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Biomedical subjects

A Desideri

Publications and source records attributed to A Desideri.

At least 37 records · Page 2Linked to original sources
PubMed2001

Prognostic interaction between viability and residual myocardial ischemia by dobutamine stress echocardiography in patients with acute myocardial infarction and mildly impaired left ventricular function.

Dobutamine stress echocardiography (DSE) accurately detects viable myocardium and residual ischemia in patients with acute myocardial infarction (AMI). The prognostic interaction of viability and ischemia has not been completely clarified in these patients. This study assesses the long-term effect of viability, ischemia, or their combination on survival in patients with AMI and mildly impaired left ventricular (LV) function. Four hundred eleven patients (age 57 +/- 9 years) underwent predischarge DSE (up to 40 microg/kg/min plus atropine if needed) after uncomplicated AMI and were prospectively followed for 23 months (range 1 to 78). According to DSE findings, patients were divided into 4 groups: viability only, ischemia only, combination of viability and ischemia, and scar. Adverse outcome occurred in 64 patients: 34 patients had hard events (9 cardiac deaths, 25 nonfatal AMI) and 30 patients had unstable angina requiring hospitalization. The combination of viability and ischemia, diabetes mellitus, and non-Q-wave AMI were significant predictors of all events at univariate and multivariate analysis. The same variables were also univariate predictors of hard events, but multivariate analysis indicated only the combination of viability and ischemia and diabetes as independent predictors. The event-free survival of patients with combined viability and ischemia was significantly lower (hazard ratio 3 [95% confidence interval 1.8 to 11]) compared with patients with ischemia only. Thus, viability and ischemia show a significant adverse prognostic interaction in patients with AMI and preserved LV function.

Adult↗
PubMed2001

Superefficient enzymes.

Diffusion-controlled enzymes are characterized by second-order rate constants in the range 10(8)-10(10) M(-1)s(-1). These values are at the upper end of the observed rates of many enzyme-substrate reactions and have been predicted by theoretical studies on bimolecular reaction in solution. Such enzymes are considered to be perfect, since their rate-limiting step is not due to any chemical event but to the diffusional association rate between the enzyme and the substrate. Often the enzyme-substrate encounter is facilitated either through the presence of a strong attractive electric field, produced by charges on the enzyme surface, or through the reduction in the dimension of the search process. Here we provide a brief review of some of the enzymes characterized by a very fast second-order constant, focusing attention on triose phosphate isomerase and Cu,Zn superoxide dismutase taken as typical examples of such highly tuned enzymes.

Animals↗
PubMed2001

Structure and hydration of the DNA-human topoisomerase I covalent complex.

The structure and hydration of reconstituted human topoisomerase I comprising the core and the carboxyl-terminal domains in covalent complex with 22-basepair DNA duplex has been investigated by molecular dynamics simulation. The structure and the intermolecular interactions were found to be well maintained over the simulation. The complex displays a high degree of flexibility of the contact area, confirmed by the presence of numerous water-mediated protein-DNA hydrogen bonds comparable in quantity and distribution to the direct ones. The interaction between the enzyme and the solvent also provides the key for interpreting the experimental reduction of activity or affinity observed upon single residue mutation. Finally, four long lasting water molecules are observed in the proximity of the active site, one of which in the appropriate position to accept a proton from the active Tyr723.

Amino Acid Substitution↗
PubMed2001

Dynamics-function correlation in Cu, Zn superoxide dismutase: a spectroscopic and molecular dynamics simulation study.

A single mutation (Val29-->Gly) at the subunit interface of a Cu, Zn superoxide dismutase dimer leads to a twofold increase in the second order catalytic rate, when compared to the native enzyme, without causing any modification of the structure or the electric field distribution. To check the role of dynamic processes in this catalytic enhancement, the flexibility of the dimeric protein at the subunit interface region has been probed by the phosphorescence and fluorescence properties of the unique tryptophan residue. Multiple spectroscopic data indicate that Trp83 experiences a very similar, and relatively hydrophobic, environment in both wild-type and mutant protein, whereas its mobility is distinctly more restrained in the latter. Molecular dynamics simulation confirms this result, and provides, at the molecular level, details of the dynamic change felt by tryptophan. Moreover, the simulation shows that the loops surrounding the active site are more flexible in the mutant than in the native enzyme, making the copper more accessible to the incoming substrate, and being thus responsible for the catalytic rate enhancement. Evidence for increased, dynamic copper accessibility also comes from faster copper removal in the mutant by a metal chelator. These results indicate that differences in dynamic, rather than structural, features of the two enzymes are responsible for the observed functional change.

