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PubMed2006

Global surveillance of in vitro activity of micafungin against Candida: a comparison with caspofungin by CLSI-recommended methods.

Micafungin is an echinocandin antifungal agent that has recently been approved for the prevention of invasive fungal infection and the treatment of esophageal candidiasis. Prospective sentinel surveillance for the emergence of in vitro resistance to micafungin among invasive Candida sp. isolates is indicated. We determined the in vitro activity of micafungin against 2,656 invasive (bloodstream or sterile site) unique patient isolates of Candida spp. collected from 60 medical centers worldwide in 2004 and 2005. We performed antifungal susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI) M27-A2 method and used a 24-hour prominent inhibition endpoint for determination of the MIC. Caspofungin was tested in parallel against all isolates. Of 2,656 invasive Candida sp. isolates, species distribution was 55.6% Candida albicans, 14.4% Candida parapsilosis, 13.4% Candida glabrata, 10.1% Candida tropicalis, 2.4% Candida krusei, 1.7% Candida guilliermondii, 0.9% Candida lusitaniae, 0.6% Candida kefyr, and 0.9% other Candida species. Overall, micafungin was very active against Candida (MIC50/MIC at which 90% of the isolates tested are inhibited [MIC90], 0.015/1 microg/ml; 96% inhibited at a MIC of < or =1 microg/ml, 100% inhibited at a MIC of < or =2 microg/ml) and comparable to caspofungin (MIC50/MIC90, 0.03/0.25 mug/ml; 99% inhibited at a MIC of < or =2 microg/ml). Results by species, expressed as MIC50/MIC90 (micrograms per milliliter), were as follows: C. albicans, 0.015/0.03; C. glabrata, 0.015/0.015; C. tropicalis, 0.03/0.06; C. krusei, 0.06/0.12; C. kefyr, 0.06/0.06; C. parapsilosis, 1/2; C. guilliermondii, 0.5/1; C. lusitaniae, 0.12/0.25; other Candida spp., 0.25/1. Although the species distribution varied considerably among the different geographic regions, there was no difference in micafungin activity across the regions. Micafungin has excellent in vitro activity against invasive clinical isolates of Candida from centers worldwide.

Antifungal Agents↗

PubMed1981

Enzymatic measurement of choline-containing phospholipids in bile.

An enzymatic method, previously used to determine choline-containing phospholipids in serum, was applied to the estimation of phospholipid concentration in bile. The method combines three enzymatic reactions: a) release of choline by phospholipase D; b) choline oxidation by choline oxidase, a reaction which generates hydrogen peroxide; and c) formation of a red quinone dye by peroxidase. The method is an endpoint, spectrophotometric determination. It is simple, sensitive, and reproducible. Accuracy was demonstrated both by linear recoveries of the choline-containing phospholipids in bile and a good correlation with a chemical determination. No interferences by bile acids and/or cholesterol were observed; bile pigment interference was removed by bleaching with white light. This method which determines lipid choline is simpler than the widely used chemical determination of lipid phosphorus.

Alcohol Oxidoreductases↗

PubMed2006

Antifungal effects on metabolite profiles of medically important yeast species measured by nuclear magnetic resonance spectroscopy.

Drug-induced inhibition of fungal growth is used in the diagnostic laboratory to predict therapeutic efficacy but is relatively slow, and determination of endpoints can be problematic. Nuclear magnetic resonance (NMR) spectroscopy identifies the metabolic complement of microorganisms while monitoring utilization of constituents of the incubation medium. This technique may provide a rapid and objective indicator of antifungal effects. We evaluated the effects of caspofungin, amphotericin B (AMB), and voriconazole on metabolic profiles of yeast species cultured in RPMI-2% glucose-morpholinepropanesulfonic acid buffer in microtiter plates in a proof-of-principle study. 1H NMR spectra were obtained using Bruker NMR spectrometers at 1H frequencies of 600 and 360 MHz. Metabolites were identified by two-dimensional correlation NMR spectra, and relative peak integrals were calculated from one-dimensional 1H NMR spectra. MICs were determined by a modification of the Clinical and Laboratory Standards Institute broth microdilution method M27-A. Utilization of glucose and branched-chain and aromatic amino acid substrates was accompanied by fungal production of acetate, acetaldehyde, ethanol, formate, fumarate, glycerol, lactate, pyruvate, and succinate. Clear-cut metabolic endpoints indicating a greater than 50% reduction in substrate utilization and fungal metabolite production which correlated with MICs were noted at 16 and 24 h for all three drugs. At 8 h, reductions of greater than 50% for selected metabolites were noted for caspofungin and AMB. Direct NMR-based observation of metabolic alterations in yeast cultures reveals changes in key metabolic pathways and should be evaluated formally as a rapid technique for determining susceptibility to antifungal drugs.

