Kayser-Fleischer rings are pigmented corneal rings at the limbus of the cornea in Descemet's membrane that have been deemed pathognomonic of Wilson's disease. However, we have observed four exceptions in patients with non-Wilsonian liver disease. Three patients had primary biliary cirrhosis and one patient had chronic aggressive hepatitis with cirrhosis. Pigmented corneal rings were seen only by slit-lamp examination. Hepatic, serum, and urinary copper and serum ceruloplasmin levels were significantly elevated in the patients with primary biliary cirrhosis. Radiocopper (64Cu or 67Cu) studies in patients with primary biliary cirrhosis showed plasma disappearance curves which allowed a clear distinction from Wilson's disease in that all three patients with primary biliary cirrhosis showed a secondary rise in radiocopper that presumably represented copper incorporation into ceruloplasmin. In one patient, in whom 64Cu in ceruloplasmin was studied specifically, incorporation was found to be normal.

In a double-blind study of four patients with hereditary angioedema, the efficacy of methyltestosterone (taken daily in 10-mg linguet form) in preventing attacks was shown. There were 19 episodes during 11.8 months of placebo administration, compared with only four attacks during the 46 months of cumulative methyltestosterone treatment (P less than 0.001). The mean serum C4 protein level was twice as high in all patients when they were taking the drug (176 +/- 36 mug/ml) as compared with the placebo (84 +/- 21 mug/ml), and rose to normal range in three of four patients.

Investigators at 30 centers evaluated an intravenous hepatitis B immune globulin preparation in the therapy of fulminant type B hepatitis. Patients with serum positive for hepatitis B surface antigen were treated at stage II to stage IV of hepatic encephalopathy. A central computer program randomized cases for treatment with hyperimmune globulin or albumin placebo. During the first 6 months, the dose of hepatitis B immune globulin was 1.32 g of immunoglobulin G protein; during the last 7 months, it was 5.28 g. Neither dose eliminated antigenemia. In the placebo group, death occurred in four of eight cases randomized at stage II, five of eight at stage III, and 10 of 12 at stage IV. In the group treated with hyperimmune globulin, death occurred in three of five patients randomized at stage II, seven of 12 at stage III, and six of eight at stage IV. The study, therefore, showed no benefit of treatment with exogenous antibody.

Nine patients with familial Mediterranean fever (FMF) were admitted to a controlled, double-blind trial to determine if there are patients with this disease who are able to abort their acute episodes of pain and fever with short courses of colchicine taken at the onset of attacks. Five patients completed their treatment assignments, and colchicine was significantly effective in aborting the attacks of three but was ineffective in two. The remaining four patients could not be assessed because of insufficient numbers of courses. During the 10 months of the trial, 28 courses of colchicine and 31 of placebo were taken during the early stages of FMF attacks. Twenty-one (75%) colchicine courses were followed by attacks considered to have been aborted, compared to only three (10%) placebo courses. This trial shows that patients can recognize the prodrome of their FMF attacks and that some patients can consistently abort their attacks with short courses of colchicine taken at the very onset of symptoms.

Postprandila glycaemia and rise in serum insulin after carbohydrate-containing meals were reduced by the addition of guar flour or pectin, or both. After a liquid test meal (four subjects) the 30-min blood glucose was reduced from 6.33 +/- 0.19 mmol/litre (114 +/- mg/dl), mean +/- SEM, in the control subjects of 4.77 +/- 0.17 mmol/litre (86 +/- 3 mg/dl) by addition of guar gum (P less than 0.05). The mean insulin level was also significantly lower at 15 min. A breakfast test meal (bread, butter, marmalade, and tea) resulted in a mean 15-min blood glucose of 6.18 +/- 0.21 mmol/litre (111 +/- 4 mg/dl) in eight subjects; 10 g of pectin added to the marmalade reduced this level to 5.64 +/- 0.17 mmol/litre (102 +/- 3 mg/dl) (P less than 0.01). The insulin levels were significantly lower at 15, 30, and 45 min. A similar meal in which guar was added to the bread and pectin to the marmalade resulted in significant reductions of blood glucose at 15 min (P less than 0.002) and 30 min (P less than 0.01). The insulin values were also significantly lower throughout the first 90 min of the test. This action of unavailable carbohydrate may prove useful in the dietary control of diabetes.