Amino Acid Sequence↗
PubMed2001

An electrochemical multienzymatic biosensor for determination of cholesterol.

This paper describes an electrochemical biosensor for free cholesterol monitoring. The sensor is a multienzymatic electrodic system in which horseradish peroxidase and cholesterol oxidase are simultaneously immobilized within a polymeric film, on the surface of a pyrolitic graphite electrode. From voltammetric and amperometric (flow-injection) data obtained, the efficiency, reproducibility and stability of the system are discussed. Results obtained, of interest for basic and applied biochemistry, represent a first step for construction of a mediator-free biosensor with potentialities for a successful application in the biosensor area.

Biosensing Techniques↗
PubMed2001

Molecular dynamics simulation of the antimicrobial salivary peptide histatin-5 in water and in trifluoroethanol: a microscopic description of the water destructuring effect.

The results of 520 ps molecular dynamics simulation of histatin-5, a small peptide present in human saliva and possessing antimicrobial activity, dissolved in water and in 2,2,2-trifluoroethanol, are reported. The simulations indicate that histatin-5 is destabilized in water and begins to unfold after 250 ps, while in organic solvent it maintains a regular secondary structure throughout the trajectory. Analysis of the peptide-solvent hydrogen bonds indicates that 2,2,2-trifluoroethanol is a poorer proton acceptor than water. The fluorine atom of the alcohol is almost never engaged in a hydrogen bond and the organic solvent interacts mainly with the peptide through its hydroxyl group. For some residues analysis of the solvent residence time indicated longer values for 2,2,2-trifluoroethanol than for water. The most striking difference is related to the number of times the solvent enters and leaves the first coordination shell of the peptide. This value was more than one order of magnitude higher for water than for the alcohol, suggesting that this may be the main cause of alpha-helix destabilization perpetrated by water.

Amino Acid Sequence↗
PubMed2001

Cytochrome c reconstituted from two peptide fragments displays native-like redox properties.

Recombination of two fragments of horse cytochrome c (the heme-containing N-fragment, residues 1-56, and the C-fragment, residues 57-104), which are substantially unstructured at neutral pH, gives rise to a 1:1 fragment complex with a compact conformation, in which the alpha helical structure and the native Met80-Fe(III) axial bond are recovered. With respect to the native protein, the ferric complex shows a less rigid atomic packing and a decreased stability [Delta(DeltaG(o))D = 14.7 kJ.mol(-1)], ascribed to perturbations involving the Trp59 microenvironment and, to a lower extent, the heme pocket region. The redox potential, E1/2 = 234 +/- 5 mV vs. normal hydrogen electrode at 25 degrees C, is close to that of the intact protein, consistent with recovery of the native Met80-heme Fe(III) axial bond. Furthermore, the fragment complex shows reactivity similar to intact cytochrome c, in the reaction with cytochrome c oxidase. We conclude that the absence in the complex of some native cross-links and interlocked packing important for protein rigidity and stability is not as relevant for maintaining the native redox properties of the protein, provided that some structural requirements (i.e. recovering of the native-like alpha helical structure) are fulfilled and coordination of Met80 to the heme-iron is restored.

Animals↗
PubMed2001

Non-invasive diagnostic and prognostic assessment of single-vessel coronary artery disease: focus on stress echocardiography.

AIMS: Revascularization procedures are increasingly applied in patients with single-vessel coronary artery disease in spite of the fact that a prognostic benefit has been proved only for soft end-points. This review summarizes the results of stress echocardiography in the diagnostic and prognostic assessment of these patients. METHODS AND RESULTS: The diagnostic and prognostic assessment of patients with single-vessel disease using stress (exercise, dobutamine, adenosine and dipyridamole) echocardiography are focused upon in the light of pathophysiological considerations and the results of clinical studies. Factors affecting test accuracy are individually addressed and comparisons made with different stress testing modalities, including exercise electrocardiography and nuclear techniques. Finally, therapeutic options are discussed and the superior accuracy of the physiological assessment of coronary stenosis as compared to the simple anatomic evaluation emphasized. CONCLUSIONS: Patients with single-vessel disease represent an anatomically heterogeneous group. Although the suboptimal performance of any technique in their evaluation has to be acknowledged, stress echocardiography can effectively contribute to selection of the management strategy.

Cardiotonic Agents↗
PubMed2001

The stress echo prognostic gender gap.

AIMS: To investigate whether myocardial ischaemia elicitable during pharmacological stress echocardiography portends different prognosis in men and women. METHODS AND RESULTS: The study group was made by 1733 patients (941 men, 792 women) who underwent dipyridamole (n=1008) or dobutamine (n=725) stress echo for evaluation of known or suspected coronary artery disease. An ischaemic response was found in 460 patients (308 men, 152 women). Considering the whole ischaemic population, women were older (P<0.0001) and more likely to have hypertension (P=0.02) and hypercholesterolaemia (P=0.04) than men. No difference in age and risk factors was evidenced between the two sexes in the subset of 203 patients with ischaemia and suspected coronary artery disease. During follow-up (25 +/- 24 months for the ischaemic and 37 +/- 25 months for the non-ischaemic sample), there were 113 cardiac events (45 deaths and 68 infarctions) and 232 revascularizations. Revascularization rate in ischaemic population was similar in both sexes (P=0.36). Multivariate predictors of cardiac events in the whole ischaemic group were resting WMSI (HR=2.7, 95% CI 1.3--3.3;P=0.0050), female gender (HR=2.2, 95% CI 1.2--3.7;P=0.0062), age > or = l65 years (HR=1.9, 95% CI=1.0--3.6;P=0.0427), and Delta WMSI (HR=2.1, 95% CI=1.0--3.7;P=0.0447). Female gender (HR=2.7, 95% CI 1.1--6.3;P=0.0233) was the only independent prognostic predictor in patients with ischaemia and suspected coronary artery disease. Five-year infarction-free survival was 82% in men and 71% in women in the whole ischaemic population (P=0.0041) as well as in the ischaemic group with suspected coronary artery disease (CAD) (P=0.0175). In the non-ischaemic sample resting WMSI (HR=4.8), history of myocardial infarction (HR=2.5), and hypercholesterolaemia (HR=1.8) were independent predictors of outcome at multivariate analysis, whilst the gender had no prognostic importance. CONCLUSIONS: Our results show that female gender is an independent predictor of cardiac events in patients with myocardial ischaemia induced by pharmacological stress echocardiography.

Age Factors↗
PubMed2001

Structure and stability of the insulin dimer investigated by molecular dynamics simulation.

Molecular dynamics simulation indicates that the dynamical behaviour of the insulin dimer is asymmetric. Atomic level knowledge of the interaction modes and protein conformation in the solvation state identifies dynamical structures, held by hydrogen bonds that stabilize, mainly in one monomer, the interaction between the chains. Dynamic cross-correlation analysis shows that the two insulin monomers behave asymmetrically and are almost independent. Solvation energy, calculated to evaluate the contribute of each interface residue to the dimer association pattern, well compares with the experimental association state found in protein mutants indicating that this parameter is an important factor to explain the association properties of mutated insulin dimers.

Computer Simulation↗
PubMed2001

Role of the helix capping in the stability of the mouse prion (180-213) segment: investigation through molecular dynamics simulations.

Molecular dynamics simulation of the 180-213 segment, forming the B and C helices in the mouse prion protein, and of three mutants, where the capping box residues or the hydrophobic staple motif residues were selectively mutated, have been carried out. The results indicate that the wild type segment is stable over all the trajectory, whilst the mutants display different degrees of destabilization. In detail mutation of Asp202 brings to a rapid unfolding of helix C likely because of the concomitant loss of a hydrogen bond and of a negative charge able to stabilize the dipole in the first turn of the helix. A lower destabilizing effect is observed upon mutation Thr199. On the other hand mutation of Phe198 and Val203, the hydrophobic staple residues, brings to an incorrect orientation of the first helix relative to the second one due to a weakening of the hydrophobic interaction. The results confirm the importance of the presence of both motifs for the structural integrity of the isolated fragment and suggest that these residues may have a main role in the structural transition observed in the inherited human prion diseases.

