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Showing papers in "The New England Journal of Medicine in 1993"


Journal ArticleDOI
TL;DR: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Abstract: Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Methods A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

21,148 citations


Journal ArticleDOI
TL;DR: The prevalence of undiagnosed sleep-disordered breathing is high among men and is much higher than previously suspected among women, and is associated with daytime hypersomnolence.
Abstract: Background Limited data have suggested that sleep-disordered breathing, a condition of repeated episodes of apnea and hypopnea during sleep, is prevalent among adults. Data from the Wisconsin Sleep Cohort Study, a longitudinal study of the natural history of cardiopulmonary disorders of sleep, were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health. Methods A random sample of 602 employed men and women 30 to 60 years old were studied by overnight polysomnography to determine the frequency of episodes of apnea and hypopnea per hour of sleep (the apnea-hypopnea score). We measured the age- and sex-specific prevalence of sleep-disordered breathing in this group using three cutoff points for the apnea-hypopnea score (≥ 5, ≥ 10, and ≥ 15); we used logistic regression to investigate risk factors. Results The estimated prevalence of sleep-disordered breathing, defined as an apnea-hypopnea score of 5 or higher, was 9 percent for w...

9,642 citations


Journal ArticleDOI
TL;DR: It is suggested that fine-particulate air pollution, or a more complex pollution mixture associated with fine particulate matter, contributes to excess mortality in certain U.S. cities.
Abstract: Background Recent studies have reported associations between particulate air pollution and daily mortality rates. Population-based, cross-sectional studies of metropolitan areas in the United States have also found associations between particulate air pollution and annual mortality rates, but these studies have been criticized, in part because they did not directly control for cigarette smoking and other health risks. Methods In this prospective cohort study, we estimated the effects of air pollution on mortality, while controlling for individual risk factors. Survival analysis, including Cox proportional-hazards regression modeling, was conducted with data from a 14-to-16-year mortality follow-up of 8111 adults in six U.S. cities. Results Mortality rates were most strongly associated with cigarette smoking. After adjusting for smoking and other risk factors, we observed statistically significant and robust associations between air pollution and mortality. The adjusted mortality-rate ratio for the most po...

7,194 citations


Journal ArticleDOI
TL;DR: The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes.
Abstract: The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

6,464 citations


Journal ArticleDOI
TL;DR: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.
Abstract: Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was Results Two hundred seven patients received captopril, and 202 placebo Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0007) The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 20 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 15 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 10 mg per deciliter (884 mumol per liter) The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 003) Among the patients whose base-line serum creatinine concentration was > or = 15 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 001) Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups Conclusions Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone

4,772 citations


Journal ArticleDOI
TL;DR: The results of the National Polyp Study support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent coloreCTal cancer.
Abstract: Background The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. Methods The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. Results Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned...

4,310 citations


Journal Article
TL;DR: The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.
Abstract: BACKGROUND Although many patients with intermediate-grade or high-grade (aggressive) non-Hodgkin's lymphoma are cured by combination chemotherapy, the remainder are not cured and ultimately die of their disease. The Ann Arbor classification, used to determine the stage of this disease, does not consistently distinguish between patients with different long-term prognoses. This project was undertaken to develop a model for predicting outcome in patients with aggressive non-Hodgkin's lymphoma on the basis of the patients' clinical characteristics before treatment. METHODS Adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death. RESULTS In 2031 patients of all ages, our model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival. CONCLUSIONS The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.

