The effects of ex-vivo depletion of T lymphocytes from donor bone marrow using a monoclonal anti-T-cell antibody (CT-2) and complement on the outcome of allogeneic bone marrow transplantation was evaluated in a prospective, randomized, double-blind study of 40 patients with leukemia. Patients receiving T-cell-depleted bone marrow had a lower incidence of acute graft-versus-host disease than control patients (3 of 20 compared with 13 of 20; p = 0.004), and mortality due to acute graft-versus-host disease was reduced. Five patients in the T-cell-depletion group developed graft failure; all control patients had sustained engraftment (p less than 0.05). Clinically apparent relapse of leukemia occurred in 7 patients from the T-cell-depletion group and in 2 controls (p, not significant). Cytogenetic evidence of residual leukemia was also detected in the 5 patients with graft failure without overt relapse. Infections and overall survival were similar in the two groups. The effects of T-cell depletion on engraftment and recurrence of leukemia require further evaluation.

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.

To evaluate the association between in-vitro resistance of herpes simplex virus type 2 to acyclovir and breakthrough recurrences of herpes despite chronic suppressive therapy, we determined the in-vitro sensitivity of herpes simplex virus isolated before, during, and after therapy. One hundred eighty-three virus isolates from 107 patients were tested. Before therapy, the median amount of drug required to inhibit 50% of the virus in tissue culture (ID50) was 0.91 microgram/mL. The median ID50 after therapy was 0.99. Six isolates from patients with culture-positive breakthrough recurrences were evaluated. The median ID50 was 0.90 microgram/mL (range, 0.39 to 1.55). The development of breakthrough recurrences could not be correlated with infection with strains of herpes simplex virus type 2 that were resistant to acyclovir in vitro. Acyclovir-resistant strains are not commonly recovered from patients during acyclovir therapy, nor does there seem to be a high frequency of resistance after 4 months of chronic suppressive therapy.

In patients with stage IV Hodgkin's disease mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was randomly tested against MOPP alternated monthly with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). All 88 evaluable patients had not received chemotherapy and 25 had had a relapse after primary irradiation. The complete remission rate with MOPP/ABVD was 88.9% (40 of 45 patients), and with MOPP, 74.4% (32 of 43 patients). The 8-year results show that MOPP/ABVD was superior to MOPP in terms of freedom from progression (64.6% compared to 35.9%; p less than 0.005), relapse-free survival (72.6% compared to 45.1%; p less than 0.01), total survival (83.9% compared to 63.9%; p less than 0.06), and survival of complete responders (94.8% compared to 77.1%; p = 0.04). The delivery of MOPP/ABVD was not associated with an increased incidence of major toxicity. The early sequential rotation of two equally effective and non-cross-resistant drug combinations can substantially improve the likelihood of cure in patients with Hodgkin's disease.

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.

Disorders determined wholly or in part by genetic factors constitute a substantial number of human diseases. This realization has grown during the past 2 decades with the recognition of many specific heritable conditions and the identification of familial risk factors for common disorders. New technologies, such as fetal visualization, chorionic villus sampling, molecular cloning methods, and gene transfer technology, provides a framework for dealing with genetically determined illness in unprecedented ways. Several current and potential applications of these methods are examined, as is the use of restriction fragment length polymorphisms to survey the variability within the genome and to generate markers permitting the prospective detection of genetic disorders. The promise and limitations of chorionic villus biopsy sampling are considered for early prenatal diagnosis. The future of gene therapy in hereditary diseases is examined, and some of the substantial social and ethical considerations engendered by these new developments are explored.

The effect of an increasing serum ionized calcium concentration on blood pressure during hemodialysis was studied in a prospective cross-over trial. Twelve patients were dialyzed three times with a dialysate Ca concentration of 5.5 mg/dL and three times with one of 7.5 mg/dL. Dialysis with the high Ca dialysate was associated with less fall in the mean arterial pressure (p less than 0.001). No statistically significant changes occurred in serum osmolality, body weight, or heart rate after dialysis at the two dialysate Ca levels. Increasing the Ca concentration in dialysate may protect against intradialytic hypotension in some patients.

A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.

