Showing papers in "The New England Journal of Medicine in 1991"
TL;DR: Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis of the internal carotid artery.
Abstract: Background Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis. Methods We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up. Results Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients--an absolute risk reduction (+/- SE) 17 +/- 3.5 percent (P less than 0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent--an absolute risk reduction of 10.6 +/- 2.6 percent (P less than 0.001). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P less than 0.001). Conclusions Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery.
7,496 citations
TL;DR: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
Abstract: Background Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35. Methods Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months. Results There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001). Conclusions The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
7,460 citations
TL;DR: The number of microvessels per 200x field in the areas of most intensive neovascularization in an invasive breast carcinoma may be an independent predictor of metastatic disease either in axillary lymph nodes or at distant sites (or both).
Abstract: Background. Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without). Methods. Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocyto-chemically for factor VIII. The microvessels were carefully counted (per 200×field), and their density was graded (1 to 4+), in the most active areas of neovascularization, without knowledge of the outcome in the patient, the presence or absence of metastases, or any other pertinent variable. Results. Both microvessel counts and density grades correlated with metastatic disease. The mean (±SD) count and grade in the patients with metastases were 101±49.3 and 2.95±1.00 vessels, respect...
5,699 citations
TL;DR: There is a substantial amount of injury to patients from medical management, and many injuries are the result of substandard care.
Abstract: Background As part of an interdisciplinary study of medical injury and malpractice litigation, we estimated the incidence of adverse events, defined as injuries caused by medical management, and of the subgroup of such injuries that resulted from negligent or substandard care. Methods We reviewed 30,121 randomly selected records from 51 randomly selected acute care, nonpsychiatric hospitals in New York State in 1984. We then developed population estimates of injuries and computed rates according to the age and sex of the patients as well as the specialties of the physicians. Results Adverse events occurred in 3.7 percent of the hospitalizations (95 percent confidence interval, 3.2 to 4.2), and 27.6 percent of the adverse events were due to negligence (95 percent confidence interval, 22.5 to 32.6). Although 70.5 percent of the adverse events gave rise to disability lasting less than six months, 2.6 percent caused permanently disabling injuries and 13.6 percent led to death. The percentage of adverse events...
4,580 citations
TL;DR: Infection with H. pylori is associated with an increased risk of gastric adenocarcinoma and may be a cofactor in the pathogenesis of this malignant condition.
Abstract: Background. Infection with Helicobacter pylori has been linked with chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. In a nested case–control study, we explored whether H. pylori infection increases the risk of gastric carcinoma. Methods. From a cohort of 128,992 persons followed since the mid-1960s at a health maintenance organization, 186 patients with gastric carcinoma were selected as case patients and were matched according to age, sex, and race with 186 control subjects without gastric carcinoma. Stored serum samples collected during the 1960s were tested for IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Data on cigarette use, blood group, ulcer disease, and gastric surgery were obtained from questionnaires administered at enrollment. Tissue sections and pathology reports were reviewed to confirm the histologic results. Results. The mean time between serum collection and the diagnosis of gastric carcinoma was 14.2 years. Of the 109 patient...
3,882 citations
TL;DR: The high proportion that are due to management errors suggests that many others are potentially preventable now, and reducing the incidence of these events will require identifying their causes and developing methods to prevent error or reduce its effects.
Abstract: Background In a sample of 30,195 randomly selected hospital records, we identified 1133 patients (3.7 percent) with disabling injuries caused by medical treatment. We report here an analysis of these adverse events and their relation to error, negligence, and disability. Methods Two physician-reviewers independently identified the adverse events and evaluated them with respect to negligence, errors in management, and extent of disability. One of the authors classified each event according to type of injury. We tested the significance of differences in rates of negligence and disability among categories with at least 30 adverse events. Results Drug complications were the most common type of adverse event (19 percent), followed by wound infections (14 percent) and technical complications (13 percent). Nearly half the adverse events (48 percent) were associated with an operation. Adverse events during surgery were less likely to be caused by negligence (17 percent) than nonsurgical ones (37 percent). The proportion of adverse events due to negligence was highest for diagnostic mishaps (75 percent), noninvasive therapeutic mishaps ("errors of omission") (77 percent), and events occurring in the emergency room (70 percent). Errors in management were identified for 58 percent of the adverse events, among which nearly half were attributed to negligence. Conclusions Although the prevention of many adverse events must await improvements in medical knowledge, the high proportion that are due to management errors suggests that many others are potentially preventable now. Reducing the incidence of these events will require identifying their causes and developing methods to prevent error or reduce its effects.