Amantadine HCl administration has resulted in accelerated resolution of influenza A illness. Prolonged abnormalities in pulmonary function have been described in uncomplicated influenza A. To study the effect of amantadine on these changes, we evaluated young adults with documented natural influenza A with clear chest examinations and X rays. Subjects received placebo or amantadine in random, double-blind fashion. Physiologic studies included maximal expiratory flow volume curves with air and helium-oxygen mixtures. Air flow rates were unchanged in all subjects throughout. Initially, both groups showed comparable decreases in mean helium-oxygen maximal expiratory flow rates. The amantadine group showed accelerated physiologic improvement: significant increase in helium-oxygen flow rates occurred within 7 days (P less than 0.05). The rate of improvement in the helium-oxygen flow rates in the placebo group was not statistically significant. These studies confirm peripheral airways dysfunction after uncomplicated influenza A and suggest that amantadine is associated with accelerated resolution of this dysfunction.

To determine the effects of early ambulation on peripheral venous thrombosis in the coronary care unit, 29 patients with acute myocardial infarction had daily 125I-fibrinogen point counting of both legs using a standard portable technique in the first 3 to 7 days after admission. Twenty-one patients underwent early ambulation during the initial 3 days, while 8 remained at complete bed rest for 5 days. Only 2 of 21 early ambulated patients had positive fibrinogen point counts, in contrast to 5 of 8 nonambulated patients (P less than 0.01). With heart failure, only 2 of 9 ambulated patients had positive point counts, compared with 4 of 5 nonambulated patients (P less than 0.05). In 16 patients undergoing venography, point counts were confirmed in 6 positive and 10 negative findings. These results show that the high frequency of peripheral venous thrombosis in immobilized acute myocardial infarction patients, particularly those with heart failure, can be effectively reduced by early ambulation.

The effect of low-dose intramuscular insulin therapy was compared with that of high-dose insulin therapy by intravenous and subcutaneous routes in 48 patients with diabetic ketoacidosis. A simplified protocol was devised to compare efficacy of the two methods of therapy in a randomized manner. Plasma glucose dropped to less than 250 mg/dl in the low-dose group in 6.7 +/- 0.8 h and in the high-dose group in 4.5 +/- 0.8 h (P = not significant). The amount of insulin necessary to lower plasma glucose to 250 mg/dl was 263 +/- 45 U in the high-dose group and 46 +/- 5 U in the low-dose group. Twenty five percent in the high-dose group and none in the low-dose group developed hypoglycemia. Other biochemical and clinical variables in the two groups were comparable. No treatment complications were noted in the low-dose group. Our studies suggest that low-dose intramuscular insulin therapy is simple and as effective as high-dose therapy in the treatment of diabetic ketoacidosis without the risk of hypoglycemia and with a diminished incidence of hypokalemia. Furthermore, the favorable response of these patients to low-dose insulin therapy suggests the absence of insulin resistance in diabetic ketoacidosis.

We evaluated the effect of ethanol on exercise performance until angina in 12 patients in a double-blind, randomized study. The mean resting heart rate times systolic blood pressure was not changed after Fresca but was increased after 2 ounces of ethanol (P less than 0.001) and after 5 ounces of ethanol (P less than 0.01). Compared to the control periods, the mean exercise time until angina was not different after Fresca but was decreased after 2 ounces of ethanol (P less than 0.001) and after 5 ounces of ethanol (P less than 0.001). Compared to the control periods, the mean maximal ischemic ST-segment depression after angina was not changed after Fresca but was increased after 2 ounces of ethanol (P less than 0.01) and after 5 ounces of ethanol (P less than 0.001). Drinking 5 ounces or 2 ounces of ethanol decreases exercise duration until angina and increases ischemic ST-segment depression after angina.