4,310 citations


Journal ArticleDOI
TL;DR: The frequency of use of unconventional therapy in the United States is far higher than previously reported and expenditure associated with use in 1990 amounted to approximately $13.7 billion, comparable to the $12.8 billion spent out of pocket annually for all hospitalizations in theUnited States.
Abstract: Background Many people use unconventional therapies for health problems, but the extent of this use and the costs are not known. We conducted a national survey to determine the prevalence, costs, and patterns of use of unconventional therapies, such as acupuncture and chiropractic. Methods We limited the therapies studied to 16 commonly used interventions neither taught widely in U.S. medical schools nor generally available in U.S. hospitals. We completed telephone interviews with 1539 adults (response rate, 67 percent) in a national sample of adults 18 years of age or older in 1990. We asked respondents to report any serious or bothersome medical conditions and details of their use of conventional medical services; we then inquired about their use of unconventional therapy. Results One in three respondents (34 percent) reported using at least one unconventional therapy in the past year, and a third of these saw providers for unconventional therapy. The latter group had made an average of 19 visits to suc...

4,223 citations


Journal ArticleDOI
TL;DR: The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous standard thrombolytic regimens.
Abstract: BACKGROUND: The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute myocardial infarction are unresolved questions. The current trial was designed to compare new, aggressive thrombolytic strategies with standard thrombolytic regimens in the treatment of acute myocardial infarction. Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained reperfusion would improve survival. METHODS: In 15 countries and 1081 hospitals, 41,021 patients with evolving myocardial infarction were randomly assigned to four different thrombolytic strategies, consisting of the use of streptokinase and subcutaneous heparin, streptokinase and intravenous heparin, accelerated tissue plasminogen activator (t-PA) and intravenous heparin, or a combination of streptokinase plus t-PA with intravenous heparin. ("Accelerated" refers to the administration of t-PA over a period of 1 1/2 hours--with two thirds of the dose given in the first 30 minutes--rather than the conventional period of 3 hours.) The primary end point was 30-day mortality. RESULTS: The mortality rates in the four treatment groups were as follows: streptokinase and subcutaneous heparin, 7.2 percent; streptokinase and intravenous heparin, 7.4 percent; accelerated t-PA and intravenous heparin, 6.3 percent, and the combination of both thrombolytic agents with intravenous heparin, 7.0 percent. This represented a 14 percent reduction (95 percent confidence interval, 5.9 to 21.3 percent) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies (P = 0.001). The rates of hemorrhagic stroke were 0.49 percent, 0.54 percent, 0.72 percent, and 0.94 percent in the four groups, respectively, which represented a significant excess of hemorrhagic strokes for accelerated t-PA (P = 0.03) and for the combination strategy (P < 0.001), as compared with streptokinase only. A combined end point of death or disabling stroke was significantly lower in the accelerated-tPA group than in the streptokinase-only groups (6.9 percent vs. 7.8 percent, P = 0.006). CONCLUSIONS: The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous standard thrombolytic regimens

3,690 citations


Journal ArticleDOI
TL;DR: Whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy is determined.
Abstract: Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was ≥ 500 mg per day and the serum creatinine concentration was ≤ 2.5 mg per deciliter (221 μmol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. Results Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P =0.007). The associated reductions in risk...

3,618 citations


Journal ArticleDOI
TL;DR: Cutting mortality in the annually screened group was accompanied by improved survival in those with colorectal cancer and a shift to detection at an earlier stage of cancer.
Abstract: Background Although tests for occult blood in the feces are widely used to screen for colorectal cancers, there is no conclusive evidence that they reduce mortality from this cause. We evaluated a fecal occult-blood test in a randomized trial and documented its effectiveness. Methods We randomly assigned 46,551 participants 50 to 80 years of age to screening for colorectal cancer once a year, to screening every two years, or to a control group. Participants who were screened submitted six guaiac-impregnated paper slides with two smears from each of three consecutive stools. About 83 percent of the slides were rehydrated. Participants who tested positive underwent a diagnostic evaluation that included colonoscopy. Vital status was ascertained for all participants over 13 years of follow-up. A committee determined causes of death. A single pathologist determined the stage of cancer for each tissue specimen. Differences in mortality from colorectal cancer, the primary study end point, were monitored with the...