Amino Acid Sequence↗
PubMed2001

Incremental prognostic value of stress echocardiography as an adjunct to exercise electrocardiography after uncomplicated myocardial infarction.

OBJECTIVE: To assess the prognostic value of stress echocardiography as an adjunct to exercise electrocardiography in patients with uncomplicated acute myocardial infarction. DESIGN: 496 patients underwent a maximum exercise ECG and pharmacological stress echocardiography (406 dobutamine and 90 dipyridamole) within 15 days of uncomplicated acute myocardial infarction and were followed for a mean of 25 months (range 1-74 months) for reinfarction, unstable angina, and cardiac death. Patients undergoing revascularisation were omitted. RESULTS: Exercise ECG was positive in 162 patients (32.6%) and low threshold positive (< 100 W) in 91 (18%). Stress echocardiography was positive in 239 patients (48%) (194 with dobutamine and 45 with dipyridamole stress). The agreement between the two tests was 63% (kappa = 0.24, 95% confidence interval 0.15 to 0.33). Sixty nine spontaneous events occurred (14 cardiac deaths, 26 reinfarctions, and 29 with unstable angina requiring hospital admission), and 126 patients underwent revascularisation (39 coronary angioplasty and 87 bypass surgery). By receiver operating characteristic curve analysis, stress echocardiography provided incremental prognostic information compared with clinical data. A low threshold positive exercise ECG was associated with a worse outcome, but there was a fivefold increase in risk in patients with positive stress echocardiography who also had a high threshold (> 100 W) positive exercise ECG. Event-free survival of patients with both tests positive was significantly less than in patients with only one positive test or with both tests negative. CONCLUSIONS: Stress echocardiography provides additional prognostic information after uncomplicated acute myocardial infarction, but the greatest gain is found in patients with a high threshold positive exercise ECG.

Cardiotonic Agents↗
PubMed2001

Angiographic and prognostic correlates of cardiac output by cardiopulmonary exercise testing in patients with anterior myocardial infarction.

STUDY OBJECTIVE: To assess the diagnostic and prognostic value of cardiac output assessed by cardiopulmonary exercise testing in patients with anterior acute myocardial infarction (AMI) and left ventricular dysfunction. PATIENTS AND SETTING: Forty-six patients with AMI (7 female patients; mean +/- SD age, 55 +/- 8 years; ejection fraction, 39 +/- 7%) underwent cardiopulmonary exercise testing and coronary angiography following hospital discharge. MEASUREMENT AND RESULTS: Cardiac output was estimated from oxygen uptake (VO(2)) during exercise according to a method based on the linear regression between arteriovenous oxygen content difference and percent maximum VO(2). Angiograms were scored using Gensini and Duke "jeopardy" scores. Cardiac output at anaerobic threshold (COAT) < or = 7.3 L/min was the best cutoff value for identifying multivessel coronary artery disease (relative risk, 3.1). Angiographic scores were significantly higher in patients with COAT < 7.3 L/min as compared to those with COAT > 7.3 L/min (82 +/- 8 vs 53 +/- 7 and 6 +/- 2 vs 4 +/- 3, respectively; p < 0.05) and were inversely and significantly correlated to COAT. Conversely, no correlation was found with ECG changes. COAT, VO(2) at anaerobic threshold, and peak VO(2) were univariate prognostic indicators. However, using Cox's model, COAT was the only multivariate predictor of outcome (odds ratio, 0.28; 95% confidence interval [CI], 0.09 to 0.9). Moreover, COAT < 7.3 L/min was associated to an increased risk of further cardiac events (odds ratio, 5; 95% CI, 1.4 to 17) and provided a significant discrimination of survival for the combined end point of cardiac death, reinfarction, and clinically driven revascularization. CONCLUSIONS: COAT is a safe and feasible tool providing additional diagnostic and prognostic information in patients with AMI.

Aged↗
PubMed2001

Stress echocardiography for risk stratification of diabetic patients with known or suspected coronary artery disease.

