Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma.

Traditionally, non-small cell lung cancer (NSCLC) has been evaluated as a unique entity in genotyping studies. However, recent biological data suggest that different NSCLC subtypes, specifically adenocarcinomas (AC) and squamous cell carcinomas (SCC), differentially alter cancer behavior. Several studies have associated a p53 polymorphism at codon 72 with NSCLC susceptibility. This study investigated whether different p53 genotypes altered the overall risk of developing AC versus SCC. Polymorphisms in metabolizing enzymes, together with prolonged exposure to tobacco carcinogens, can result in accumulation of DNA damage; these effects may potentiate the effects of subtle differences in p53 function. Thus, interactions between polymorphisms of p53 and either GSTM1 or GSTT1 were also evaluated. We analyzed 1168 incident lung cancer cases and 1256 control subjects using multiple logistic regression. Histological data were available for 1144 cases (98%): 585 with AC, 284 with SCC, and 275 with other histological subtypes (large cell, small cell, mixed, and other). An increase in the NSCLC risk posed by the p53 Pro allele (versus Arg/Arg) was seen in AC compared with controls [adjusted odds ratio (OR), 1.36; 95% confidence interval (CI), 1.1-1.7] but not in SCC (adjusted OR, 1.04; 95% CI, 0.8-1.4). Among AC and SCC cancer patients, individuals with the GSTM1-null genotype had an OR of 1.80 (95% CI, 1.1-2.8; case-only analysis) of having AC versus SCC if they also carried a p53 Pro allele. We conclude that different genotype combinations of p53 and GSTM1 increase the risk of developing specific histological subtypes of NSCLC.

The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74-1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08-3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76-1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.

The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior.

We conducted a hospital-based case-control study of 814 lung cancer patients and 1123 controls to examine the association of the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene polymorphism with lung cancer susceptibility. Using PCR-RFLP genotyping assay techniques, we analyzed DNA samples to detect the variant forms of the NQO1 gene in exon 6 on chromosome 16q. We examined the relationship between lung cancer odds and NQO1 genotypes after adjusting for age, gender, and smoking behavior using generalized additive modeling. We found no overall association between NQO1 genotypes and lung cancer susceptibility, regardless of age, gender, family history of cancer, or histological cell type. However, our data demonstrated that in both former and current smokers, there was an association between NQO1 genotypes and lung cancer susceptibility that was dependent upon cigarette smoking duration and smoking intensity. For both current and former smokers, smoking intensity was more important in predicting cancer risk than smoking duration for all of the genotypes. Among former smokers, individuals with the T/T genotype were predicted to have a greater cancer risk than those with the C/C genotype for smoking durations up to 37 years. The predicted cancer risk for former smokers with the C/T versus T/T genotype depended on both smoking intensity and smoking duration. Our results support the concept that differential susceptibility to lung cancer is a function of both an inheritable trait in NQO1 metabolism and individual smoking characteristics.

Birth and first-year costs for mothers and infants attributable to maternal smoking.

Maternal smoking during pregnancy has been linked to high costs. This study estimates the magnitude of excess costs attributable to smoking during pregnancy for mothers and infants. The model estimates smoking-attributable costs for 11 infant and maternal conditions. From a claims database of 7784 mothers and 7901 infants who had deliveries during 1996, we estimated total cost over the infants' first year of life for each mother and infant and identified each complication of interest, based on ICD-9 codes. The average cost for smokers and non-smokers could not be computed directly because smoking status is not available in claims data. Therefore, the population attributable risk percentage (PAR%) due to smoking for each complication was identified from the literature. Multiple linear regression was used to provide estimates of the incremental cost associated with each smoking-related complication. The total cost attributable to smoking was computed as a function of the incremental cost of each complication and the PAR% for each complication. The conditions associated with the largest incremental costs compared to patients without those conditions were abruptio placenta ($23,697) and respiratory distress syndrome ($21,944). Because they were more common, the conditions with the largest smoking-attributable cost were low birth weight ($914) and lower respiratory infection ($428). The sum of the additional costs attributable to smoking for all conditions yielded a total in the first year after birth ranging from $1142 to $1358 per smoking pregnant woman. It was concluded that maternal smoking during pregnancy results in an economic burden to payers and society. These estimates may be useful in formal cost-effectiveness evaluations of individual smoking cessation strategies.

Recurrent ischemia after thrombolysis for acute myocardial infarction.

BACKGROUND: Reliable predictors have yet to be found for recurrent ischemia after thrombolysis for acute myocardial infarction (AMI), nor do we know whether early angiography can herald recurrent ischemia. This study sought to investigate the relationship between recurrent ischemia and cardiac procedures after thrombolysis for AMI. METHODS: The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial prospectively studied recurrent ischemia, which was defined as the presence of angina and changes in hemodynamics or the electrocardiogram. Cox regression analysis was used to identify predictors of recurrent ischemia. Other variables examined included time to coronary angiography and revascularization. RESULTS: Of 21,772 US GUSTO-I patients, 6313 (29%) had recurrent ischemia before discharge. Women (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.17-1.33) and patients with hypercholesterolemia (HR 1.14, 95% CI 1.07-1.22) or prior angina (HR 1.40, 95% CI 1.32-1.49) had a higher likelihood of recurrent ischemia. Current smoking and hours to thrombolysis were inversely related to recurrent ischemia (HR 0.86, 95% CI 0.81-0.92, HR 0.97, 95% CI 0.95- 0.99, respectively). Patients who underwent angiography before recurrent ischemia had a marginally increased risk of ischemia within 12 hours after angiography (HR 1.2, 95% CI 1.1-1.4); ultimately, they had a considerably lower risk 1 week after angiography than did patients without angiography (HR 0.57, 95% CI 0.45-0.72). CONCLUSIONS: Female sex, hypercholesterolemia, prior angina, and nonsmoking status weakly predict recurrent ischemia. Early coronary angiography reduces recurrent ischemia, probably because high-risk patients are identified and revascularized.

Use of an asbestos exposure score and the presence of pleural and parenchymal abnormalities in a lung cancer case series.

To assess whether there was an association between asbestos exposure and abnormalities on chest x-rays or CT scans, chest radiographs and CT scans of 103 asbestos-exposed patients with known lung cancer were reviewed for pleural or parenchymal abnormalities. Asbestos exposure was assessed using an asbestos exposure index that integrated time and intensity of reported exposure via a weighting scheme. Chest CT scans were clearly more sensitive in detecting pleural or parenchymal abnormalities than were standard PA chest x-rays. Furthermore, there was a significant correlation between higher asbestos exposure index scores and abnormalities on CT scans. Multivariable logistic regression models were used to investigate the relationship between the asbestos exposure index score and pleural or parenchymal abnormalities after adjusting for gender, pack-years of smoking, and cell type. None of these variables was associated with abnormalities on chest x-rays or CT scans. An asbestos exposure score > 10 was associated with pleural or parenchymal abnormalities (OR = 4.93; 95%CI 1.05-23.12). The results suggest that assessment of asbestos exposures by means of an algorithm-based index can classify the exposures accurately for epidemiologic studies.

An economic evaluation of a chlorhexidine chip for treating chronic periodontitis: the CHIP (chlorhexidine in periodontitis) study.

BACKGROUND: The authors previously suggested that an adjunctive, controlled-release chlorhexidine, or CHX, chip may reduce periodontal surgical needs at little additional cost. This article presents an economic analysis of the CHX chip in general dental practice. METHODS: In a one-year prospective clinical trial, 484 chronic periodontitis patients in 52 general practices across the United States were treated with either scaling and root planing, or SRP, plus any therapy prescribed by treating, unblinded dentists; or SRP plus other therapy as above but including the CHX chip. Economic data were collected from bills, case report forms and 12-month treatment recommendations from blinded periodontist evaluators. RESULTS: Total dental charges were higher for SRP + CHX chip patients vs. SRP patients when CHX chip costs were included (P = .027) but lower when CHX chip costs were excluded (P = .012). About one-half of the CHX chip acquisition cost was offset by savings in other charges. SRP + CHX chip patients were about 50 percent less likely to undergo surgical procedures than were SRP patients (P = .021). At the end of the trial, periodontist evaluators recommended similar additional procedures for both groups: SRP, about 46 percent; maintenance, about 37 percent; surgery, 56 percent for SRP alone and 63 percent for SRP + CHX chip. CONCLUSIONS: Adjunctive CHX chip use for general-practice patients with periodontitis increased costs but reduced surgeries over one year. At study's end, periodontists recommended similar additional surgical treatment for both groups. CLINICAL IMPLICATIONS: In general practice, routine use of the CHX chip suggests that costs will be partially offset by reduced surgery over at least one year.

Does the completeness of prostate sampling predict outcome for patients undergoing radical prostatectomy?: data from the CAPSURE database.

OBJECTIVES: To determine whether more complete sampling of the radical prostatectomy (RP) specimen better predicts outcome after surgery. METHODS: We reviewed pathology reports from 1383 patients enrolled in CaPSURE (a longitudinal registry of patients with prostate cancer) who underwent RP. Specimens were considered step-sectioned only if the entire specimen was submitted for analysis and if sections were taken at 0.5-cm intervals or less. Otherwise, specimens were considered non-step-sectioned. Pathologic stage, Gleason score, surgical margin status, and outcome were compared between groups. Prostate-specific antigen (PSA) recurrence was defined as a PSA level of 0.2 ng/mL or greater on two consecutive occasions after RP. Secondary cancer treatment consisted of radiation or androgen deprivation after RP. Adjuvant treatments occurred within 6 months of RP, and nonadjuvant treatments occurred more than 6 months after RP. Kaplan-Meier event rates of PSA recurrence and secondary treatment were calculated for patients in the step-sectioned and non-step-sectioned groups. RESULTS: No significant differences were found between patients in the step-sectioned and non-step-sectioned groups with respect to pathologic tumor stage, prostatectomy Gleason score, or margin status. Patients in whom step-sectioning was performed had a lower serum PSA at diagnosis than patients in the non-step-sectioned group. When examining all patients, no differences were observed in the use of secondary treatments or PSA recurrence based on the method of pathologic analysis. However, patients with negative margins in whom step-sectioning was performed exhibited significantly lower secondary nonadjuvant treatment use and appeared to have a lower risk of PSA recurrence than similar patients in the non-step-sectioned group. CONCLUSIONS: These data suggest that more complete pathologic analysis of the surgical specimen may better predict outcome for some patients undergoing RP. Additional research is warranted to determine whether such differences justify the additional resources necessary to recommend routine step-sectioning.

Impact of positive surgical margins on prostate cancer recurrence and the use of secondary cancer treatment: data from the CaPSURE database.

PURPOSE: We determined the impact of positive surgical margins on prostate specific antigen (PSA) recurrence and secondary treatment in patients who underwent radical prostatectomy as definitive local treatment for prostate cancer. MATERIALS AND METHODS: We reviewed the pathology reports of 1,383 patients in the CaPSURE database, a longitudinal disease registry of men with prostate cancer, who underwent radical prostatectomy as definitive local treatment. Pathological stage, Gleason score, and the number and location of any positive surgical margins were determined in each patient. PSA recurrence was defined as PSA 0.2 ng./ml. or greater on 2 consecutive occasions after radical prostatectomy. Secondary cancer treatment consisted of radiation or androgen deprivation after radical prostatectomy. Adjuvant and nonadjuvant secondary treatment was given within and more than 6 months after radical prostatectomy, respectively. Kaplan-Meier event rates of PSA recurrence and secondary treatment were calculated for patients with positive and negative surgical margins. We performed multivariate Cox proportional hazards analysis to adjust for clinical differences in groups. RESULTS: Patients with positive surgical margins were significantly more likely to undergo secondary adjuvant or nonadjuvant cancer treatment and have PSA recurrence than those with negative margins. After adjusting for patient age, ethnicity, PSA at diagnosis, pathological stage and Gleason score, surgical margin status was an important independent predictor of PSA recurrence and secondary treatment (p = 0.06 and 0.0011, respectively). The number of positive margins and positive margin location had little impact on the outcomes measured. CONCLUSIONS: These data indicate that surgical margin status is an independent predictor of PSA recurrence and secondary cancer treatment in patients who underwent radical prostatectomy as definitive local therapy for prostate cancer.

Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo.

OBJECTIVE: To compare the functional status and well-being of patients with rheumatoid arthritis (RA) who were randomly assigned to receive placebo, etanercept 10 mg, or etanercept 25 mg during a 26-week, phase III, double-blind clinical trial. BACKGROUND: No single indicator of disease activity, severity, or therapeutic efficacy has been established for RA. During the past decade, health-related quality of life, a multidimensional way to assess physical, emotional, and social aspects of a disease or its treatment, has become an important outcome in RA studies and in assessments of RA drug therapies. METHODS: A total of 234 patients completed the Health Assessment Questionnaire (HAQ), the Short-Form 36 (SF-36) (n = 48 patients), items assessing energy and mental health from the Medical Outcomes Study (MOS), and a single-item rating scale assessing current health (feeling thermometer) at baseline and several times during 6 months. RESULTS: Significant improvements from baseline to last assessment were reported with etanercept versus placebo and in the HAQ Disability Index score (ie, the total HAQ score) and all 8 HAQ categories (P < 0.05), with the exception of grip. Significant improvements with etanercept in the MOS energy and mental health subscales, current health (from the feeling thermometer), and mental and physical function components of the SF-36 were reported (P < 0.05). CONCLUSIONS: Patients receiving 10- or 25-mg doses of etanercept reported significantly better functional status and well-being than did patients receiving placebo.

Identification and expression of two baculovirus gp37 genes.

The gp37 genes of the Mamestra brassicae and Lymantria dispar multicapsid nucleopolyhedroviruses (MbMNPV and LdMNPV) have been identified and characterized. Both genes were similar to other baculovirus gp37 genes and to entomopoxvirus fusolin genes. Phylogenetic analysis showed that baculovirus gp37 genes and entomopoxvirus fusolin genes form two distinct and well-separated clades. There was no evidence of recent gene transfer between the two groups. The gp37 genes also showed a distant similarity to bacterial cellulose- and chitin-binding protein genes, but the significance of this is unclear. MbMNPV and LdMNPV gp37 were both transcribed from consensus baculovirus late transcription start sites. MbMNPV gp37 was additionally transcribed from a putative early transcription start site. Tunicamycin treatment of MbMNPV-infected cells confirmed that MbMNPV GP37 is N-glycosylated. Confocal immunofluorescence microscopy revealed that the protein is located exclusively in the cytoplasm, probably in the endoplasmic reticulum.

Safety of radiographic imaging during pregnancy.

Maternal illness during pregnancy is not uncommon and sometimes requires radiographic imaging for proper diagnosis and treatment. The patient and her physician may be concerned about potential harm to the fetus from radiation exposure. In reality, however, the risks to the developing fetus are quite small. The accepted cumulative dose of ionizing radiation during pregnancy is 5 rad, and no single diagnostic study exceeds this maximum. For example, the amount of exposure to the fetus from a two-view chest x-ray of the mother is only 0.00007 rad. The most sensitive time period for central nervous system teratogenesis is between 10 and 17 weeks of gestation. Nonurgent radiologic testing should be avoided during this time. Rare consequences of prenatal radiation exposure include a slight increase in the incidence of childhood leukemia and, possibly, a very small change in the frequency of genetic mutations. Such exposure is not an indication for pregnancy termination. Appropriate counseling of patients before radiologic studies are performed is critical.

Recombinant glycoproteins that inhibit complement activation and also bind the selectin adhesion molecules.

Soluble human complement receptor type 1 (sCR1, TP10) has been expressed in Chinese hamster ovary (CHO) DUKX-B11 cells and shown to inhibit the classical and alternative complement pathways in vitro and in vivo. A truncated version of sCR1 lacking the long homologous repeat-A domain (LHR-A) containing the C4b binding site has similarly been expressed and designated sCR1[desLHR-A]. sCR1[desLHR-A] was shown to be a selective inhibitor of the alternative complement pathway in vitro and to function in vivo. In this study, sCR1 and sCR1[desLHR-A] were expressed in CHO LEC11 cells with an active alpha(1,3)-fucosyltransferase, which makes possible the biosynthesis of the sialyl-Lewisx (sLex) tetrasaccharide (NeuNAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc) during post-translational glycosylation. The resulting glycoproteins, designated sCR1sLex and sCR1[desLHR-A]sLex, respectively, retained the complement regulatory activities of their DUKX B11 counterparts, which lack alpha(1-3)-fucose. Carbohydrate analysis of purified sCR1sLex and sCR1[desLHR-A]sLex indicated an average incorporation of 10 and 8 mol of sLex/mol of glycoprotein, respectively. sLex is a carbohydrate ligand for the selectin adhesion molecules. sCR1sLex was shown to specifically bind CHO cells expressing cell surface E-selectin. sCR1[desLHR-A]sLex inhibited the binding of the monocytic cell line U937 to human aortic endothelial cells, which had been activated with tumor necrosis factor-alpha to up-regulate the expression of E-selectin. sCR1sLex inhibited the binding of U937 cells to surface-adsorbed P-selectin-IgG. sCR1sLex and sCR1[desLHR-A]sLex have thus demonstrated both complement regulatory activity and the capacity to bind selectins and to inhibit selectin-mediated cell adhesion in vitro.

