We have previously reported that long-term therapy with warfarin is effective for preventing recurrent venous thromboembolism in patients with proximal-vein thrombosis but that there is an appreciable risk of hemorrhage. To determine whether that risk could be reduced without a loss of effectiveness, we randomly allocated 96 patients with proximal-vein thrombosis to a group receiving less intense anticoagulant therapy, with a mean prothrombin time of 26.9 seconds using the Manchester comparative reagent (corresponding Simplastin time, 15 seconds), or a group given more intense therapy, with a mean Simplastin time of 19.4 seconds (corresponding prothrombin time 41 seconds with the Manchester comparative reagent) (P less than 0.001). Two of 47 patients (4 per cent) in the less intensely treated group had hemorrhagic complications, as compared with 11 of 49 patients (22 per cent) in the more intensely anticoagulated group (P = 0.015 by the two-tailed test). This difference was due to minor bleeding episodes. The frequency of recurrent venous thromboembolism was low in both groups (2 per cent). Our findings indicate that less intense anticoagulant therapy is associated with a low frequency of recurrent venous thromboembolism (2 per cent) and a reduced risk of hemorrhage.

We studied risk factors for postoperative infections at the operative site after hysterectomies. Data were collected prospectively on all women undergoing vaginal hysterectomies (323 patients) or abdominal hysterectomies (1125 patients) at the Boston Hospital for Women between February 1976 and April 1978. Logistic-regression analysis indicated that factors significantly associated (P less than 0.05) with a higher risk of infection at the operative site were increased duration of operation, lack of antibiotic prophylaxis, younger age, being a clinic patient, and an abdominal approach. After these variables were accounted for, the variables of obesity, preoperative functional and anatomical diagnoses, postoperative anatomical and pathological diagnoses, estimated blood loss, menopausal status, and operation by a specific surgeon did not add predictive power. An increasing duration of operation was associated with a decreasing effect of antibiotic prophylaxis, the preventive fraction of which diminished from 80 per cent at one hour to an unmeasurable effect at 3.3 hours.

We evaluated the efficacy of hepatitis B vaccine (Heptavax-B) containing only the ad subtype in a randomized, placebo-controlled, double-blind trial among 865 staff members of 43 hemodialysis units in the United States. Surface antibody developed in 92.6 per cent of the subjects after two doses of vaccine and in 96 per cent after the six-month booster. The incidence of infections with hepatitis B virus (with or without hepatitis) was 9.9 per cent in placebo recipients and 2.2 per cent in vaccine recipients (P less than 0.01). The two cases of hepatitis B among vaccine recipients did not occur in subjects in whom antibody had developed. In 81 per cent of the hepatitis events, the virus was of the ay subtype. The indicence of ay virus was 8.2 per cent among placebo recipients and 1.2 per cent among vaccine recipients (P less than 0.005). We conclude that these data confirm the efficacy of the vaccine and demonstrate subtype cross-protection.

The nausea and vomiting experienced by one in four cancer patients in anticipation of chemotherapy is probably a learned response to treatment. To determine whether behavioral approaches for altering learned responses might be useful treatments for these symptoms, we compared the effects of "systematic desensitization" (a behavioral treatment in which relaxation is learned as a response to situations in which patients have had anticipatory nausea and vomiting) with those of counseling and of no treatment. Sixty ambulatory cancer patients with anticipatory nausea and vomiting before their third and fourth chemotherapy treatments were randomized equally to the three groups. Significantly more patients receiving desensitization reported no anticipatory nausea before their fifth and sixth chemotherapy treatments than patients given counseling (P less than 0.05) or no treatment (P less than 0.01). Desensitized patients also reported significantly less severe anticipatory nausea (P less than 0.01) and vomiting (P less than 0.05) and a shorter duration of anticipatory nausea (P less than 0.01). We conclude that systematic desensitization appears to have an antiemetic effect in cancer patients who receive chemotherapy, and may be useful in the management of these problems.

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

It has been known for more than 25 years that certain plant foods, such as kidney beans and wheat, contain a substance that inhibits the activity of salivary and pancreatic amylase. More recently, this antiamylase has been purified and marketed for use in weight control under the generic name "starch blockers." Although this approach to weight control is highly popular, it has never been shown whether starch-blocker tablets actually reduce the absorption of calories from starch. Using a one-day calorie-balance technique and a high-starch (100 g) meal (spaghetti, tomato sauce, and bread), we measured the excretion of fecal calories after normal subjects had taken either placebo or starch-blocker tablets. If the starch-blocker tablets had prevented the digestion of starch, fecal calorie excretion should have increased by 400 kcal. However, fecal calorie excretion was the same on the two test days (mean +/- S.E.M., 80 +/- 4 as compared with 78 +/- 2). We conclude that starch-blocker tablets do not inhibit the digestion and absorption of starch calories in human beings.

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patient's body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

We carried out a randomized double-blind controlled secondary-prevention trial of oxprenolol over seven years. Forty milligrams of oxprenolol or placebo was given twice daily to 1103 men 35 to 65 years old who had an acute myocardial infarction between 1 and 90 months previously. Overall, there was no difference in mortality or cardiac events between the placebo and oxprenolol groups. The major influence on prognosis was the time at which treatment was started after infarction. In 417 patients in whom treatment was started within four months of infarction oxprenolol increased the six-year cumulative survival rate from 77 to 95 per cent (P less than 0.001). In 274 patients with treatment starting between 5 and 12 months of infarction the survival rate was similar in the two groups, but in 412 patients entered between 1 and 7 1/2 years after their first infarction oxprenolol reduced the six-year survival rate from 92 to 79 per cent (P = 0.002). The increased mortality in this latter group mainly occurred late after withdrawal from active treatment. The value of low-dose oxprenolol in secondary prevention appears to be confined to patients treated relatively soon after myocardial infarction.

