Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada?

BACKGROUND: One-year follow-up data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial show that use of low-molecular-weight heparin (enoxaparin) compared with unfractionated heparin in patients hospitalized with unstable angina or non-Q-wave myocardial infarction is associated with a 10% reduction in the cumulative 1-year risk of death, myocardial infarction, or recurrent angina. Given the higher acquisition cost of enoxaparin relative to unfractionated heparin, we assessed whether the reduced use of revascularization procedures and related care makes enoxaparin a cost-saving therapy in Canada. METHODS AND RESULTS: We analyzed cumulative 1-year resource use data on the 1259 ESSENCE patients enrolled in Canadian centers (40% of the total ESSENCE sample). Patient-specific data on use of drugs, diagnostic cardiac catheterization, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and hospital days were available from the initial hospital stay and cumulative to 1 year. Hospital resources were costed with the use of data from a teaching hospital in southern Ontario that is a participant in the Ontario Case Costing Project. During the initial hospital stay, use of enoxaparin was associated with reduced use of diagnostic catheterization and revascularization procedures, with the largest effect being reduced use of percutaneous transluminal coronary angioplasty (15.0% vs 10.6%; P =.03). At 1 year, the reduced risk and costs of revascularization more than offset increased drug costs for enoxaparin, producing a cost-saving per patient of $1485 (95% confidence interval $-93 to $3167; P =.06). Sensitivity analysis with lower hospital per diem costs from a community hospital in Ontario still predicts cost savings of $1075 per patient over a period of 1 year. CONCLUSIONS: The acquisition and administration cost of enoxaparin is higher than for unfractionated heparin ($101 vs $39), but in patients with acute coronary syndrome, the reduced need for hospitalization and revascularization over a period of 1 year more than offsets this initial difference in cost. Evidence from this Canadian substudy of ESSENCE supports the view that enoxaparin is less costly and more effective than unfractionated heparin in this indication.     

Deoxyribonucleotide pools, base pairing, and sequence configuration affecting bromodeoxyuridine- and 2-aminopurine-induced mutagenesis.

Despite recent experiments showing that BrdUrd-induced mutagenesis can be independent of the level of bromouracil (BrUra) substitution [Kaufman, E.R. & Davidson, R.L. (1978) Proc. Natl. Acad. Sci. USA 75, 4982-4986; Aebersold, P.M. (1976) Mutat. Res. 36, 357-362], BrUra.G base mispairs are a major determinant of mutagenesis. We propose that the experiments cited above are sensitive predominantly to G . C leads to A . T transitions driven by the immeasurably small but highly mutagenic substitution of BrUra for cytosine and not by the gross substitution of BrUra for thymine in DNA. More generally, we show how accumulated evidence suggests that both BrdUrd and 2-aminopurine have two mutagenic effects intracellularly: perturbation of normal deoxyribonucleoside triphosphate pools and analogue mispairs in DNA. We propose a molecular basis for various observations of normal exogenous deoxyribonucleosides as synergists and counteragents to base analogue mutagenesis. A model is proposed to explain the antipolarity of BrdUrd and 2-aminopurine mutagenesis--i.e., why mutants at hot spots for induction by one base analogue are usually hot spots for reversion by the other. It is concluded that the configuration of the neighboring nucleotides surrounding the base analogue mispair, and not the base analogue's preference for inducing A . T leads to G . C or G . C leads to A . T errors, is responsible for the antipolarity of BrdUrd and 2-aminopurine mutagenesis.     

Antibiotic susceptibility of the newly cultivated agent of human granulocytic ehrlichiosis: promising activity of quinolones and rifamycins.

Human granulocytic ehrlichiosis (HGE) is a rapidly emerging tick-borne infection which presents as an acute febrile illness and is associated with hematologic abnormalities, elevated hepatic transaminase levels, and characteristic intracellular organisms in peripheral blood granulocytes. Although HGE has been successfully treated with tetracyclines, its susceptibility to other antibiotics remains unknown. No clear treatment alternative exist for young children, pregnant women, or allergic individuals, in whom tetracyclines are contra-indicated. We performed in vitro antibiotic susceptibility tests with this recently isolated agent grown in the human promyelocytic leukemia cell line HL-60. Doxycycline (MIC, 0.25 micrograms/ml), rifampin (MIC, 0.5 micrograms/ml), rifabutin (MIC, < or = 0.125 micrograms/ml), ciprofloxacin and ofloxacin (both with MICs of 2 micrograms/ml), and trovafloxacin (MIC, < or = 0.125 micrograms/ml) ciprofloxacin and ofloxacin (both with MICs of 2 micrograms/ml), and trovafloxacin (MIC, < or = 0.125 micrograms/ml) demonstrated significant activity against the HGE agent. These agents were also bactericidal. The HGE agent was resistant to clindamycin, trimethoprim-sulfamethoxazole, and imipenem-cilastatin, as well as to ampicillin, ceftriaxone, erythromycin, and azithromycin, antibiotics commonly used to treat Lyme disease. Both chloramphenicol and gentamicin had weak inhibitory activities but were not bactericidal. Our findings confirm the observed clinical efficacy of doxycycline and further suggest that the rifamycins and quinolones, particularly trovafloxacin, hold promise as alternative agents for treating this new infection.     