3,734 citations
TL;DR: There was an excess of deathsDue to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide.
Abstract: Background and Methods. In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. Results. Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.0...
2,896 citations
TL;DR: The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.
Abstract: Background and Methods. To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator—Heart Failure Trial. Results. Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine—isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was m...
2,686 citations
TL;DR: Preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.
Abstract: Background We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. Methods Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. Results After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. Conclusions These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.
2,408 citations
TL;DR: The combination of measurement of the serum PSA concentration and rectal examination, with ultrasonography performed in patients with abnormal findings, provides a better method of detecting prostate cancer thanrectal examination alone.
Abstract: Background. Prostate-specific antigen (PSA) is secreted exclusively by prostatic epithelial cells, and its serum concentration is increased in men with prostatic disease, including cancer. We evaluated its usefulness in the detection and staging of prostate cancer. Methods. We measured serum PSA concentrations in 1653 healthy men 50 or more years old. Those with PSA values ≥4.0 μg per liter then underwent rectal examination and prostatic ultrasonography. Ultrasound-directed prostatic needle biopsies were performed in the men with abnormal findings on rectal examination, ultrasonography, or both. The results were compared with those in 300 consecutively studied men 50 or more years old who underwent ultrasound-directed biopsy because of symptoms or abnormal findings on rectal examination. Results. Serum PSA levels ranged from 4.0 to 9.9 μ9 per liter in 6.5 percent of the 1653 men (107). Nineteen of the 85 men in this group (22 percent) who had prostatic biopsies had prostate cancer. Serum PSA leve...
2,232 citations
TL;DR: Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.
Abstract: Background. Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine β-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine β-synthase deficiency. Methods. We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine β-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 μmol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The ...
TL;DR: The findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure.
Abstract: Background. Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. Methods. We randomly assigned 1088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with 40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). Results. As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent...
TL;DR: Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.
Abstract: Background The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results. Methods We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes. Results After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke. Conclusions Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.
TL;DR: Infection with H. pylori is strongly associated with an increased risk of gastric carcinoma, and the association was strong even for men in whom the diagnosis was made 10 or more years after the serum sample was obtained.
Abstract: Background. Helicobacter pylori are gram-negative spiral bacteria that are associated with chronic gastritis, a known precursor of gastric carcinoma. Persons at high risk for gastric carcinoma have been shown to have a high prevalence of H. pylori infection. Methods. We studied the relation of H. pylori infection and gastric carcinoma in a cohort of Japanese American men living in Hawaii. The 5908 men were enrolled and examined from 1967 to 1970. By 1989, 109 cases of pathologically confirmed gastric carcinoma had been identified. The stored serum of each patient with gastric carcinoma and of each matched control subject was tested for the presence of serum lgG antibody to H. pylori. Results. Ninety-four percent of the men with gastric carcinoma and 76 percent of the matched control subjects had a positive test for H. pylori antibodies, for an odds ratio of 6.0 (95 percent confidence interval, 2.1 to 17.3). As the level of antibody to H. pylori increased, there was a progressive increase in the r...
TL;DR: The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouredacil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.
Abstract: Background Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone. Methods Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). Results After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0...
TL;DR: A prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic throm bocytopenic purpura finds plasma exchange is more effective than plasma infusion.
Abstract: Background. Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura. Methods. One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after s...
TL;DR: Regular aspirin use at low doses may reduce the risk of fatal colon cancer in people who used aspirin 16 or more times per month for at least one year.
