The New England Journal of Medicine

Lepor, Herbert; Williford, William O.; Barry, Michael J.; Brawer, Michael K.; Dixon, Christopher M.; Gormley, Glenn; Haakenson, Clair; Machi, Madeline; Narayan, Perinchery; Padley, Robert J.

doi: 10.1056/NEJM199608223350801pmid: 8684407

BackgroundMen with benign prostatic hyperplasia can be treated with α1-adrenergic–antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5α-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared.MethodsWe compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year.ResultsThe mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups.ConclusionsIn men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Hylek, Elaine M.; Skates, Steven J.; Sheehan, Mary A.; Singer, Daniel E.

doi: 10.1056/NEJM199608223350802pmid: 8678931

BackgroundTo avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case–control study.MethodsWe studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used the INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patient's hospital admission.ResultsThe risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.9; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0).ConclusionsAmong patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation.

Davies, H. Dele; McGeer, Allison; Schwartz, Benjamin; Green, Karen; Cann, Darlene; Simor, Andrew E.; Low, Donald E.; ,

doi: 10.1056/NEJM199608223350803pmid: 8684408

BackgroundSeveral reports suggest that the incidence of invasive group A streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, is increasing.MethodsDuring 1992 and 1993 we conducted prospective, population-based surveillance of invasive group A streptococcal disease in Ontario, Canada. We reviewed clinical and laboratory records, searched for secondary cases of invasive disease, and cultured specimens from household contacts.ResultsWe identified 323 patients with invasive group A streptococcal infections, for an annual incidence of 1.5 cases per 100,000 population. The rates were highest in young children and the elderly. Fifty-six percent of the patients had underlying chronic illness. Risk factors for disease included infection with the human immunodeficiency virus, cancer, diabetes, alcohol abuse, and chickenpox. The most common clinical presentations were soft-tissue infection (48 percent), bacteremia with no septic focus (14 percent), and pneumonia (11 percent). Necrotizing fasciitis occurred in 6 percent of patients, and toxic shock in 13 percent. The mortality rate was 15 percent overall, but it was 29 percent among those over 64 years of age (P<0.001) and 81 percent among those with toxic shock (P<0.001). Fourteen percent of the cases were nosocomial, and 4 percent occurred in nursing home residents, often in association with disease outbreaks. Invasive disease occurred in 2 household contacts of patients with infection, for an estimated risk of 3.2 per 1000 household contacts (95 percent confidence interval, 0.39 to 12 per 1000).ConclusionsThe elderly and those with underlying medical conditions are at greatest risk for invasive group A streptococcal disease, toxic shock, and necrotizing fasciitis. Invasive streptococcal infection is associated with a substantial risk of transmission in households and health care institutions.

Shafritz, Adam B.; Shore, Eileen M.; Gannon, Francis H.; Zasloff, Michael A.; Taub, Rebecca; Muenke, Maximilian; Kaplan, Frederick S.

doi: 10.1056/NEJM199608223350804pmid: 8678932

BackgroundFibrodysplasia ossificans progressiva is a heritable disorder of connective tissue characterized by congenital malformation of the great toes and postnatal formation of ectopic bone. Although the disorder was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are potent bone-inducing morphogens that participate in the developmental organization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossificans progressiva.MethodsWe studied lymphoblastoid cell lines established from peripheral-blood mononuclear cells of patients with fibrodysplasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis and ribonuclease protection assays to measure the expression of messenger RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistochemical analysis to examine protein expression.ResultsAmong the bone morphogenetic proteins and mRNAs examined, only bone morphogenetic protein 4 and its mRNA were present in increased levels in cells derived from an early fibroproliferative lesion in a patient with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 mRNA was expressed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysplasia ossificans progressiva but from only 1 of 12 normal subjects (P<0.001). Bone morphogenetic protein 4 and its mRNA were detected in the lymphoblastoid cell lines from a man with fibrodysplasia ossificans progressiva and his three affected children (two girls and a boy), but not from the children's unaffected mother. No other bone morphogenetic proteins were detected.ConclusionsOverexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva.