Chediak-Higashi gene in humans. I. Impairment of natural - killer function

Natural-killer (NK)-cell function was profoundly depressed in donors homozygous for the Chediak-Steinbrinck-Higashi syndrome (C-HS) gene when compared with age- and sex-matched normals. This apparent defect was not simply a result of a delayed response because little cytolysis was evident in kinetics experiments even after 24 h of incubation. NK cells from C-HS donors failed to lyse adherent (MDA, CEM, and Alab) or nonadherent (K562 and Molt-4) tumor cell lines or nontransformed human fetal fibroblasts. Therefore, the apparent C-HS defect was not a result of a shift in target selectivities. In addition, the depressed reactivity did not appear to be a result of suppressor cells or factors because: (a) enriched NK populations (nonadherent lymphocytes bearing receptors for the Fc portion of IgG) from C-HS donors were low in NK-cell function, (b) C-HS mononuclear cells did not inhibit the cytotoxicity of normal cells in coculture experiments, and (c) cells from the C-HS donors remained poorly reactive even after culture for up to 7 d. The nature of the defective NK activity in C-HS patients is not clear but may lie within the lytic mechanism rather than at the level of the recognition structure or population size because the frequency of target-binding cells was normal. In vitro NK activity could be partially restored by interferon treatment. Combined with the results presented in the following paper (4), these observations suggest that the C-HS gene causes a selective immunodeficiency disorder, mainly involving NK cells. This finding, in conjunction with the high incidence of spontaneous possibly malignant, lymphoproliferative disorders in these patients, may have important implications regarding the theory of immune surveillance mediated by NK cells.     

Distribution and turnover of cholesterol in humans

The relationships between some parameters of cholesterol metabolism and body weight were studied in 22 subjects. Cholesterol-4-(14)C, complexed with plasma lipoprotein, was injected intravenously and from the resultant specific activity-time curves a number of indexes of cholesterol turnover were calculated. These were based on the two-pool model previously described by Goodman and Noble and included estimates of the sizes of the two pools, the production rate of cholesterol in the system, the rate constants for cholesterol removal from the two pools and transfer between the pools, and the metabolic clearance of cholesterol.Single and multiple regression analysis was used to define the relationships between the turnover and distribution of cholesterol and the total weight and fat content of the body.The amount of cholesterol in the more rapidly turning over pool A, which probably includes cholesterol in liver, plasma, erythrocytes, and part of the viscera such as intestine, varied from 14.9 to 32.7 g. The mean value for the extraplasma part of pool A was 17.9 g. Making certain assumptions it was possible to derive estimates of the probable lower and upper values for size of pool B (exchangeable cholesterol in tissues other than in pool A), which were, on average, 35 and 60 g. The daily production rate of cholesterol (assumed to be equivalent to total turnover rate) varied between 0.73 and 1.68 g/day.The production rate of cholesterol and the size of pool B were significantly related to total body, and particularly to excess body, weight. When the plasma content was excluded, the amount of cholesterol in pool A was not related to weight. For a body of ideal weight the production rate was 1.10 g/day and the size of pool B between 32 and 53 g. For each kilogram of excess weight the expected increments were 0.0220 g/day and 0.90 g, respectively.The plasma cholesterol concentration was not related to the production rate or to the amount of cholesterol in the two pools. It was, however, inversely related to the fractional rate of removal from pool A and to the metabolic clearance rate of cholesterol which suggests that inadequate excretion could be of importance in the development of hypercholesterolemia.     

Clinical efficacy of cefotaxime in serious infections

Thirty-five patients underwent 38 treatment courses with cefotaxime. Documented infections included 11 bacteremias, 7 cases of nosocomial pneumonia, 6 surgical wound infections, 3 bone infections, 1 biliary infection, and 1 urinary tract infection. Granulocytopenic patients with fever received 15 courses of empiric cefotaxime therapy alone; in 8 courses, no definite site of infection or pathogen was isolated. Broad-spectrum antibiotics had been administered to 23 patients before cefotaxime. Thirty-seven bacterial pathogens were isolated from 25 patients. Three such pathogens were resistant to cefotaxime and required alternative therapies. Pathogenic isolates included 13 Serratia marcescens, 12 Pseudomonas aeruginosa, 4 Escherichia coli, 2 Klebsiella pneumoniae, 2 Providencia stuartii, 1 Enterobacter cloacae, 1 Haemophilus influenzae, 1 Enterococcus, and 1 Staphylococcus aureus. Of the treatment courses, 25 of 38 resulted in a favorable response to cefotaxime, including 9 of 15 in granulocytopenic patients. Superinfection was seen in one patient. The emergence of resistance was documented in another patient. Of 15 patients with multiply resistant pathogens, 12 improved with cefotaxime. Of 12 patients with Pseudomonas aeruginosa, 6 favorably responded. Possible complications of cefotaxime were observed in 14 of 42 treatment courses. Cefotaxime is most useful in treatment of infections due to multiply resistant, gram-negative pathogens other than Pseudomonas aeruginosa.     

Characteristics of human large granular lymphocytes and relationship to natural killer and K cells

Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcγR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcγR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.     

Effects of incentive items on participation in a randomized chemoprevention trial

Behavioral research has an important role in increasing and maintaining participation in disease prevention trials, both in interventions and in follow-up visits. We conducted a randomized experiment among participants in the lung cancer chemoprevention trial, CARET (Carotene and Retinol Efficacy Trial) to test the effects of providing two incentives on retention. The items used for this study were a Certificate of Appreciation and one of two lapel pins, provided in a 2 2 design. Providing incentives, whether alone or in combination, had no statistically significant effect on retention by the two-year follow-up point. The successful implementation of this randomized incentive study has two implications for future research: (1) study of behavioral interventions and issues is feasible in the context of large controlled trials of disease end-points; and (2) such study is necessary to determine whether selected incentives can increase retention.