same product in an independent study in another state, and linked a specific phage type with the disease associated with milk. The milk associated with disease came from a group of farms on which listeriosis in dairy cows was known to have occurred at the time of the outbreak. Multiple serotypes of L. monocytogenes were isolated from raw milk obtained from these farms after the outbreak. At the plant where the milk was processed, inspections revealed no evidence of improper pasteurization. These results support the hypothesis that human listeriosis can be a foodborne disease and raise questions about the ability of pasteurization to eradicate a large inoculum of L. monocytogenes from contaminated raw milk.

Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial.

Abstract: We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months) The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 86 per cent in the groups given aspirin and 170 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0008) The corresponding figures for either cardiac death alone or death from any cause were 30 per cent in the groups given aspirin and 117 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0004) Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0072), 56 per cent (P = 0009), and 43 per cent (P = 0035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina

Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures

Abstract: We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic—clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P<0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic—clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete c...

Isolation of HTLV-III from Cerebrospinal Fluid and Neural Tissues of Patients with Neurologic Syndromes Related to the Acquired Immunodeficiency Syndrome

Abstract: We conducted virus-isolation studies on 56 specimens from the nervous system of 45 patients in order to determine whether human T-cell lymphotropic virus Type III (HTLV-III) is directly involved in the pathogenesis of the neurologic disorders frequently encountered in the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. We recovered HTLV-III from at least one specimen from 24 of 33 patients with AIDS-related neurologic syndromes. In one patient, HTLV-III was isolated from the cerebrospinal fluid during acute aseptic meningitis associated with HTLV-III seroconversion. HTLV-III was also isolated from cerebrospinal fluid from six of seven patients with AIDS or its related complex and unexplained chronic meningitis. In addition, of 16 patients with AIDS-related dementia, 10 had positive cultures for HTLV-III in cerebrospinal fluid, brain tissue, or both. Furthermore, we cultured HTLV-III from the spinal cord of a patient with myelopathy and from the sural nerve of a patient with peripheral neuropathy. These findings suggest that HTLV-III is neurotropic, is capable of causing acute meningitis, is responsible for AIDS-related chronic meningitis and dementia, and may be the cause of the spinal-cord degeneration and peripheral neuropathy in AIDS and AIDS-related complex.

Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.

Abstract: We analyzed survival and causes of death among 163 patients with primary hemochromatosis diagnosed between 1959 and 1983. The mean follow-up period was 10.5 +/- 5.6 years (+/- S.D.). Cumulative survival was 92 per cent at 5 years, 76 per cent at 10 years, 59 per cent at 15 years, and 49 per cent at 20 years. Life expectancy was reduced in patients with cirrhosis of the liver as compared with those without cirrhosis (P less than or equal to 0.05), in patients with diabetes mellitus as compared with those without diabetes (P less than or equal to 0.002), and in patients who could not be depleted of iron during the first 18 months of venesection therapy as compared with those who could be depleted (P less than or equal to 0.001). Prognosis was not influenced by sex (P less than or equal to 0.5). Patients without cirrhosis had a life expectancy that was not different from that expected in an age- and sex-matched normal population. Analysis of the causes of death in 53 patients, as compared with the normal population, showed that liver cancer was 219 times more frequent among the patients (16 patients), cardiomyopathy was 306 times more frequent (3 patients), liver cirrhosis was 13 times more frequent (10 patients), and diabetes mellitus was 7 times more frequent (3 patients). Death rates for other causes, including extrahepatic carcinomas (seven patients), were not different from the rates expected. We conclude that patients with hemochromatosis diagnosed in the precirrhotic stage and treated by venesection have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.

In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis.

Abstract: After the death of a 12-year old girl with newly discovered insulin-dependent diabetes mellitus, we used monoclonal antibodies in an effort to identify the cells invading the pancreas. The majority of infiltrating lymphocytes were of the T cytotoxic/suppressor phenotype, but other T-cell subpopulations were present. Some of the T cells were "activated" (positive for HLA-DR antigen, and the interleukin-2 receptor). Immunocytes bearing IgG were scattered in the gland, and complement-fixing IgG antibodies were deposited in some islets. Increased expression of Class I (HLA-A, B, and C) molecules was observed in the affected islet cells, and in damaged islets showing scant lymphocytic infiltration, some beta cells (still producing insulin), but not glucagon or somatostatin cells, were HLA-DR positive. The capillary endothelium was markedly dilated and strongly HLA-DR positive. These findings may contribute to an understanding of the sequence of events leading to the destruction of beta cells in classic Type I diabetes mellitus.

Bronchiolitis obliterans organizing pneumonia.