Analysis of risk factors for development of atrial fibrillation early after cardiac valvular surgery.

Atrial fibrillation (AF) commonly develops after cardiac valvular surgery. The objective of this study was to identify risk factors for postoperative AF following valvular surgery. A cohort of 915 consecutive adult patients undergoing isolated valvular surgery with preoperative sinus rhythm was analyzed. Univariate and independent multivariate risk factors for postoperative AF were determined. A second cohort of 305 patients with the same inclusion criteria was used to validate the multivariate predictors. Patients studied had a mean age of 56.1 +/- 14.7 years, 57.9% were men, 79.6% had a normal left ventricular ejection fraction, and their mean left atrial size was 46.2 +/- 9.3 mm. The incidence of postoperative AF was 36.7%. Independent predictors of postoperative AF included: advanced age (odds ratio [OR] 1.506 per decade, 95% confidence interval, [CI] 1.35 to 1.68, p = 0.0001); mitral stenosis (OR 2.066, CI 1.21 to 3.52, p = 0.0077); left atrial enlargement (OR 1.468, CI 1.07 to 2.01, p = 0.0165); use of systemic hypothermia (OR 0.572, CI 0.422 to 0.776, p = 0.0003); and a history of cardiac surgery (OR 0.676, CI 0.465 to 0.981, p = 0.0393). Among these variables, advanced age, mitral stenosis, and left atrial enlargement were confirmed as independent risk factors in the validation cohort.

Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators.

BACKGROUND: After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG). METHODS AND RESULTS: Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin. CONCLUSIONS: Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.

Cost of cardiac care in the three years after coronary catheterization in a contained care system: critical determinants and implications.

OBJECTIVES: We sought to determine the clinical, angiographic, treatment and outcome correlates of the intermediate-term cost of caring for patients with suspected coronary artery disease (CAD). BACKGROUND: To adequately predict medical costs and to compare different treatment and cost reduction strategies, the determinants of cost must be understood. However, little is known about the correlates of costs of treatment of CAD in heterogeneous patient populations that typify clinical practice. METHODS: From a consecutive series of 781 patients undergoing cardiac catheterization in 1992 to 1994, we analyzed 44 variables as potential correlates of total (direct and indirect) in-hospital, 12- and 36-month cardiac costs. RESULTS: Mean (+/-SD) patient age was 65+/-10 years; 71% were men, and 45% had multiple vessel disease. The initial treatment strategy was medical therapy alone in 47% of patients, percutaneous intervention (PI) in 30% and coronary artery bypass graft surgery (CABG) in 24%. The 36-month survival and event-free (death, infarction, CABG, PI) survival rates were 89.6+/-0.2% and 68.4+/-0.4%, respectively. Median hospital and 36-month costs were $8,301 and $28,054, respectively, but the interquartile ranges for both were wide and skewed. Models for log(e) costs were superior to those for actual costs. The variances accounted for by the all-inclusive models of in-hospital, 12- and 36-month costs were 57%, 60% and 71%, respectively. Baseline cardiac variables accounted for 38% of the explained in-hospital costs, whereas in-hospital treatment and complication variables accounted for 53% of the actual costs. Noncardiac variables accounted for only 9% of the explained costs. Over time, complications (e.g., late hospital admission, PI, CABG) and drug use to prevent complications of heart transplantation became more important, but many baseline cardiac variables retained their importance. CONCLUSIONS: 1) Variables readily available from a comprehensive cardiovascular database explained 57% to 71% of cardiac costs from a hospital perspective over 3 years of care; 2) the initial revascularization strategy was a key determinant of in-hospital costs, but over 3 years, the initial treatment become somewhat less important, and late complications became more important determinants of costs.