We have reported early attenuation of hemodynamic effects of transdermal nitroglycerin in patients with heart failure. We now report nitroglycerin plasma levels in those same patients. We administered transdermal nitroglycerin, 60 mg/24 h, to eight patients or placebo to seven patients in a double-blind fashion, and monitored pulmonary wedge pressure and nitroglycerin plasma levels for 24 hours. After placebo administration, nitroglycerin plasma levels and pulmonary wedge pressure remained unchanged. During transdermal nitroglycerin administration, the plasma nitroglycerin level rose from 0.04 +/- 0.12 ng/mL at baseline to near peak levels at 2 hours (7.43 +/- 7.21 ng/mL). Between 2 and 24 hours, levels fluctuated at a steady state. Pulmonary wedge pressure fell from 22 +/- 7 mm Hg at control to a nadir of 14 +/- 5 mm Hg at 4 hours (p less than 0.01). Despite persistently high plasma nitroglycerin levels, by 18 hours pulmonary wedge pressure was no longer significantly reduced (20 +/- 9 mm Hg). These results indicate that rapid development of tolerance is the cause of attenuated hemodynamic efficacy of transdermal nitroglycerin.

To estimate the effect of cost sharing on seeking care for serious and minor symptoms, we analyzed data for 3539 persons aged 17 to 61 from the Rand Health Insurance Experiment. Participants were randomly assigned to a free-care group or to insurance plans requiring them to pay part of the costs (cost-sharing group). Annual surveys were administered to determine if participants had serious and minor symptoms during the preceding month and whether they saw a physician. Serious symptoms were judged by a panel of physicians to warrant care in most instances; minor symptoms were judged neither to be severe nor to warrant care in most instances. The cost-sharing group was nearly one third less likely than the free-care group to see a physician when they had minor symptoms (6.3% compared with 9.0%; p less than 0.04). The free-care and cost-sharing groups did not differ significantly in seeking care for serious symptoms (22.3% compared with 17.9%; p = 0.095). However, for participants with low socioeconomic status who began the study in poor health, the prevalence of serious symptoms was higher in the cost-sharing than the free-care group (29.1% compared with 23.8%, p less than 0.004).

We compared the effect of 50- or 100-mg doses of oral doxepin or a placebo on basal gastric acid secretion, salivary flow, and pulse rate in seven asymptomatic patients with chronic duodenal ulcer disease. Acid secretion and salivary flow were measured for four 1-hour periods beginning at 3.5, 5.5, 7.5, and 9.5 hours after medication, with plasma sampling for measurement of doxepin at the midpoint of each collection period. Compared to placebo, the 50- and 100-mg doses of doxepin reduced mean basal acid output by 46% and 37%, respectively. There was no significant difference in the effect of the 50- or 100-mg dose on acid secretion even though mean plasma concentrations of doxepin were higher with the 100-mg than with the 50-mg dose (p less than 0.01). Salivary flow was reduced by 62% and 84% with the 50- and 100-mg doses, respectively, whereas doxepin had no effect on mean pulse rate.

We studied cardiovascular effects related to ophthalmic timolol maleate, a beta-adrenergic blocker commonly used to treat chronic glaucoma. Twenty normal subjects were randomly assigned to two double-blind treatment groups each with ten subjects. One group received two drops of ophthalmic timolol (0.5%) twice daily for 4 weeks, and the other received two drops of placebo (artificial tears) twice daily for 4 weeks. Ophthalmic timolol significantly decreased resting and maximal exercise heart rate after the first dose and maximal exercise heart rate during chronic dosing. Chronic timolol administration reduced oxygen consumption at maximal exercise and blunted the augmentation in exercise capacity seen during chronic placebo therapy. Cardiac sympathetic tone and inotropy were reduced after ophthalmic timolol treatment. Despite the presence of drug-induced cardiovascular effects, the plasma levels of timolol were often undetectable and never exceeded 2.8 ng/mL.

The effects of ferrous sulfate and aluminum hydroxide on the oral zinc tolerance test after administration of 25 mg of elemental zinc as sulfate were studied in six hemodialysis patients and six normal controls. Fasting plasma zinc levels, the 2-hour plasma zinc peak, and the area under the plasma zinc curve were significantly lower in patients compared with values in controls (plasma zinc, 92 +/- 4 compared with 108 +/- 3 micrograms/dL, p less than 0.025; 2-hour plasma zinc peak, 159 +/- 8 compared with 228 +/- 17 micrograms/dL, p less than 0.025; and area under the curve, 193 +/- 41 compared with 316 +/- 39 micrograms h/dL, p less than 0.025). Ferrous sulfate (300 mg orally), when administered along with zinc sulfate, decreased the area under the curve significantly (in patients by 28%, in controls by 40%) in comparison with the results obtained when zinc sulfate was given alone. When 30 mL of aluminum hydroxide was administered orally with zinc sulfate, the area under the curve decreased by 60% in controls and 75% in patients (p less than 0.005). These results confirm the presence of diminished zinc absorption in patients with renal failure and show that ferrous sulfate and aluminum hydroxide, which worsen this defect, also impair zinc absorption in normal subjects.