Abstract: Background and Methods. Experiments in animals and two epidemiologic studies in humans suggest that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) may be protective against colon cancer. We tested this hypothesis in a prospective mortality study of 662,424 adults who provided information in 1982 on the frequency and duration of their aspirin use. Death rates from colon cancer were measured through 1988. The possible influence of other risk factors for colon cancer was examined in multivariate analyses for 598 case patients and 3058 matched control subjects drawn from the cohort. Results. Death rates from colon cancer decreased with more frequent aspirin use in both men and women. The relative risk among persons who used aspirin 16 or more times per month for at least one year was 0.60 in men (95 percent confidence interval, 0.40 to 0.89) and 0.58 in women (95 percent confidence interval, 0.37 to 0.90). The risk estimates were unaffected when we excluded persons who reported at ent...
TL;DR: The protective effect of physical activity was strongest in persons at highest risk for NIDDM, defined as those with a high body-mass index, a history of hypertension, or a parental history of diabetes.
Abstract: Background. Physical activity is recommended by physicians to patients with non-insulin-dependent diabetes mellitus (NIDDM), because it increases sensitivity to insulin. Whether physical activity is effective in preventing this disease is not known. Methods. We used questionnaires to examine patterns of physical activity and other personal characteristics in relation to the subsequent development of NIDDM in 5990 male alumni of the University of Pennsylvania. The disease developed in a total of 202 men during 98,524 man-years of follow-up from 1962 to 1976. Results. Leisure-time physical activity, expressed in kilocalories expended per week in walking, stair climbing, and sports, was inversely related to the development of NIDDM. The incidence rates declined as energy expenditure increased from less than 500 kcal to 3500 kcal. For each 500-kcal increment in energy expenditure, the age-adjusted risk of NIDDM was reduced by 6 percent (relative risk, 0.94; 95 percent confidence interval, 0.90 to 0.98). This ...
TL;DR: Psychological stress was associated in a dose-response manner with an increased risk of acute infectious respiratory illness, and this risk was attributable to increased rates of infection rather than to an increased frequency of symptoms after infection.
Abstract: Background. It is not known whether psychological stress suppresses host resistance to infection. To investigate this issue, we prospectively studied the relation between psychological stress and the frequency of documented clinical colds among subjects intentionally exposed to respiratory viruses. Methods. After completing questionnaires assessing degrees of psychological stress, 394 healthy subjects were given nasal drops containing one of five respiratory viruses (rhinovirus type 2, 9, or 14, respiratory syncytial virus, or coronavirus type 229E), and an additional 26 were given saline nasal drops. The subjects were then quarantined and monitored for the development of evidence of infection and symptoms. Clinical colds were defined as clinical symptoms in the presence of an infection verified by the isolation of virus or by an increase in the virus-specific antibody titer. Results. The rates of both respiratory infection (P<0.005) and clinical colds (P<0.02) increased in a dose-response manner...
TL;DR: A randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection was conducted in this article, where the patients received either a single 100mg intravenous dose of HA-1A or placebo.
Abstract: Background HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia Methods To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection The patients received either a single 100-mg intravenous dose of HA-1A(in 35 g of albumin) or placebo (35 g of albumin) Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol Results Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0014) For the patients with gram-negative bacteremia and sho
TL;DR: Mutations within exon 8 of the Gs alpha gene that result in increased activity of theGs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome.
Abstract: Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, cafe au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the a subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hyb...
TL;DR: This work summarizes recent developments in pathogenesis, clinical presentation, treatment, and prevention of tuberculosis in HIV-infected persons over the past several years, as well as the effects of new antiretroviral therapies on antituberculosis regimens.
Abstract: Tuberculosis remains an important problem in patients with human immunodeficiency virus (HIV) infection in the United States, with an estimated 6000 to 9000 new cases annually.1 The case rates are extraordinarily high among indigent patients and substance abusers, and one third of these patients are also infected with HIV.2 Much has been learned about the pathogenesis, clinical presentation, treatment, and prevention of tuberculosis in HIV-infected persons over the past several years. We summarize recent developments in these areas, as well as the effects of new antiretroviral therapies on antituberculosis regimens. HIV Infection and Susceptibility to Tuberculosis HIV-infected persons are at . . .
TL;DR: The "pain rate" is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20, and even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival.