Journal ArticleDOI
TL;DR: Evidence is provided of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men, and public policy recommendations with regard to the use ofitamin E supplements should await the results of additional studies.
Abstract: Background The oxidative modification of low-density lipoproteins increases their incorporation into the arterial intima, an essential step in atherogenesis. Although dietary antioxidants, such as vitamin C, carotene, and vitamin E, have been hypothesized to prevent coronary heart disease, prospective epidemiologic data are sparse. Methods In 1986, 39,910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C, carotene, and vitamin E in addition to other nutrients. During four years of follow-up, we documented 667 cases of coronary disease. Results After controlling for age and several coronary risk factors, we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E, the multivariate relative risk was 0.64 (95 percent confidence in...


Journal ArticleDOI
TL;DR: CHOP remains the best available treatment for patients with advanced-stage intermediate-grade or high-grade non-Hodgkin's lymphoma.
Abstract: Background CHOP is a first-generation, combination-chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone that has cured approximately 30 percent of patients with advanced stages of intermediate-grade or high-grade non-Hodgkin's lymphoma in national cooperative-group trials. However, studies at single institutions have suggested that 55 to 65 percent of such patients might be cured by third-generation regimens such as ones consisting of low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD); prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue (ProMACE-CytaBOM); and methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). Methods To make a valid comparison of these regimens, the Southwest Oncology Group and the Eastern Cooperative Oncology Gro...

Journal ArticleDOI
TL;DR: The clinical features of ovarian cancer and recent advances in postoperative management are described, including bilateral salpingo-oophorectomy in selected women.
Abstract: Patients with ovarian cancer usually present with advanced disease, and the disease is generally managed with surgical resection followed by platinum-based chemotherapy. Recent chemotherapeutic advances have led to improved survival, and a better understanding of genetic risk factors has permitted a tailored approach to preventive strategies, such as bilateral salpingo-oophorectomy in selected women. This review describes the clinical features of ovarian cancer and recent advances in postoperative management.

Journal ArticleDOI
TL;DR: As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66, after adjustment for age and smoking.
Abstract: Background Interest in the antioxidant vitamin E as a possible protective nutrient against coronary disease has intensified with the recognition that oxidized low-density lipoprotein may be involved in atherogenesis. Methods In 1980, 87,245 female nurses 34 to 59 years of age who were free of diagnosed cardiovascular disease and cancer completed dietary questionnaires that assessed their consumption of a wide range of nutrients, including vitamin E. During follow-up of up to eight years (679,485 person-years) that was 97 percent complete, we documented 552 cases of major coronary disease (437 nonfatal myocardial infarctions and 115 deaths due to coronary disease). Results As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 (95 percent confidence interval, 0.50 to 0.87) after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, includi...

Journal ArticleDOI
TL;DR: Starting moderately vigorous sports activity, quitting cigarette smoking, maintaining normal blood pressure, and avoiding obesity were separately associated with lower rates of death from all causes and from coronary heart disease among middle-aged and older men.
Abstract: Background Recent trends toward increasing physical exercise, stopping cigarette smoking, and avoiding obesity may increase longevity. We analyzed changes in the lifestyles of Harvard College alumni and the associations of these changes with mortality. Methods Men who were 45 to 84 years of age in 1977 and who had reported no life-threatening disease on questionnaires completed in 1962 or 1966 and again in 1977 were classified according to changes in lifestyle characteristics between the first and second questionnaires. We analyzed changes in their level of physical activity, cigarette smoking, blood pressure, and body weight, and the relation of these factors to mortality between 1977 and 1985. Results Of the 10,269 men, 476 died during this period (which totaled 90,650 man-years of observation). Beginning moderately vigorous sports activity (at an intensity of 4.5 or more metabolic equivalents) was associated with a 23 percent lower risk of death (95 percent confidence interval, 4 to 42 percent; P = 0.0...