First chronic platelet glycoprotein IIb/IIIa integrin blockade. A randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions.

BACKGROUND: Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy. METHODS AND RESULTS: Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding. CONCLUSIONS: Xemilofiban, an orally active glycoprotein IIb/ IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.

Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

OBJECTIVES: This study was undertaken to define and better understand the characteristics and outcomes of patients with diabetes treated for acute myocardial infarction with contemporary thrombolysis. BACKGROUND: Although thrombolysis has substantially improved survival of patients with myocardial infarction, diabetes mellitus remains an independent predictor for a poor prognosis. METHODS: We characterized the contemporary relation between diabetes and outcome after myocardial infarction treated with thrombolytic agents from a large international cohort. Of 41,021 patients randomized to receive accelerated tissue-type plasminogen activator (t-PA), streptokinase or a combination of both agents in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study, there were 5,944 patients with diabetes and 34,888 patients without diabetes. RESULTS: Patients with diabetes were older and more likely to be female, to present with anterior wall infarction, to receive thrombolysis later and to have triple-vessel coronary artery disease. Mortality at 30 days was highest among diabetic patients treated with insulin (12.5%) compared with non-insulin-treated diabetic (9.7%) and nondiabetic (6.2%) patients (p < 0.001). Mortality was lowest among those with diabetes receiving accelerated t-PA, which is consistent with the results of the overall patient cohort. Although stroke occurred more frequently among diabetic (1.9%) than nondiabetic patients (1.4%, p < 0.001), there was no significant difference in the rates of intracranial hemorrhage. Cardiac failure, shock, atrioventricular block and atrial flutter/ fibrillation were more common among diabetic patients. The proportion of patients undergoing revascularization was similar between patients with and without diabetes, although diabetic patients were more likely to undergo coronary artery bypass graft surgery (10.4% vs. 8.3%). Diabetes remained an independent predictor for mortality at 1-year follow-up (14.5% vs. 8.9%, p < 0.001). CONCLUSIONS: Diabetes, alone and in association with its comorbidities, portends a substantially worse 30-day and 1-year prognosis for patients with myocardial infarction.

Three-dimensional mapping of the initiation of nonsustained ventricular tachycardia in the human heart.

BACKGROUND: Elucidation of the electrophysiological mechanisms of nonsustained ventricular tachycardia (VT) in humans is required to define the relationship between nonsustained VT and sustained VT. This goal requires, at least in part, analysis of transmural ventricular activation in patients with both sustained and nonsustained VTs. METHODS AND RESULTS: We analyzed three-dimensional intraoperative cardiac maps of extrastimuli and beats during 44 nonsustained VTs and the initiating beats of 6 sustained VTs from six patients with healed myocardial infarcts who were undergoing arrhythmia surgery. The coupling interval, total activation time, and diastolic interval of each extrastimulus and beat of nonsustained VT were compared with counterparts during sustained VT. Sites activated last during extrastimuli initiating nonsustained or sustained VTs occurred in the same region, and activation times were comparable. However, the site of earliest activation during the initial or subsequent beats of nonsustained VT was discordant from the site activated earliest during the first and subsequent beats of sustained VT in 74% of cases. The mean variance in coupling interval, but not total activation time or diastolic interval, was significantly greater for VT that terminated before the 10th cycle than for VT that sustained. When analyzed from the last extrastimulus up to the fifth VT cycle, the standard deviation of the coupling interval, but not of the total activation time, was greater for nonsustained than for sustained VTs. Electrode density was sufficient to define an arrhythmia mechanism for 36 beats of nonsustained VT. Twenty-one (58%) initiated in the subendocardium, midmyocardium, or epicardium by a macroreentrant mechanism, and 15 (42%) initiated in the subendocardium by a focal mechanism. CONCLUSIONS: Compared with sustained VT, nonsustained VT initiates at discordant sites, is characterized by oscillations in coupling interval but not in total activation time, and initiates by either a macroreentrant or a focal mechanism.