One half of 42 subjects treated for painful shoulders received classic acupuncture, and one half received a placebo in which the needles did not penetrate the skin. Half of each of these groups was treated in a positive setting to encourage the subject, and half in a negative setting designed to keep encouragement at a minimum. All patients were independently rated for susceptibility to hypnosis. Although range of motion did not improve, the majority of patients reported significant improvement in shoulder discomfort to a blind evaluator after treatment; placebo and acupuncture groups did not differ in this respect, however. The positive and negative settings did not affect treatment outcome. In all groups, those who were not rated as highly susceptible to hypnosis tended to fail to achieve the highest levels of relief, but such differences were not statistically significant.

A lipid intervention clinic screened 4000 employees (89% participation) and identified 150 type IV subjects (top 5 percentile triglyceride values, 100% initial participation, 6% drop out). The 150 healthy type IV subjects, ages 20 to 49, were randomly divided into treatment subgroups: A, treatment by clinic nutritionist and physician with the National Heart and Lung Institute's type IV diet for 6 weeks, then diet plus clofibrate for 18 weeks; B, same treatment by private physician; C, no intervention for 24 weeks, subjects advised of abnormality. The group A mean fasting serum triglyceride of 407 mg/dl declined 50% at 6 weeks, 61% at 12 weeks, and was unchanged at 24 weeks (P less than 0.0005 at 6, 12, 24 weeks). Group B triglyceride decreased 42%, 50%, 41% (P less than 0.0005 at 6, 12, 24 weeks). Group C triglyceride declined 20%, 1st to 24th week. Body weight decreased 8% (A) and 4% (B) at 6 weeks (P less than 0.0005) and was unchanged at 24 weeks. The maximum cholesterol decrease (A) was 11% (P less than 0.0005). Type IV hyperlipoproteinemia can readily be identified in a working population; treatment by clinic or private physician will markedly lower fasting serum triglyceride values in apparently healthy type IV subjects for at least 24 weeks.

Thirty-eight patients with diffuse glomerulonephritis of systemic lupus erythematosus were randomly assigned to add cyclophosphamide, azathioprine, or nothing to low-dose corticosteroid treatment and have been followed for a mean of 21/3 years thereafter. Of the 11 patients with unfavorable outcomes (8 deaths and 2 beginning hemodialyses), 2 occurred on cyclophosphamide, 4 on azathioprine, and 5 on prednisone only. Deaths due to infection occurred on the cytotoxics, while deaths ascribed to central nervous system lupus erythematosus occurred exclusively on prednisone only. Gradual deterioration of renal function was observed in all three groups, most frequently on prednisone only. Undesirable events, some due to drugs, were observed. At the time of reporting, the cytotoxic agents seemed to add marginally to the control of the disease; other treatment schedules should be evaluated.

A prospective, randomized drug trial compared prednisone (60 mg per day initially) to azathioprine (3 to 4 mg/kg of body weight - day initially) plus prednisone in 24 patients with life-threatening systemic lupus erythematosus. Each group contained patients matched for age, sex, disease duration, previous therapy, and clinical and laboratory features of lupus erythematosus. During a mean follow-up period of 18 to 24 months, there were no significant differences between the two groups in number of deaths, renal or extrarenal manifestations of disease, serum complement levels, DNA antibodies, antinuclear antibody titers, lupus erythematosus cells, or Coombs' antibodies. There was no convincing evidence of a steroid-sparing effect of azathioprine. Side effects attributable to steroids were equally common in both groups; infections were not increased in the combination therapy group. Azathioprine was hepatotoxic in doses of 200 mg daily or more. Azathioprine was not a useful adjunct to corticosterolds in short-term therapy of a small number of patients with severe systemic lupus.