Abstract: Background and Methods. Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. Results. There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle β0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle β+-thalassemia. The rate varied widely within each of these four groups — e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 3...
TL;DR: Radiofrequency current is highly effective in ablating accessory pathways, with low morbidity and no mortality, according to this study.
Abstract: Background Surgical or catheter ablation of accessory pathways by means of high-energy shocks serves as definitive therapy for patients with Wolff-Parkinson-White syndrome but has substantial associated morbidity and mortality. Radiofrequency current, an alternative energy source for ablation, produces smaller lesions without adverse effects remote from the site where current is delivered. We conducted this study to develop catheter techniques for delivering radiofrequency current to reduce morbidity and mortality associated with accessory-pathway ablation. Methods Radiofrequency current (mean power, 30.9 +/- 5.3 W) was applied through a catheter electrode positioned against the mitral or tricuspid annulus or a branch of the coronary sinus; when possible, delivery was guided by catheter recordings of accessory-pathway activation. Ablation was attempted in 166 patients with 177 accessory pathways (106 pathways in the left free wall, 13 in the anteroseptal region, 43 in the posteroseptal region, and 15 in the right free wall). Results Accessory-pathway conduction was eliminated in 164 of 166 patients (99 percent) by a median of three applications of radiofrequency current. During a mean follow-up (+/- SD) of 8.0 +/- 5.4 months, preexcitation or atrioventricular reentrant tachycardia returned in 15 patients (9 percent). All underwent a second, successful ablation. Electrophysiologic study 3.1 +/- 1.9 months after ablation in 75 patients verified the absence of accessory-pathway conduction in all. Complications of radiofrequency-current application occurred in three patients (1.8 percent): atrioventricular block (one patient), pericarditis (one), and cardiac tamponade (one) after radiofrequency current was applied in a small branch of the coronary sinus. Conclusions Radiofrequency current is highly effective in ablating accessory pathways, with low morbidity and no mortality.
Duke University1, University of North Carolina at Chapel Hill2, University of Pittsburgh3, Vanderbilt University4, University of South Florida5, University of Virginia6, Memorial Sloan Kettering Cancer Center7, St. Elizabeth's Medical Center8, Virginia Mason Medical Center9, Johns Hopkins University10, Medical College of Wisconsin11, University of Chicago12, Stanford University13, Amgen14, University of California, Los Angeles15
TL;DR: A randomized clinical trial to test the hypothesis that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer and the clinical implications.
Abstract: Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×l09 per liter, with a temperature ≥38.2°C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21 -day cycle. Results. The safety of the study treatment could be evaluated in 207 of the 211 pa...
TL;DR: Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility, hypothesized to result in inadequateleft ventricular mass and clinically important heart disease in later years.
Abstract: Background. Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. Methods. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. Results. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress—velocity index). The cumulative dose of doxorubicin was the most significant pr...
TL;DR: Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia and clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor.
Abstract: Background and Methods. Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor—alpha (RAR-α). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia, we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent. Results. Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular ...
TL;DR: Both HDL cholesterol and HDL2 levels were associated with a substantially decreased risk of myocardial infarction, but the HDL3 level was the strongest predictor; the relative risk was 0.3 (95 percent confidence interval, 0.2 to 0.6).
Abstract: Background. The independent contributions of subfractions of high-density lipoprotein (HDL) cholesterol (HDL2 and HDL3) and apolipoproteins in predicting the risk of myocardial infarction are unclear. Prospective data are sparse, but HDL2 is widely believed to be a more important predictor than HDL3. Methods. Blood samples were collected at base line from 14,916 men (ages, 40 to 84 years) who were participants in the Physicians' Health Study. After five years of follow-up, plasma samples from 246 men with new myocardial infarction (case subjects) were analyzed together with specimens from 246 men matched to them for age and smoking status who had not had a myocardial infarction. Results. The levels of total cholesterol and apolipoprotein B-100 were significantly associated with an increased risk of myocardial infarction (data on levels of low-density lipoprotein cholesterol were unavailable). Both HDL cholesterol and HDL2 levels were associated with a substantially decreased risk of myocardial in...
TL;DR: Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease.
Abstract: Background and Methods. Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. Results. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs...