Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial

OBJECTIVE: We examined the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass. METHODS: Patients from 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated. RESULTS: In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% (P < .0001) and requirement for red blood cell administration by 49% (P < .0001). Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo (P = .03). After we had adjusted for risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of prior aspirin therapy, small and poor distal vessel quality, and possibly use of aprotinin-treated blood as excised vein perfusate. At United States sites, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P = .72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients (P = .01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin: 1.4%; placebo: 1.6%). CONCLUSIONS: In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.     

Prevention of heterocyclic amine formation by tea and tea polyphenols

Heterocyclic amines (HCAs), formed during the cooking of meats and fish, are thought to be the genotoxic carcinogens associated with important types of human cancer in meat-eating populations, such as cancer of the breast, colon or pancreas. We studied the effect of black or green tea, and of the tea polyphenols theaflavine gallate (TFG, black tea) and epigallocatechin gallate (EGCG, green tea) on the formation of typical HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), using the model in vitro systems of J?gerstad. Green tea and black tea and solutions of TFG and EGCG lower the formation of PhIP by 62-85% during 1 h heating at 160 degrees C of 1 mmol creatinine, 1 mmol phenylalanine and 0.5 mmol glucose in 3.3 ml diethylene glycol-water (10:1), where the inhibitors replaced 0.3 ml of the water. The production of MeIQx and related HCAs, in the same system but with 1 mmol glycine instead of phenylalanine was likewise reduced, determined by amounts of mutagens formed. In the latter systems, the teas were not, or less effective, but the polyphenols were inhibitory. Thus, the tea products represent another approach to lower the formation of HCAs.     

Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library

BACKGROUND: Methods for the rapid and efficient preparation of drug candidates through combinatorial chemistry are of increasing interest. We have previously reported an indexed combinatorial library method that allows both the preparation and testing of compounds in solution. We set out to apply this method to develop more effective analogs of the known, marketed drug tacrine, an acetylcholinesterase inhibitor. RESULTS: A one-step condensation of cyclohexanones with cyanoanilines to generate tetrahydroacridine pools was developed. The resulting library of (formally) 72 tetrahydroacridines was screened against acetylcholinesterase, and a compound 10-fold more potent than tacrine, 7-nitrotacrine, was discovered. Its increased potency could be readily explained by examining the known structure of the complex of acetylcholinesterase with tetrahydroacridine. CONCLUSIONS: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool synthesis and have discovered a potentially useful acetylcholinesterase inhibitor.     

Effect of contrast concentration on abdominal enhancement in the rabbit: spiral computed tomography evaluation

BACKGROUND: Langerhans' cell histiocytosis (LCH) is an uncommon, poorly understood granulomatous disease, characterized by the idiopathic proliferation of Langerhan's cells or their marrow precursors. In 1985, the Philadelphia Work-shop adopted the term "Langerhans' cell histiocytosis" (LCH) to differentiate it from reactive and neoplastic causes of histiocytosis. METHODS: This study includes 73 pediatric patients diagnosed with this condition in Dublin, Ireland, and Nottingham, England, during a 34-year period (1959 to 1993). These patients are reviewed with respect to clinical presentation, difficulty with making a histological diagnosis, their management, and outcome. RESULTS: A total of 49 patients (67%) had head and neck involvement. Bony involvement was the most frequent sign, most frequently located in the skull. There were 11 deaths (15%) in this series, all associated with multisystem disease, and nine of these deaths were in children younger than 2 years of age. CONCLUSIONS: The role of otolaryngologists is important in the early and accurate evaluation, staging, and diagnosis of LCH. It may mimic more common diseases, such as otitis externa, acute mastoiditis, skin rash, gingivitis, or cervical lymphadenopathy. Patients with multisystem disease may be so ill at presentation that the head and neck lesions may be overlooked. The current management of LCH has become increasingly conservative, and in the 1990s, fewer cases are given chemotherapy or radiotherapy. The prognosis is very good for single-system disease and poor for multisystem disseminated disease with early onset.     

Proline isomerization-independent accumulation of an early intermediate and heterogeneity of the folding pathways of a mixed alpha/beta protein, Escherichia coli thioredoxin

Oxidized Escherichia coli thioredoxin (Trx) is a small protein of 108 residues with one disulfide bond (C32-C35 essentially involved in the activity) and no prosthetic moieties, which folds into a structural motif containing a central twisted beta-sheet flanked by helices that is found in many larger proteins. The kinetics of refolding of Trx in vitro have been investigated using a newly developed active site titration assay and continuous or stopped-flow (SF) methods in conjunction with circular dichroism (CD) and fluorescence (Fl) spectroscopy. These studies revealed the presence of early folding intermediates with "molten globule or pre-molten globule" characteristics. Measurements of the ellipticity at 222 nm indicated that about 68% of the total change associated with refolding occurred during the dead time (4 ms) of the stopped-flow instrument, suggesting the formation of substantial secondary structure. The reconstruction of the far-UV CD spectrum of the burst intermediate using combined continuous and stopped-flow methods showed the formation of a defined secondary structure that contains more beta-structure than the native state. Kinetic measurements using SF far-UV CD and Fl over a wide range (0.087-6 M) of GuHCl concentrations at two temperatures (6 and 20 degreesC) demonstrated that the population formed during the 4 ms dead time contained multiple species that are stabilized mainly by hydrophobic interactions and undergo further folding along alternative pathways. One of these species leads directly and rapidly to the native state as demonstrated by active site titration, while the two others fold into a fourth intermediate that is slowly converted to the native protein. Double-jump experiments suggest that the heterogeneity in folding behavior results from proline isomerizations occurring in the unfolded state. Conversely, the accumulation of the burst intermediate does not depend on proline isomerizations.     