OBJECTIVE: Coronary artery disease (CAD) is a leading cause of mortality and morbidity in diabetic patients; therefore, their risk stratification is a relevant issue. Because exercise tolerance is frequently impaired in these patients, pharmacological stress echocardiography (SE) has been suggested as a valuable alternative. Our aim was to evaluate the prognostic value of this technique in diabetic patients with known or suspected CAD. RESEARCH DESIGN AND METHODS: A total of 259 consecutive diabetic patients underwent pharmacological SE (dobutamine in 108 patients and dipyridamole in 151 patients) and follow-up for 24 +/- 22 months. A comparison between the prognostic value of SE and exercise electrocardiography (ECG) was made in a subgroup of 120 subjects. RESULTS: A total of 13 cardiac deaths and 13 nonfatal infarctions occurred during follow-up, and 58 patients were revascularized. Univariate predictors of outcome were known CAD, positive SE, rest and peak wall motion score index (WMSI), and peak/rest WMSI variation. Peak WMSI was the only significant and independent prognostic indicator (odds ratio 11; 95% CI 4-29, P < 0.0001) on multivariate Cox's analysis. After adjustment for the most predictive clinical and exercise ECG variables, SE provided 43% additional prognostic information (gain in X(2) = 7, P < 0.01). Moreover, positive SE was associated with a significantly lower event-free survival. CONCLUSIONS: SE effectively predicts cardiac events in diabetic patients with known or suspected CAD and adds additional prognostic information as compared with exercise ECG.

Adrenergic beta-Agonists↗
PubMed2001

[Effectiveness and adequacy of management of acute coronary syndromes].

A rational utilization of resources represents a key issue in modern treatment of cardiac patients. The aim of our study was to highlight a few essential aspects for an efficient and appropriate management of patients with an acute coronary syndrome. Clinical evaluation of the patient's risk (i.e. clinical assessment of the probability of developing a cardiac event), incremental value of the chosen test for risk stratification, value of a strategy in modifying outcome and direct determinants of medical cost of the strategy are selected as the main aspects to be considered in order to optimize management of these patients.

Acute Disease↗
PubMed2001

Noninvasive assessment of coronary artery disease: the role of stress echocardiography.

Echocardiography combined with either exercise or pharmacological stress is a widely used method for the noninvasive assessment of coronary artery disease. This is due to the high diagnostic accuracy that does not differ substantially among the various stress modalities. In addition, stress echocardiography has a useful role in risk stratification of patients with known or suspected coronary artery disease. In particular, evidence of inducible ischemia is predictive of an unfavorable outcome, whilst its absence is associated with a very low risk of future cardiac events. These findings have strong implications in clinical decision-making. One of the main characteristics of the echographic marker of ischemia is that it is significantly more specific than the electrocardiographic one. The higher specificity of stress echocardiography translates into increased prognostic value as compared to exercise electrocardiography. Nevertheless, exercise electrocardiography has a very high negative predictive value. Moreover, compared to stress echocardiography it is safer, simpler, less costly and requires no specific competence. Based on these data, exercise electrocardiography remains the cornerstone of the noninvasive evaluation of coronary artery disease. Stress echocardiography, on the other hand, is particularly useful in those cases when exercise electrocardiography is not feasible, non-interpretable (owing to the presence of left bundle branch block or of a pacemaker or of other electrocardiographic baseline abnormalities), or when it gives inconclusive data, or a positive result at an intermediate or high workload (in such cases, precise knowledge of the site and extension of ischemia can be of crucial importance in deciding between conservative and aggressive treatment), as well as in cases in which ischemia during the test is frequently a false positive response, as in hypertensive patients, in women and in all cases of left ventricular hypertrophy.

Coronary Disease↗
PubMed2000

Anion size modulates the structure of the A state of cytochrome c.

Several studies have shown that anions induce collapse of acid-denatured cytochrome c into the compact A state having the properties of the molten globule and that the anion charge is the main determinant for the A state stabilization. The results here reported show that the anion size plays a role in determining the overall structure of the A state. In particular, small anions induce formation of an A state in which the native Met80-Fe(III) axial bond is recovered and the nativelike redox properties restored. On the other hand, the A state stabilized by large anions shows a histidine (His26 or His33) as the sixth ligand of the heme-iron, a very weak interaction between Trp59 and the heme propionate, and lacks nativelike redox properties. The two anion-stabilized states show similar stability, indicating that (i) the hydrophobic core (which is equally stabilized by all the anions investigated, independently of their size) is the region that mainly contributes to the macromolecule stabilization, and (ii) the flexible loops are responsible for the spectroscopic (and, thus, structural) and redox differences observed.

Animals↗