To evaluate the interaction between the antibiotic rifampin and the anticoagulant warfarin during chronic therapy, eight normal subjects were given daily doses of warfarin for 21 days to achieve therapeutic hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin activity and for warfarin content spectrophotometrically and chromatographically. One month later, the same warfarin dose was repeated plus rifampin, 600 mg a day orally. For the last 10 days of every experiment, there was a highly significant lessening of both the hypoprothrombinemic effect (P less than 0.001) and the blood levels of warfarin (P less than 0.001). No significant difference in the warfarin levels was found between the spectrophotometric and chromatographic methods. It is concluded that rifampin markedly decreases the hypoprothrombinemic effect of warfarin during long-term therapy by enhancing its elimination from plasma. This conclusion was reinforced by finding increased amounts of warfarin metabolites in urine and stool.

Response to therapy, renal function, and mortality were analyzed in a prospective study of 249 men with bacteriuria followed for up to 10 years. All patients received initial organism-specific antibiotic therapy followed by 2 years of continuous treatment with sulfamethizole, nitrofurantoin, methenamine mandelate, or placebo. Continuous therapy with active drugs delayed recurrence of bacteriuria and reduced acute clinical exacerbations of infection. Patients with pure Escherichia coli bacteriuria, normal intravenous pyelogram, no previous therapy, and a normal prostate had a good prognosis with short-term antibiotic therapy alone. The presence of prostatic or upper urinary tract calculi, pyelonephritic scars, or mixed or enterococcal infections predicted a poor bacteriologic prognosis. In the absence of severe urologic disease or concomitant noninfectious renal disease no patients with persistent bacteriuria developed renal failure. Continuous antibiotic therapy is of value in selected male patients with bacteriuria in reducing recurrence and acute clinical exacerbations of urinary tract infection.

Cytosine arabinoside (cytarabine) was evaluated in a randomized double-blind controlled study for the treatment of localized herpes zoster. Cytarabine was administered subcutaneously in a dose of 50 mg/m-2 body surface area once daily for 4 days, always within 14 days of onset of the first symptom and usually within 7 days. Thirty patients given cytarabine and 30 patients given placebo were well matched with respect to age, sex, and length and severity of presenting rash and pain as well as underlying disease. There was no difference in the rate of disappearance of pain or rash in either treatment group. More patients given cytarabine than patients given placebo had minimal pain and significantly more cytarabine-treated patients had persistence of neurological symptoms at 6 months' follow-up. Acute side effects, though mild, were significantly increased in the cytarabine-treated patients especially with respect to nausea and vomiting and decrease in platelet count. Cytarabine administered in this dose subcutaneously had no beneficial effect and was associated with mild side effects and persistence of neurological symptoms.

Automated feedback control methods were applied to a medical problem, in a computer program that used measured serum digoxin concentrations (as feedback) to predict future concentrations and to achieve desired concentrations. The system was validated by comparing its ability with the corresponding ability of physicians to regulate digoxin dosage. The prospective, randomized study included 51 patients. In the presence of varying amounts of feedback (serum digoxin concentration) information, the computer always predicted future digoxin concentrations as accurately as did physicians. For both computer and physician, the decrease in the prediction errors when two concentrations were known against that when no concentrations were known was significant: mean absolute error decreased from 0.40 to 0.25 ng/ml for the physicians and from 0.45 to 0.27 ng/ml for the computer. Thus the computer system is capable of simulating and reproducing a sophisticated aspect of physician behavior: "learning" about individual patient responses. The computer achieved desired concentrations more accurately than did physicians, especially when two or more previous digoxin concentrations were abailable (mean absolute achievement error for computer, 0.28 ng/ml; for physicians, 0.50 ng/ml).

Alternate-day corticosteroid therapy was compared with two daily corticosteroid regimens for the treatment of giant cell arteritis. In a prospective study 60 patients with this disease were randomly assigned to three treatment groups: group A, 15 mg of prednisone every 8 hours; group B, 45 mg of prednisone every morning; and group C, 90 mgof prednisone every other morning. After 1 month of treatment, the arteritis seemed to be completely suppressed in 18 patients in group A and 16 in group B but in only 6 in group C. In the 14 other patients in group C, the continuing symptoms were cyclic and developed during the day steroids were not given. By changing to a daily regimen, the arteritis was controlled in most patients in group C. Adverse reactions to prednisone were noted frequently in groups A and B but rarely in group C.