Journal ArticleDOI
TL;DR: As compared with t-PA therapy for acute myocardial infarction, immediate PTCA reduced the combined occurrence of nonfatal reinfarction or death, was associated with a lower rate of intracranial hemorrhage, and resulted in similar left ventricular systolic function.
Abstract: Background The success of thrombolytic therapy for acute myocardial infarction is limited by bleeding complications, the impossibility of reperfusing all occluded coronary arteries, recurrent myocardial ischemia, and the relatively small number of patients who are appropriate candidates for this therapy. We hypothesized that these problems could be overcome by the use of immediate percutaneous transluminal coronary angioplasty (PTCA), without previous thrombolytic therapy. Methods At 12 clinical centers, 395 patients who presented within 12 hours of the onset of myocardial infarction were treated with intravenous heparin and aspirin and then randomly assigned to undergo immediate PTCA (without previous thrombolytic therapy, 195 patients) or to receive intravenous tissue plasminogen activator (t-PA, 200 patients) followed by conservative care. Radionuclide ventriculography was performed to assess ventricular function within 24 hours and at six weeks. Results Among the patients randomly assigned to PTCA, 90...

Journal ArticleDOI
TL;DR: Preliminary results suggest that pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endethelin- 1 may contribute to the vascular abnormalities associated with this disorder.
Abstract: Background Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. Methods We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. Results In the controls, endothelin-1-like immu...

Journal ArticleDOI
TL;DR: Inhalation of nitric oxide by patients with severe adult respiratory distress syndrome reduces the pulmonary-artery pressure and increases arterial oxygenation by improving the matching of ventilation with perfusion, without producing systemic vasodilation.
Abstract: Background The adult respiratory distress syndrome is characterized by pulmonary hypertension and right-to-left shunting of venous blood. We investigated whether inhaling nitric oxide gas would cause selective vasodilation of ventilated lung regions, thereby reducing pulmonary hypertension and improving gas exchange. Methods Nine of 10 consecutive patients with severe adult respiratory distress syndrome inhaled nitric oxide in two concentrations for 40 minutes each. Hemodynamic variables, gas exchange, and ventilation-perfusion distributions were measured by means of multiple inert-gas-elimination techniques during nitric oxide inhalation; the results were compared with those obtained during intravenous infusion of prostacyclin. Seven patients were treated with continuous inhalation of nitric oxide in a concentration of 5 to 20 parts per million (ppm) for 3 to 53 days. Results Inhalation of nitric oxide in a concentration of 18 ppm reduced the mean (±SE) pulmonary-artery pressure from 37 ±3 mm Hg to 30 ±2...

Journal ArticleDOI
TL;DR: Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.
Abstract: Background Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. Methods We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. Results A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number...

Journal ArticleDOI
TL;DR: This study supports the hypothesis that more rapid and complete restoration of coronary flow through the infarct-related artery results in improved ventricular performance and lower mortality among patients with myocardial infarction.
Abstract: BACKGROUND Although it is known that thrombolytic therapy improves survival after acute myocardial infarction, it has been debated whether the speed with which coronary-artery patency is restored after the initiation of therapy further affects outcome. METHODS To study this question, we randomly assigned 2431 patients to one of four treatment strategies for reperfusion: streptokinase with subcutaneous heparin; streptokinase with intravenous heparin; accelerated-dose tissue plasminogen activator (t-PA) with intravenous heparin; or a combination of both activators plus intravenous heparin. Patients were also randomly assigned to cardiac angiography at one of four times after the initiation of thrombolytic therapy: 90 minutes, 180 minutes, 24 hours, or 5 to 7 days. The group that underwent angiography at 90 minutes underwent it again after 5 to 7 days. RESULTS The rate of patency of the infarct-related artery at 90 minutes was highest in the group given accelerated-dose t-PA and heparin (81 percent), as compared with the group given streptokinase and subcutaneous heparin (54 percent, P < 0.001), the group given streptokinase and intravenous heparin (60 percent, P < 0.001), and the group given combination therapy (73 percent, P = 0.032). Flow through the infarct-related artery at 90 minutes was normal in 54 percent of the group given t-PA and heparin but in less than 40 percent in the three other groups (P < 0.001). By 180 minutes, the patency rates were the same in the four treatment groups. Reocclusion was infrequent and was similar in all four groups (range, 4.9 to 6.4 percent). Measures of left ventricular function paralleled the rate of patency at 90 minutes; ventricular function was best in the group given t-PA with heparin and in patients with normal flow through the infarct-related artery irrespective of treatment group. Mortality at 30 days was lowest (4.4 percent) among patients with normal coronary flow at 90 minutes and highest (8.9 percent) among patients with no flow (P = 0.009). CONCLUSIONS This study supports the hypothesis that more rapid and complete restoration of coronary flow through the infarct-related artery results in improved ventricular performance and lower mortality among patients with myocardial infarction. This would appear to be the mechanism by which accelerated t-PA therapy produced the most favorable outcome in the GUSTO trial.