Amphotericin B↗

PubMed2002

Influence of QRS duration on the prognostic value of T wave alternans.

INTRODUCTION: T wave alternans (TWA) is a promising new noninvasive marker of arrhythmia vulnerability that quantifies beat-to-beat changes in ventricular repolarization. Secondary repolarization abnormalities are common in subjects with wide QRS complexes. However, the relationship between TWA and QRS prolongation has not been evaluated. The goal of this study was to determine if QRS prolongation influences the prevalence or prognostic value of TWA. METHODS AND RESULTS: The study consisted of 108 consecutive patients with coronary artery disease and left ventricular ejection fraction < or = 40% who were referred for electrophysiologic studies. Patients underwent TWA testing using bicycle ergometry in the absence of beta-blockers or antiarrhythmic drugs. The primary endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator therapy. The prognostic value of TWA was assessed in the entire cohort and in two subgroups: QRS < 120 msec (normal, n = 62) and QRS > or = 120 msec (prolonged, n = 46). TWA (hazard ratio 2.2, P = 0.03) and QRS prolongation (hazard ratio 2.2, P = 0.01) were both significant and independent predictors of arrhythmic events. QRS prolongation had no effect on the prevalence of positive TWA tests (QRS < 120 msec: 48%, QRS > or = 120 msec: 50%, P = NS). TWA was a highly significant predictor of events in patients with a normal QRS (hazard ratio 5.8, P = 0.02). In contrast, TWA was not useful for risk stratification in subjects with QRS prolongation (hazard ratio 1.1, P = 0.8). CONCLUSION: TWA is useful only for risk stratification in the absence of QRS prolongation. The presence of QRS prolongation and left ventricular ejection fraction < or = 40% may be sufficient evidence of an adverse prognosis that additional risk stratification is not useful or necessary.

Adult↗

PubMed2003

Sensitive assay for antifungal activity of glucan synthase inhibitors that uses germ tube formation in Candida albicans as an end point.

We implemented a simple, sensitive, objective, and rapid cellular assay to reveal the antifungal activity of a novel class of glucan synthase inhibitors. The assay, especially useful for early drug discovery, measures the transformation of Candida albicans from the yeast form to the hyphal form. Test compounds were ranked by potency (50% inhibitory concentration) and efficacy (percent inhibition of germ tube formation); the intra-assay coefficients of variation for these parameters were 17 and 5%, respectively. The germ tube formation assay proved useful for the early-stage antifungal characterization of a novel class of glucan synthase inhibitors discovered at Pharmacia. Drug concentrations required in this assay to inhibit germ tube formation were lower for 90% of the novel compounds than the concentrations required to determine MICs. The method may have utility for other mechanistic classes of antifungal compounds during the hit-to-lead transition of drug discovery.

Antifungal Agents↗

PubMed2004

The autoradiographic test for unscheduled DNA synthesis: a sensitive assay for the detection of DNA repair in the HepG2 cell line.