In an effort to decrease deaths from gram-negative bacteremia and endotoxin shock, we treated bacteremic patients with human antiserum to endotoxin (lipopolysaccharide) core. Antiserum was prepared by vaccinating healthy men with heat-killed Escherichia coli J5; this mutant lacks lipopolysaccharide oligosaccharide side chains, so that the core, which is nearly identical to that of most other gram-negative bacteria, is exposed for antibody formation. In a randomized controlled trial, patients were given either J5 antiserum or preimmune control serum intravenously, near the onset of illness. The number of deaths in the bacteremic patients was 42 of 109 (39 per cent) in controls and 23 of 103 (22 per cent) in recipients of J5 antiserum (P = 0.011). In those with profound shock, mortality was 30 of 39 (77 per cent) in controls and 18 of 41 (44 per cent) in recipients of J5 antiserum (P = 0.003). We conclude that human antiserum to the lipopolysaccharide core can substantially reduce deaths from gram-negative bacteremia.

We compared the effects of initial electrical shocks using 175 and 320 J (joules) in 249 patients with ventricular fibrillation. Survival was unrelated to the energy level used for defibrillation. Reversion to an organized rhythm occurred in a similar proportion of both treatment groups after one or two shocks. The rhythm identified after the first shock was related to outcome (the survival rate was 42 per cent in patients with supraventricular rhythm, 30 per cent in persistent ventricular fibrillation, 26 per cent in idioventricular rhythm, and 14 per cent in asystole; P less than 0.02). Fibrillation recurred in 68 per cent of patients who had been initially defibrillated to an organized rhythm. Repeated shocks at the higher energy level resulted in a higher incidence of atrioventricular block after defibrillation (24 per cent of patients receiving 320 J and 9 per cent of those receiving shocks of lower energy; P less than 0.005). Patients who survived required fewer shocks than patients who later died in the hospital (2.6 shocks as compared with 3.6; P less than 0.005). We conclude that initial defibrillatory shocks using 175 J are as safe and effective as shocks of nearly twice that energy level.

We evaluated protriptyline, a nonsedating tricyclic antidepressant, as a treatment for obstructive sleep apnea in a double-blind crossover study of five men. After two weeks of treatment, with no change in body weight, daytime somnolence was markedly reduced and nocturnal oxygenation was improved, although apnea duration and frequency were not significantly decreased. Rapid-eye-movement (REM) stage time as a fraction of the total sleep time was reduced during treatment from 0.231 +/- 0.031 to 0.107 +/- 0.013 (mean +/- S.E.M.) (P less than 0.05). REM apnea time as a fraction of total sleep time was reduced from 0.145 +/- 0.022 to 0.054 +/- 0.006 (P less than 0.05). REM reduction during treatment with protriptyline can account for decreased REM apnea time. Similar decreases in REM stage time and REM apnea duration and similar improvement in oxygenation continued after six months of treatment. In addition, body weight, apnea, and arousal frequency were decreased at this time. Although the obstructive sleep apnea was not resolved, it was reduced. Protriptyline can be effective in patients with sleep apnea when the disorder is not life-threatening.

In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.

We conducted a double-blind, placebo-controlled trial to assess the value of vidarabine therapy for the prevention of complications from herpes zoster in immunocompromised patients. Of 121 patients with localized herpes zoster of 72 hours duration or less, 63 received vidarabine and 58 received the placebo. Populations were matched for pertinent characteristics. Therapy accelerated cutaneous healing and decreased the rates of cutaneous dissemination (from 24 per cent [14 patients] to 8 per cent [5 patients]) (P = 0.014); and of zoster-related visceral complications (from 19 per cent [11 patients] to 5 per cent [3 patients]) (P = 0.015). therapy also decreased the total duration of post-herpetic neuralgia (P = 0.047). Patients with lymphoproliferative cancers and those 38 years of age or older were at greatest risk for complications and benefited most from therapy. There was no serious drug toxicity. We conclude that vidarabine therapy, when started within the first three days, is valuable for the reduction of complications related to herpes zoster.

In a randomized trial of adjuvant chemotherapy, immunotherapy, or immunochemotherapy, 761 evaluable patients with pathological Stage II cutaneous melanoma anywhere on the body or with pathological Stage I melanoma of the trunk (Clark's level 3 to 5) were studied by the World Health Organization International Melanoma Group. Wide local excision and excisional regional lymphadenectomy alone were performed in 185 patients and the results were compared with those of surgery plus chemotherapy with dacarbazine (in 192 patients), surgery plus immunotherapy with bacille Calmette-Guérin vaccine (in 203), and surgery plus chemotherapy combined with immunotherapy (in 181). The rates of disease-free survival and overall survival at 36 months were 30.4 +/- 8.3 per cent (mean +/- S.E.) and 41.6 +/- 10.0 per cent, respectively, after surgical treatment alone; 37.2 +/- 7.9 per cent and 46.5 +/- 8.3 per cent after surgery plus chemotherapy; 34.8 +/- 7.9 per cent and 48.7 +/- 8.7 per cent after surgery plus immunotherapy; and 33.6 +/- 7.9 per cent and 50.0 +/- 8.8 per cent after surgery plus a combination of chemotherapy and immunotherapy. None of the differences between groups was significant, and thus no effect of adjuvant therapy could be demonstrated in this study.