Javaheri, S.; Parker, T.J.; Wexler, L.; Liming, J.D.; Lindower, P.; Roselle, G.A.

doi: 10.1056/NEJM199608223350805pmid: 8678934

BackgroundTheophylline has been used to treat central apnea associated with Cheyne–Stokes respiration (periodic breathing). We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction.MethodsFifteen men with compensated heart failure (left ventricular ejection fraction, 45 percent or less) participated in the study. Their base-line polysomnograms showed periodic breathing, with more than 10 episodes of apnea and hypopnea per hour. In a double-blind crossover study, the patients received theophylline or placebo orally twice daily for five days, with one week of washout between the two periods.ResultsAfter five days of treatment, the mean (±SD) plasma theophylline concentration was 11±2 μg per milliliter. Theophylline therapy resulted in significant decreases in the number of episodes of apnea and hypopnea per hour (18±17, vs. 37±23 with placebo and 47±21 at base line; P<0.001), the number of episodes of central apnea per hour (6±14, vs. 26±21 and 26±20, respectively; P<0.001), and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent (6±11 percent, vs. 23±37 and 14±14 percent, respectively; P<0.04). There were no significant differences in the characteristics of sleep, the frequency of ventricular arrhythmias, daytime arterial-blood gas values, or the left ventricular ejection fraction during the base-line, placebo, and theophylline phases of the study.ConclusionsIn patients with stable heart failure, oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep.

Jackson, Alan C.; Lopez-Corella, Eduardo

doi: 10.1056/NEJM199608223350806pmid: 8684409

Figure 1. Three large Negri bodies, which are eosinophilic viral inclusion bodies, can be seen in the cytoplasm of a cerebellar Purkinje cell obtained at autopsy from an eight-year-old boy in Mexico City (hematoxylin and eosin, ×2300). These viral inclusions are the pathological hallmark of rabies. The boy, bitten on the forearm by a dog that died of rabies 15 days later, had numbness and tingling at the site of the bite several days later. He presented at a clinic one month after the bite, and rabies vaccination with Fuenzalida vaccine (suckling-mouse-brain vaccine) was initiated. Two days later he was . . .

Knox, Tamsin A.; Olans, Lori B.

doi: 10.1056/NEJM199608223350807pmid: 8678935

Liver disease is a rare complication of pregnancy, but when it occurs it may do so in a dramatic and tragic fashion for both mother and infant. Diseases such as acute fatty liver of pregnancy (AFLP) may begin innocuously with mild symptoms and liver-enzyme abnormalities but, if left untreated, can progress to jaundice, liver failure, and death. Some of the normal physiologic changes of pregnancy can mimic abnormalities associated with liver disease. In an uncomplicated pregnancy, many laboratory-test results may appear abnormal according to standards derived from a nonpregnant population. Serum albumin concentrations decrease from a mean of 4.2 g . . .

Gorlin, Jed B.; Ferry, Judith A.

doi: 10.1056/NEJM199608223350808pmid: 8684410

Presentation of Case A seven-year-old boy was admitted to the hospital because of fever, lymphadenopathy, hepatosplenomegaly, and eosinophilia. The boy had been in good health until two months earlier, when fever and disorientation developed. He was taken to another hospital, where a seizure occurred. Meningoencephalitis was diagnosed, antibiotics were administered intravenously, and he received phenytoin and carbamazepine. He recovered and was discharged taking both agents; phenytoin was discontinued after one month. Two weeks before admission to this hospital, the fever recurred, particularly in the early morning hours; the temperature rose as high as 38.9°C, with anorexia. Eleven days before admission, . . .

Walsh, Patrick C.

doi: 10.1056/NEJM199608223350809pmid: 8678937

Medications to treat benign prostatic hyperplasia fall into two main categories: α1-adrenergic–antagonist drugs, which relax smooth muscle in the prostate, and drugs that inhibit 5α-reductase, which shrink the prostate by blocking the formation of the chief intracellular androgen, dihydrotestosterone.1 The main question is, Which drug is better, or would a combination of the two work best? In this issue of the Journal, Lepor et al. report the results of a landmark study by the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group that attempts to answer this question.2 The authors found that treatment with terazosin, an α . . .

Rosendaal, F.R.

doi: 10.1056/NEJM199608223350810pmid: 8678938

Treatment with oral anticoagulant drugs (i.e., coumarin derivatives such as warfarin) is effective in the prevention of venous and arterial thromboembolism. In patients with atrial fibrillation, anticoagulation reduces the risk of stroke by 70 percent.1 The principal problem with anticoagulation is the variability of the effect of coumarin derivatives on the hemostatic system; patients may require very different doses (up to 10-fold differences) to reach the same level of anticoagulation, and the required dose may also vary over time in an individual patient. Since underanticoagulation is ineffective and overanticoagulation may lead to hemorrhage, anticoagulant treatment needs to be monitored and . . .