We assessed the DNA-repair capacity of HepG2 cells, which were derived from a human hepatoma, by the unscheduled DNA synthesis assay, using the autoradiography protocol (UDS-AR). We evaluated DNA repair following exposure to direct mutagens (4-nitroquinoline-N-oxide (4-NQO), methyl methanesulfonate (MMS)), to mutagens requiring metabolic activation (benzo[a]pyrene (B[a]P), 2-acetylaminofluorene (2-AAF), N-dimethylnitrosoamine (NDMA)) or to structurally related non-mutagens such as pyrene and 4-acetylaminofluorene (4-AAF). All positive compounds tested induced UDS in HepG2 cells. With 4-NQO and MMS, a concentration-dependent increase in net nuclear grains per cell was observed, with 73 and 90% of cells, respectively, in repair at the highest concentration. B[a]P, 2-AAF and NDMA displayed similar dose-dependent UDS responses, but the percentage of cells in repair was lower (about 45%) than that for 4-NQO and MMS. We assessed the genotoxicity of the compounds tested by determining IC(5NNG): the concentration required to induce 5NNG. The compounds studied were ranked in order of IC(5NNG) as follows: 4-NQO = B[a]P > 2-AAF > MMS > NDMA. The UDS assay discriminated between mutagens and non-mutagens, as pyrene and 4-AAF failed to induce DNA repair. The present study demonstrates that UDS can be used as an endpoint for the detection of DNA damage in HepG2 cells.

Analysis of Variance↗

PubMed2002

Blood pressure as a surrogate end point for hypertension.

OBJECTIVE: To review relevant literature and provide opinions regarding the use of blood pressure as a surrogate measure to predict cardiovascular risk. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1990-January 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles that related to the interpretation of blood pressure as a surrogate measure were reviewed. Information that was relevant to this topic was included. DATA SYNTHESIS: The measurement of blood pressure is subject to numerous sources of error and bias. Patients who perform home blood pressure testing and self-report these values frequently leave out high values and add ghost values into logbooks. Additionally, analysis of recent data suggests that at any given level of blood pressure that is achieved, cardiovascular risk reduction may not be the same with different therapeutic agents. It is also now recommended that systolic blood pressure be used in preference to diastolic blood pressure to determine risk and to assess management strategies. Although 24-hour blood pressure measurements may be the best predictors of cardiovascular risk, this has not been demonstrated in a long-term morbidity trial. CONCLUSIONS: Blood pressure is a relatively poor surrogate measure. Unfortunately, no alternatives are available at this time. Therefore, every attempt must be made to accurately determine blood pressure and to assess risk and benefit from specific antihypertensive agents. Systolic blood pressure should be the predominant blood pressure measure used to evaluate patients, especially middle-aged and elderly individuals.

Antihypertensive Agents↗

PubMed2006

In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance.

Caspofungin is being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for emergence of in vitro resistance to caspofungin among invasive Candida spp. isolates is indicated. We determined the in vitro activity of caspofungin against 8,197 invasive (bloodstream or sterile-site) unique patient isolates of Candida collected from 91 medical centers worldwide from 1 January 2001 to 31 December 2004. We performed antifungal susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) M27-A2 method and used a 24-h prominent inhibition endpoint for determination of the MIC. Of 8,197 invasive Candida spp. isolates, species distribution was as follows: 54% Candida albicans, 14% C. glabrata, 14% C. parapsilosis, 11% C. tropicalis, 3% C. krusei, and 4% other Candida spp. Overall, caspofungin was very active against Candida (MIC50/MIC90, 0.03/0.25 microg/ml; 98.2% were inhibited at a MIC of < or = 0.5 microg/ml and 99.7% were inhibited at a MIC of < or = 1 microg/ml). Results by species (expressed as MIC50/MIC90 and the percentage inhibited at < or = 1 microg/ml) were as follows: C. albicans, 0.03/0.06, 99.9; C. glabrata, 0.03/0.06, 99.9; C. parapsilosis, 0.5/0.5, 99.0; C. tropicalis, 0.03/0.06, 99.7; C. krusei, 0.12/0.5, 99.0; and C. guilliermondii, 0.5/1, 94.4. Of the 25 isolates with caspofungin MICs of >1 microg/ml, 12 isolates were C. parapsilosis, 6 isolates were C. guilliermondii, 2 isolates were C. rugosa, and 1 isolate each was C. albicans, C. glabrata, C. krusei, C. lusitaniae, and C. tropicalis. There was no significant change in caspofungin activity over the 4-year study period. Likewise, there was no difference in activity by geographic region. Caspofungin has excellent in vitro activity against invasive clinical isolates of Candida from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging caspofungin resistance among invasive clinical isolates of Candida.