Abstract: In 50 of 94 patients with bronchiolitis obliterans we found no apparent cause or associated disease, and the bronchiolitis obliterans occurred with patchy organizing pneumonia. Histologic characteristics included polypoid masses of granulation tissue in lumens of small airways, alveolar ducts, and some alveoli. The fibrosis was uniform in age, suggesting that all repair had begun at the same time. The distribution was patchy, with preservation of background architecture. Clinically, there was cough or flu-like illness for 4 to 10 weeks, and crackles were heard in the lungs of 68 per cent of the patients. Radiographs showed an unusual pattern of patchy densities with a "ground glass" appearance in 81 per cent. Physiologically, there was restriction in 72 per cent of the patients, and 86 per cent had impaired diffusing capacity. Obstruction was limited to smokers. The mean follow-up period was four years. With corticosteroids, there was complete clinical and physiologic recovery in 65 per cent of the subjects; two died from progressive disease. This disorder differs from bronchiolitis obliterans with irreversible obstruction. It was confused most often with idiopathic pulmonary fibrosis. In view of the benign course and therapeutic response, a histologic distinction is important.

The treatment of cancer pain.

Abstract: Pain is one of the most feared consequences of cancer Control of pain from cancer should be possible with the approaches discussed above Changing attitudes toward the effective use of narcotic analgesics, the development of novel routes and methods of administration, and a clinical approach based on scientific principles and humane care offer the promise of improved management of pain in patients with cancer

Efficacy of low-dose methotrexate in rheumatoid arthritis.

Abstract: Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Reduction of Plasma Lipids, Lipoproteins, and Apoproteins by Dietary Fish Oils in Patients with Hypertriglyceridemia

Abstract: Dietary fish oils, which are rich in omega-3 fatty acids, have been reported to reduce plasma lipid levels in normolipidemic subjects. We examined the effects of fish oil in 20 hypertriglyceridemic patients: 10 with Type IIb hyperlipidemia and 10 with Type V. These patients were put on three diets differing primarily in fatty acid composition and fat content. The control diet contained a fatty acid mixture typical of a low-fat therapeutic diet (ratio of polyunsaturated to saturated fat, 1.4), the fish-oil diet contained omega-3 fatty acids, and the vegetable-oil diet was rich in the omega-6 fatty acid, linoleic acid. Each diet was followed for four weeks. In the Type IIb group, the fish-oil diet led to decreases in both plasma cholesterol (-27 per cent) and triglyceride (-64 per cent), as compared with the control diet. Very-low-density lipoproteins (VLDLs) were also reduced markedly. The vegetable-oil diet had much less effect. With fish oil, the Type V group had marked decreases in total cholesterol and triglyceride levels (-45 and -79 per cent, respectively). VLDL levels were dramatically lowered, as were apoprotein E levels. The vegetable-oil diet (unlike the fish-oil diet) produced a rapid and significant rise in plasma triglyceride levels. We conclude that fish oils and fish may be useful components of diets for the treatment of hypertriglyceridemia.

A Prospective Study of Postmenopausal Estrogen Therapy and Coronary Heart Disease

Abstract: To clarify the possible role of postmenopausal estrogen use in coronary heart disease, we surveyed 121,964 female nurses, aged 30 to 55 years, with mailed questionnaires, beginning in 1976. Information on hormone use and other potential risk factors was updated and the incidence of coronary heart disease was ascertained through additional questionnaires in 1978 and 1980, with a 92.7 per cent follow-up. End points were documented by medical records. During 105,786 person-years of observation among 32,317 postmenopausal women who were initially free of coronary disease, 90 women had either nonfatal myocardial infarctions (65 cases) or fatal coronary heart disease (25 cases). As compared with the risk in women who had never used postmenopausal hormones, the age-adjusted relative risk of coronary disease in those who had ever used them was 0.5 (95 per cent confidence limits, 0.3 and 0.8; P = 0.007), and the risk in current users was 0.3 (95 per cent confidence limits, 0.2 and 0.6; P = 0.001). The relative risks were similar for fatal and nonfatal disease and were unaltered after adjustment for cigarette smoking, hypertension, diabetes, high cholesterol levels, a parental history of myocardial infarction, past use of oral contraceptives, and obesity. These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease.

Replication of Epstein–Barr Virus within the Epithelial Cells of Oral Hairy Leukoplakia, an AIDS-Associated Lesion

Abstract: We conducted a study to identify the viruses in tissue specimens of oral "hairy" leukoplakia, a lesion that is found in immunosuppressed male homosexuals and that is associated with the subsequent development of the acquired immunodeficiency syndrome. When stained for papillomavirus core antigen, 49 of 67 biopsy specimens (73 per cent) yielded positive results in epithelial-cell nuclei. Electron microscopy showed papillomavirus-like particles in all of 25 specimens, and the herpes-type virus described in a previous report was seen in 23 of the 25 specimens. Three specimens had both types of particle in the same individual epithelial cells. Immunofluorescence for herpes simplex virus, varicella-zoster virus, and cytomegalovirus gave negative results in all cases, but 19 of 20 specimens showed intense nuclear staining in epithelial cells for the viral capsid antigen of Epstein-Barr virus (EBV). DNA hybridization using EBV probes in Southern blots demonstrated EBV DNA in all of 13 specimens and found 200 or more viral DNA molecules per cellular genome in 11 of the 13. The whole EBV genome was also demonstrated in the specimens and found to be in linear virion form. We conclude that EBV replicates within the epithelial cells in hairy leukoplakia.