Journal ArticleDOI
TL;DR: Overweight during adolescence has important social and economic consequences, which are greater than those of many other chronic physical conditions and discrimination against overweight persons may account for these results.
Abstract: Background and Methods Overweight in adolescents may have deleterious effects on their subsequent self-esteem, social and economic characteristics, and physical health. We studied the relation between overweight and subsequent educational attainment, marital status, household income, and self-esteem in a nationally representative sample of 10,039 randomly selected young people who were 16 to 24 years old in 1981. Follow-up data were obtained in 1988 for 65 to 79 percent of the original cohort, depending on the variable studied. The characteristics of the subjects who had been overweight in 1981 were compared with those for young people with asthma, musculoskeletal abnormalities, and other chronic health conditions. Overweight was defined as a body-mass index above the 95th percentile for age and sex. Results In 1981, 370 of the subjects were overweight. Seven years later, women who had been overweight had completed fewer years of school (0.3 year less; 95 percent confidence interval, 0.1 to 0.6; P = 0.009...

Journal ArticleDOI
TL;DR: One of the most frequent and serious problems confronting clinicians is the management of a serious infection and the systemic response to infection, a syndrome termed sepsis, when this syndrome results in hypotension and organ dysfunction, called septic shock.
Abstract: One of the most frequent and serious problems confronting clinicians is the management of a serious infection and the systemic response to infection, a syndrome termed sepsis. When this syndrome results in hypotension and organ dysfunction, it is called septic shock. Septic shock is the most common cause of death in intensive care units,1 and it is the 13th most common cause of death in the United States2. The incidence of the two disorders continues to rise: 400,000 cases of sepsis and 200,000 episodes of septic shock are estimated to occur annually, resulting in more than 100,000 deaths1. . . .

Journal ArticleDOI
TL;DR: A multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries finds that pancreatitis may be a risk factor for pancreatic cancer, but the magnitude of the relation between these two diseases is unclear.
Abstract: Background The results of case-control studies and anecdotal reports suggest that pancreatitis may be a risk factor for pancreatic cancer, but there have been no studies of sufficient size and power to assess the magnitude of the relation between these two diseases. Methods and Results We undertook a multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean (±SD) follow-up of 7.4 ±6.2 years. The expected number of cases of cancer calculated from country-specific incidence data and adjusted for age and sex was 2.13, yielding a standardized incidence ratio (the ratio of observed to expected cases) of 26.3 (95 percent confidence interval, 19.9 to 34.2). For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8...

Journal ArticleDOI
TL;DR: Obesity, insulin resistance, and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM.
Abstract: Background The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. Methods A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic-euglycemic clamp study were performed in 200 nondiabetic Pima Indians (87 women and 113 men; mean [±SD] age, 26 ±6 years). The subjects were followed yearly thereafter for an average of 5.3 years. Results Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM. The six-year cumulative incidence of NIDDM was 39 percent in persons with values belo...