Reflux esophagitis may be unresponsive to standard medical therapy with an H2-receptor antagonist drug. Twenty-five patients with chronic reflux esophagitis, refractory to cimetidine treatment alone, were randomly assigned in a double-blind design to receive cimetidine (1200 mg/d), in combination with metoclopramide (40 mg/d) or placebo. Nine of twelve patients receiving cimetidine with metoclopramide had significant symptomatic improvement at the end of the 8-week study period, compared with 3 of 12 patients receiving cimetidine with placebo (p less than 0.02). Endoscopic appearance improved in 9 patients receiving metoclopramide and in 4 patients receiving placebo (p less than 0.05). Neither group had significant improvement in lower esophageal sphincter pressure, 24-hour esophageal pH recordings, and esophageal histologic findings. Side effects were common with cimetidine and metoclopramide but were rarely disabling. This combination is efficacious in the management of chronic reflux esophagitis but, because of frequent side effects, should be reserved for patients refractory to treatment with cimetidine alone.

Fifteen patients with chronic type B hepatitis were treated with corticosteroids in a randomized, double-blind, placebo-controlled trial lasting 28 days. Ten patients received prednisolone, 60 mg/d for 2 weeks, then 30 mg/d for another 2 weeks; 5 patients received placebo. Serum aminotransferase levels decreased significantly during prednisolone therapy but 4 to 10 weeks after abrupt withdrawal of the drug, they rebounded to levels greater than those before treatment. This exacerbation of disease lasted for several months and was prolonged and symptomatic in 3 patients. Hepatitis B virus levels did not change substantially during treatment. Follow-up examinations showed no improvement in biochemical or serologic features of the disease in any of the 15 patients; follow-up liver biopsies showed a worsening in 4 of 7 treated patients but in 0 of 5 control patients. Thus, a 28-day course of prednisolone produced no beneficial effects in patients with mild-to-moderate chronic type B hepatitis; on the contrary, such treatment may be harmful.

In a randomized, double-blinded study, patients with chronic obstructive pulmonary disease and hypercapnia were fed low, moderate, and high carbohydrate diets to determine the effect on metabolic and ventilatory values. The low carbohydrate diet consisted of 28% carbohydrate calories and 55% fat calories and resulted in significantly lower production of CO2 (p less than 0.002), respiratory quotient (p less than 0.001), and arterial Pco2 (p less than 0.05). At the end of the 15-day study, both the forced vital capacity (p less than 0.05) and the forced expiratory volume in 1 second (p less than 0.05) had improved by 22% over baseline values. Total calories given surpassed daily caloric requirements. This approach, together with a low carbohydrate, high fat mixture, may be beneficial for such patients.

ONCOCIN is a chemotherapy protocol advisor used experimentally in a university oncology clinic. The program combines formal protocol guidelines with judgments of oncologists who have experience adjusting therapy in complex clinical situations. We compared the chemotherapy administered by clinic physicians with the treatment that would have been recommended by ONCOCIN in 415 visits for 39 patients with lymphoma seen before the program's introduction. In 189 visits the program agreed with the therapy actually administered. In a blinded evaluation, four experts on lymphoma failed to find a significant difference between the treatments selected by physicians and those proposed by ONCOCIN. Further analyses showed that ONCOCIN tended to attenuate drug doses or delay treatment more than the experts recommended, whereas the physicians were less likely to attenuate doses to the extent the experts suggested. Our results show that ONCOCIN provides advice on lymphoma treatment similar to the treatment provided in a university oncology clinic.

The blood pressure response of 48 hypertensive persons and 32 normotensive persons to elemental calcium (as the carbonate or citrate salt), 1000 mg/d for 8 weeks, was assessed in a randomized, double-blind, placebo-controlled, crossover trial. Compared with placebo, Ca2+ significantly lowered supine systolic blood pressure by 3.8 mm Hg, standing systolic blood pressure by 5.6 mm Hg (p less than 0.02), and supine diastolic blood pressure by 2.3 mm Hg (p less than 0.05) in hypertensive persons. The response in normotensive persons differed significantly from that in hypertensives (p less than 0.03) as their blood pressure was unchanged. Twenty-one (44%) hypertensive and 6 (19%) normotensive persons achieved a reduction in standing systolic arterial pressure of 10 mm Hg or greater. Reported adverse effects were similar between calcium and placebo phases and did not necessitate withdrawal of any patient from the trial. Treatment with 1000 mg/d of oral Ca2+ for 8 weeks represents a safe, well-tolerated, nonpharmacologic intervention that lowers blood pressure in selected patients with mild to moderate hypertension.