Antifungal Agents↗

PubMed2002

Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial.

BACKGROUND: External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS: After stratification by tumour size (< or = 10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS: Median follow-up was 3.3 years (range 0.27-5.6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5-30], p=0.01). Tumour size and anatomical site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment (p=0.0481). INTERPRETATION: Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomical site of the tumour.

Aged↗

PubMed2004

Clinical trial design for microarray predictive marker discovery and assessment.

Transcriptional profiling technologies that simultaneously measure the expression of thousands of mRNA species represent a powerful new clinical research tool. Similar to previous laboratory analytical methods including immunohistochemistry, PCR and in situ hybridization, this new technology may also find its niche in routine diagnostics. Outcome predictors discovered by these methods may be quite different from previous single-gene markers. These novel tests will probably combine the information embedded in the expression of multiple genes with mathematical prediction algorithms to formulate classification rules and predict outcome. The performance of machine learning-algorithm-based diagnostic tests may improve as they are trained on larger and larger sets of samples, and several generations of tests with improving accuracy may be introduced sequentially. Several gene-expression profiling-technology platforms are mature enough for clinical testing. The most important next step that is needed for further progress is the development and validation of multigene predictors in prospectively designed clinical trials to determine the true accuracy and clinical value of this new technology. This manuscript reviews methodological and statistical issues relevant to clinical trial design to discover and validate multigene predictors of response to therapy.

Clinical Trials as Topic↗

PubMed2005

Cardiovascular morbidity associated with nonadherence to statin therapy.

STUDY OBJECTIVE: To measure the extent of cardiovascular morbidity associated with nonadherence to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. DESIGN: Retrospective cohort study. DATA SOURCE: Linked administrative health databases in Saskatchewan, Canada. PATIENTS: A total of 1221 patients aged 30-70 years who received a new prescription for a statin drug between 1994 and 2001, within 1 year of their first cardiovascular event (i.e., myocardial infarction, unstable angina, ischemic stroke, percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass graft [CABG]). MEASUREMENTS AND MAIN RESULTS: Adherence was measured by the fill frequency (number of prescriptions filled during the observation period divided by months of observation). Patients with a fill frequency of 80% or greater were classified as adherent (661 patients); those with a fill frequency of 60% or less were classified as nonadherent (395 patients). The remaining 165 patients who had adherence rates of 61-79% were excluded from the analysis. The primary end point included a composite of myocardial infarction, unstable angina, PTCA, CABG, and death. Among 1056 patients, adherence was not associated with a reduction of the primary end point. However, patients in the adherent group were half as likely to experience a subsequent myocardial infarction as the patients in the nonadherent group (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.20-0.99, p=0.047). In patients younger than 65 years (both adherent and not), the associated reduction in myocardial infarction was even more profound (HR 0.14, 95% CI 0.04-0.46, p=0.001) and was accompanied by a trend for a lower frequency of unstable angina (HR 0.37, 95% CI 0.13-1.03, p=0.06). In patients 65 years or older (301 patients), adherence was not associated with significant changes in cardiovascular end points. CONCLUSION: A detectable excess of cardiovascular morbidity appears to be associated with nonadherence to statin therapy. Our analysis suggests that many occurrences of myocardial infarction could be prevented with improvements in adherence. Larger studies are necessary to determine the association between adherence and other cardiovascular end points.

Adult↗

PubMed2006

Platelet-dependent coagulation assays for factor VIII efficacy measurement after substitution therapy in patients with haemophilia A.