Journal ArticleDOI
TL;DR: Despite an overall decline in death rates in the United States since 1960, poor and poorly educated people still die at higher rates than those with higher incomes or better educations, and this disparity increased between 1960 and 1986.
Abstract: Background There is an inverse relation between socioeconomic status and mortality. Over the past several decades death rates in the United States have declined, but it is unclear whether all socioeconomic groups have benefited equally. Methods Using records from the 1986 National Mortality Followback Survey (n = 13,491) and the 1986 National Health Interview Survey (n = 30,725), we replicated the analysis by Kitagawa and Hauser of differential mortality in 1960. We calculated direct standardized mortality rates and indirect standardized mortality ratios for persons 25 to 64 years of age according to race, sex, income, and family status. Results The inverse relation between mortality and socioeconomic status persisted in 1986 and was stronger than in 1960. The disparity in mortality rates according to income and education increased for men and women, whites and blacks, and family members and unrelated persons. Over the 26-year period, the inequalities according to educational level increased for whites an...

Journal ArticleDOI
TL;DR: Advances in the isolation and characterization of liver cells, in conjunction with progress in matrix and cytokine biology, have led to important new insights about the cellular basis of hepatic fibrosis, including the hepatic lipocyte.
Abstract: Hepatic fibrosis is a common response to chronic liver injury from many causes, including alcohol, persistent viral and helminthic infections, and hereditary metal overload. Emerging evidence suggests that cellular mechanisms of hepatic fibrosis are shared among these different insults and, moreover, that the liver's response is a paradigm for parenchymal wound healing in other tissues. Advances in the isolation and characterization of liver cells, in conjunction with progress in matrix and cytokine biology, have led to important new insights about the cellular basis of hepatic fibrosis. In particular, the hepatic lipocyte (also known as the stellate, fat-storing, perisinusoidal, or Ito . . .

Journal ArticleDOI
TL;DR: The incidence of damage to the anal sphincter and the relation of injury to symptoms, anorectal physiologic function, and the mode of delivery was sought to determine.
Abstract: Background Lacerations of the anal sphincter or injury to sphincter innervation during childbirth are major causes of fecal incontinence, but the incidence and importance of occult sphincter damage during routine vaginal delivery are unknown. We sought to determine the incidence of damage to the anal sphincter and the relation of injury to symptoms, anorectal physiologic function, and the mode of delivery. Methods We studied 202 consecutive women six weeks before delivery, 150 of them six weeks after delivery, and 32 with abnormal findings six months after delivery. Symptoms of anal incontinence and fecal urgency were assessed, and anal endosonography, manometry, perineometry, and measurement of the terminal motor latency of the pudendal nerves were performed. Results Ten of the 79 primiparous women (13 percent) and 11 of the 48 multiparous women (23 percent) who delivered vaginally had anal incontinence or fecal urgency when studied six weeks after delivery. Twenty-eight of the 79 primiparous women (35 p...

Journal ArticleDOI
TL;DR: REM sleep is associated with profound sympathetic activation in normal subjects, possibly linked to changes in muscle tone and the hemodynamic and sympathetic changes during REM sleep could play a part in triggering ischemic events in patients with vascular disease.
Abstract: Background The early hours of the morning after awakening are associated with an increased frequency of events such as myocardial infarction and ischemic stroke. The triggering mechanisms for these events are not clear. We investigated whether autonomic changes occurring during sleep, particularly rapid-eye-movement (REM) sleep, contribute to the initiation of such events. Methods We measured blood pressure, heart rate, and sympathetic-nerve activity (using microneurography, which provides direct measurements of efferent sympathetic-nerve activity related to muscle blood vessels) in eight normal subjects while they were awake and while in the five stages of sleep. Results The mean (±SE) amplitude of bursts of sympathetic-nerve activity and levels of blood pressure and heart rate declined significantly (P<0.001), from 100 ±9 percent, 90 ±4 mm Hg, and 64 ±2 beats per minute, respectively, during wakefulness to 41 ±9 percent, 80 ±4 mm Hg, and 59 ±2 beats per minute, respectively, during stage 4 of non-REM sl...