Strength of character through the ethics of nursing

"A Practice-Based Bioethic" is a regular column in Advanced Practice Nursing Quarterly. A practice-based approach is derived from, and therefore is intended to be appropriate to, the situation of a patient, the purpose of the health care setting, and the role of the nurse. It is based on a shared state of awareness, the foundation on which ethical interactions between nurse and patient occur.     

Effects of insulin therapy on non-insulin-dependent diabetics with secondary oral hypoglycemic agent failure

A recent trend among physicians is the categorisation of lung scans as normal [excludes pulmonary embolism (PE)], high probability (confirms PE) and non-diagnostic (no judgement on PE risk). The low probability scan is therefore being eliminated as a functional category. This occasional survey contends that such an approach is misguided. Correction of the original PIOPED data with certain assumptions provides a more reproducible, albeit restricted, low probability scan category which excludes PE in 97% of cases in the low pre-test clinical category. Patients with a low probability scan with risk factors for PE (i.e. medium clinical risk) will require further investigation. More important, the very low probability scan category excludes PE in 98% of patients with low and more than 92% of patients with medium pre-test clinical likelihood. The demise of "low probability" is premature.     

A clinical evaluation in children of the Pharmacia ImmunoCAP system for inhalant allergens

BACKGROUND: The Pharmacia ImmunoCAP system (CAP) for assaying serum IgE specific antibodies was evaluated in a clinical setting against skin-prick test (SPT) performed using Dome/Hollister-Steir allergen extracts. The five common inhalant allergens D. pteronyssinus, D. farinae, mould mix, grass mix and cat epithelium were tested concurrently by both methods in 167 children aged 7.5-12 years. The specific SPT for D. pteronyssinus and D. farinae were also tested against the CAP house dust mite (HDM) mix. OBJECTIVE: The purpose of the study was to determine the sensitivity and specificity of the Pharmacia ImmunoCAP system for detecting serum IgE specific antibodies to inhalant allergens in a clinical setting, using SPT result as the "gold standard'. METHODS: The SPTs were performed using Dome/Hollister-Steir allergen extracts. The serum IgE specific antibodies were quantitated using the radioimmunoassay version of the Pharmacia ImmunoCAP system. A history of allergic disease was assessed using a validated questionnaire. RESULTS: SPT gave more positive reactions than CAP with the exception of cat epithelium. The concordance between SPT and CAP results was 91% over all the tests. The concordance with SPT was slightly higher for the specific CAP for D. pteronyssinus and D. farinae (93% and 95% respectively) than for the CAP HDM mix (86% and 90% respectively). There was a higher proportion of positive results for both SPT and CAP in the 115 children defined as having a history of allergic disease. Using SPT defined allergy as the gold standard, the sensitivity of the CAP system was 87% for the two specific house dust mites but was lower for cat epithelium (67%), mould mix (59%) and grass mix (46%). The sensitivity of the CAP system improved for D. pteronyssinus (96%) and the HDM mix (91%) when tested in subjects defined as having a history of allergy associated disease. The specificity of the CAP system showed less variation between allergens and ranged from 90-99%. CONCLUSION: The results of this study of children aged 7.5-12 years demonstrate that, for the inhalant allergens tested, the Pharmacia ImmunoCAP system performs well in the setting of known allergic disease.     

Therapeutic strategies in acute myocardial infarction. Results of STIM 93 registry

A registry was set up by the national college of cardiologists practicing in general hospitals in February 1993. The data concerned mode of admission, demographic details, initial clinical and haemodynamic evaluation and hospital outcome. Special attention was given to the electrocardiographic changes before and, in patients receiving thrombolytic therapy, after treatment. An analysis of predictive factors for mortality was performed both in the group of patients "revascularised" and in the group treated conventionally. One thousand and twenty three cases from 327 centres were analysed. There were 1292 men and 531 women, with an average age of 67.9 years. The average time interval from onset of symptoms to hospital admission was 5 h 30 min, 56.8% of patients arriving within 6 hours. 36.4% of the population underwent thrombolysis or angioplasty, 75% of patients under 75 years of age admitted before the 5th hours underwent a procedure of myocardial revascularisation. The hospital mortality was 14%, 8.7% in those revascularised and 17% in patients treated conventionally. Factors predictive of mortality were age, female gender, Killip Classes III or IV, systolic blood pressure of less than 100 mmHg, heart rate of more than 100/min and contraindications of thrombolysis. The maximum ST depression, the sum of ST depression, the sum of ST elevation and depression, were also significant predictive factors of a fatal hospital outcome in the whole population group and in patients treated conventionally. In the reperfused group, only the initial sum of ST elevation and depression was predictive of mortality: 120 minutes after the beginning of thrombolysis, the sum of ST elevations and of elevations and depressions was predictive of twice the mortality when the values exceeded 0.6 mv and 1.4 mv respectively.