FVIII therapy for haemophilia A is safe and effective, with the problem of individually sufficient efficacy unsettled. Routine one-stage clotting assays and tests employing chromogenic substrates poorly detect individual haemostatic effects of FVIII due to artificial test conditions. In particular, the use of cell-free and diluted plasma samples neglect the crucial role of platelets for thrombin and fibrin formation. To optimize FVIII substitution therapy, we measured in 40 patients with severe to mild haemophilia A before and after FVIII substitution the FVIII activity in cell-free plasma samples using a one-stage clotting assay as well a chromogenic substrate assay and compared the data with those obtained with cell-based coagulation tests, i.e. thrombin generation in platelet-rich plasma (PRP) and thromboelastography (TEG) in samples of citrated whole blood (WB). To determine the maximum ex vivo haemostatic effect we added 1 unit/ml of FVIII to samples of PRP and WB and measured the maximum thrombin generation in the thrombin generation test (TGT) and the maximum clot firmness (MCF) in TEG. After FVIII substitution we observed a nearly linear relation between the individual FVIII activities administered to the patients and the activities measured in the plasma samples. However, data obtained with TGT and TEG revealed a high inter-individual variation and a very poor correlation to the administered FVIII activity. Actually, it could be shown that FVIII substitution yielding in a FVIII plasma activity of about 30% is sufficient to get an ex vivo haemostatic effect of more that 90% as measured by maximum thrombin generation and MCF. FVIII substitution up to a plasma activity of more than 90% did not further enhance the haemostatic effect. Our data clearly demonstrate that the haemostatic effect of FVIII is not only dependent on the activity that is measured in plasma but also depends on the interplay between coagulation and blood cells, in particular with platelets. The use of cell-based coagulation tests such us TGT or TEG may help to optimize FVIII therapy by determining the individual FVIII dosage that produces a maximum haemostatic effect.

Adult↗

PubMed2001

Repeated latex aeroallergen challenges employing a hooded exposure chamber: safety and reproducibility.

BACKGROUND: Bronchial, nasal, and conjunctival challenges are useful for clarifying discordant clinical history (Hx) and skin and/or serologic tests and in assessing semiquantitative changes in biologic sensitivity over time. The objective of this study was to determine the safety and reproducibility of repeated latex-allergen challenges with a hooded exposure chamber (HEC). METHODS: The HEC system comprises a powered forced-air respirator with a fitted face shield and hood that uses glove-derived latex-allergen associated cornstarch particles (LAC) to expose simultaneously the conjunctiva, nose, and lungs. Serial control and incremental LAC challenges are conducted until an endpoint based on upper and/or lower respiratory tract symptoms and peak expiratory flow rates is reached. Six latex-allergic (Hx and puncture skin test [PST]- and 5/6 radioallergosorbent test [RAST]-positive) subjects were challenged on three separate occasions at least 2 weeks apart. Serial latex PST midpoints and serum anti-latex IgE by RAST were monitored at each visit and at a fourth follow-up visit. RESULTS: All subjects responded to LAC, but not to air or control cornstarch administered as controls. All responses were confined to mild symptoms of allergic rhinoconjunctivitis and/or asthma that either resolved spontaneously or were reversed with inhaled albuterol. No subject experienced a systemic or delayed reaction. There were no significant changes in the endpoint LAC doses over the three challenge visits (P>0.2). The mean coefficient of variation for log2 endpoints within-subjects was 17.3+/-17.2% (SD). The serum latex-specific IgE was not significantly boosted by the three challenges (P>0.2). The concentration of latex extract necessary to produce an 8-mm wheal by PST was not significantly changed during the study (P>0.1), indicating that latex sensitivity was not affected by the repeated LAC exposures. CONCLUSIONS: The results of this study indicate that repeated HEC latex-allergen challenges are both reproducible and safe, and do not increase latex sensitivity.

Administration, Inhalation↗

PubMed2003

Response relationship of VAS and Likert scales in osteoarthritis efficacy measurement.

OBJECTIVE/BACKGROUND: Efficacy in osteoarthritis (OA) is principally measured using subjective visual analogue (VAS) and/or Likert scale responses. The relationship between these two scales and their relative precision in discriminating active from placebo treatment in OA patients was determined. DESIGN/METHODS: Patient overall pain assessment, and patient and investigator global assessments were each measured on a 100mm VAS and on a 0 to 4 point Likert scale in a 6-week OA study of rofecoxib vs placebo. The relationship between the VAS and Likert responses was examined graphically and via summary statistics. Analysis of variance was used to assess consistency of the VAS/Likert relationship over time and across the different endpoints. Precision was compared using effect size, and normality of VAS scale of measurement was assessed using the Shapiro-Wilk test. RESULTS: Mean VAS scores and changes from baseline at individual time points were generally highly correlated with corresponding Likert responses (r-values generally approximately 0.7-0.8). The magnitude of VAS values and changes varied depending on endpoint, on the associated magnitude of increment of Likert score, and on the Likert baseline value (i.e., where on the Likert scale the change was occurring). Precision of VAS and Likert responses to detect difference between treatments was generally similar with effect sizes approximately 1. Normality and homogeneity of variance of VAS scores was most closely approximated by actual changes in comparison to percent change or log-transformed measures. CONCLUSIONS: VAS and Likert responses are highly correlated and yield similar precision for discriminating treatments in OA patients. Since Likert responses are easier to administer and interpret, they may be preferable to measure OA response.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial.

BACKGROUND: Low concentrations of albumin in serum and long gastric emptying times have been returned to normal in dogs by salt and water restriction, or a high protein intake. We aimed to determine the effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection in human beings. METHODS: We randomly allocated ten patients to receive postoperative intravenous fluids in accordance present hospital practice (> or = 3 L water and 154 mmol sodium per day) and ten to receive a restricted intake (< or = 2 L water and 77 mmol sodium per day). All patients had no disease other than colonic cancer. The primary endpoint was solid and liquid-phase gastric emptying time, measured by dual isotope radionuclide scintigraphy on the fourth postoperative day. Secondary endpoints included time to first bowel movement and length of postoperative hospital stay. Analysis was by intention to treat. FINDINGS: Median solid and liquid phase gastric emptying times (T(50)) on the fourth postoperative day were significantly longer in the standard group than in the restricted group (175 vs 72.5 min, difference 56 [95% CI 12-132], p=0.028; and 110 vs 73.5 min, 52 [9-95], p=0.017, respectively). Median passage of flatus was 1 day later (4 vs 3 days, 2 [1-2], p=0.001); median passage of stool 2.5 days later (6.5 vs 4 days, 3 [2-4], p=0.001); and median postoperative hospital stay 3 days longer (9 vs 6 days, 3 [1-8], p=0.001) in the standard group than in the restricted group. One patient in the restricted group developed hypokalaemia, whereas seven patients in the standard group had side-effects or complications (p=0.01). INTERPRETATION: Positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delays return of gastrointestinal function and prolongs hospital stay in patients undergoing elective colonic resection.

Aged↗

PubMed2002

The new definition of myocardial infarction: diagnostic and prognostic implications in patients with acute coronary syndromes.

BACKGROUND: The clinical implications of the recently revised criteria for diagnosis of acute myocardial infarction (AMI) in patients with suspected acute coronary syndromes are unknown. METHODS: To evaluate the prognostic implications of the new diagnostic criteria for AMI, we studied 493 consecutive patients with suspected acute coronary syndromes admitted to University of Michigan, Ann Arbor, between May 1, 1999, and January 1, 2000. Patients with positive cardiac enzymes and symptoms suggestive of coronary ischemia (n = 275) were divided into 2 groups: group A, with elevated peak creatine kinase-MB fraction and/or new electrocardiographic changes suggestive of AMI regardless of troponin status (diagnosed as AMI by old criteria), and group B, with normal peak creatine kinase-MB fraction but elevated troponin I level (additional patients diagnosed as having AMI by new criteria). RESULTS: As compared with group A (n = 224), patients in group B (n = 51) were older women, with increased comorbidities such as previous stroke or aortic stenosis, and had fewer in-hospital procedures. In-hospital adverse events (reinfarction, heart failure, shock, and mortality) were similar between the groups, whereas 6-month mortality was higher among group B patients (16.3% vs 5.8%; P =.03). This difference was not statistically significant after adjustment for differences in baseline characteristics between the groups (odds ratio, 1.6; 95% confidence interval, 0.5-5.9). CONCLUSIONS: The new criteria result in a substantial increase in the diagnosis of AMI. Furthermore, they help to identify patients with acute coronary syndromes who have greater comorbidities and worse 6-month outcomes who are otherwise missed by the old criteria. Additional studies are needed to confirm these preliminary findings and to determine the financial implications of the new criteria.

Acute Disease↗

PubMed2002

Initial experience with hyperoxemic reperfusion after primary angioplasty for acute myocardial infarction: results of a pilot study utilizing intracoronary aqueous oxygen therapy.

OBJECTIVES: The purpose of this study was to evaluate the feasibility and safety of intracoronary hyperoxemic reperfusion after primary angioplasty for acute myocardial infarction (MI). BACKGROUND: Hyperoxemic therapy with aqueous oxygen (AO) attenuates reperfusion injury and preserves left ventricular (LV) function in experimental models of MI. METHODS: In a multi-center study of patients with acute MI undergoing primary angioplasty (PTCA), hyperoxemic blood (pO(2): 600 to 800 mm Hg) was infused into the infarct-related artery for 60 to 90 min after intervention. The primary end points were clinical, electrical and hemodynamic stability during hyperoxemic reperfusion and in-hospital major adverse cardiac events. Global and regional LV function was evaluated by serial echocardiography after PTCA, after AO infusion, at 24 h and at one and three months. RESULTS: Twenty-nine patients were enrolled (mean age: 58.9+/-12.6 years). Hyperoxemic reperfusion was performed successfully in all cases (mean infusion time: 80.8+/-18.2 min; mean coronary perfusate pO(2): 631+/-235 mm Hg). There were no adverse events during hyperoxemic reperfusion or the in-hospital period. Compared with baseline, a significant improvement in global wall motion score index was observed at 24 h (1.68+/-0.24 vs. 1.48+/-0.24, p < 0.001) with a trend toward an increase in ejection fraction (48.6+/-7.3% vs. 51.8+/-6.8%, p = 0.08). Progressive improvement in LV function was observed at one and three months, primarily due to recovery of infarct zone function. CONCLUSIONS: Intracoronary hyperoxemic reperfusion is safe and well tolerated after primary PTCA. These preliminary data support the need for a randomized controlled trial to determine if hyperoxemic reperfusion enhances myocardial salvage or improves long-term outcome.

Aged↗

PubMed2004

Predictors of survival end points in patients with cancer of the cervix on long-term follow-up: inferences and implications from an audit of patients treated with a specific radiotherapy protocol.

AIMS: An audit of patients with cancer of the cervix treated with a specified protocol of external beam radiotherapy (EXRT) followed by intracavitary brachytherapy (ICBT) was carried out to determine the prognosticators for major survival end points. MATERIALS AND METHODS: Patients treated between 1991 and 2003 with a uniform protocol of EXRT (50 Gy/25 fractions/5 weeks) followed by high-dose-rate ICBT (18 Gy/3 fractions/3 weeks) were selected from the database. Various clinical and treatment parameters were evaluated for extent of locoregional response at completion of EXRT, namely absence or presence of gross residual tumour (AGRT and PGRT, respectively) and survival end points. These included locoregional disease-free survival (LDFS), disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 157 evaluable patients, 145 (92%) belonged to FIGO stages II and III. Eighty-three (53%) at completion of EXRT had AGRT, which was influenced by age and gross tumour features. The estimated 10-year LDFS, DFS and OS were 38.6%, 33.1% and 38.5%, respectively. Factors significant on univariate analysis for these survival end points were EXRT duration, ICBT time, overall treatment time (OTT) and EXRT response. On multivariate analysis, AGRT to EXRT, an OTT of < or = 67 days, and patients older than 50 years were the significant favourable determinants for all the above survival end points. CONCLUSION: The audit highlights that younger people, especially those with bulky tumours that determine response to EXRT, are poor prognosticators for survival end points. They could perhaps benefit from treatment intensification regimens using chemoradiotherapy, provided that OTT is not unduly prolonged.

Adult↗