PubMed Health⌕ Search

Biomedical subjects

P Lewi

Publications and source records attributed to P Lewi.

18 recordsLinked to original sources
PubMed2003

Bioinformatic insight into the unity and diversity of cytochromes P450.

For the past few decades, cytochromes P450 (CYPs) have been the subject of extensive research, owing to the ability of these enzymes to serve as drug targets as well as to their active participation in drug metabolism. Other varieties and functions of CYPs have been discovered and this superfamily currently comprises over 2000 different protein species. In the present study, the protein sequences of CYPs were submitted to computer analysis for elucidation of the structural basis of their pronounced functional diversity. The basic local alignment search tool (BLAST) was used to demonstrate that CYP protein sequences share a certain general similarity; at the same time, it was shown that the CYP superfamily may be split into a number of groups of intimately related proteins. These groups, the families, were revealed by means of cluster analysis, which demonstrated a strong hierarchy among the animal, bacterial and fungal P450s, and the lack of such a hierarchy for plant enzymes. Multiple alignment and consensus sequence analysis were the approaches taken to find out which structural peculiarities of P450s are responsible for the deviations from the random picture. Proteins within each family were aligned and collapsed to the corresponding consensus sequences, the alignment of which produced the consensus for the whole superfamily. The latter consensus yielded a number of unity motifs (most of which being related to the heme-fixing assembly), while the cross-family comparison of consensus sequences enabled the retrieval of some diversity motifs. Three consensus sequences (for the CYP51 and CYP2 families and for the superfamily) were compared, to line up the unity and diversity motifs with the appropriate X-ray data.

Amino Acid Sequence↗
PubMed2001

The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.

Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha-APA derivative) and HBY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HBY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant.

Acetamides↗
PubMed1997

Study of the dynamics of neutralization escape mutants in a chimpanzee naturally infected with the simian immunodeficiency virus SIVcpz-ant.

Here we report on the use of spectral map analysis of time-paired sequential neutralization data of 11 serum samples of a chimpanzee naturally infected with a simian immunodeficiency virus (SIVcpz-ant) and 8 primary consecutive SIVcpz-ant isolates, taken at about 4-month intervals. The analysis reveals the existence of three SIVcpz-ant isolate and serum neutralization clusters. Each cluster groups virus isolates and/or sera based on similarities of their neutralization spectra. On average, neutralization escape mutants emerged after 15 months and mounted a neutralization response approximately 8 months later. The entire gp160 regions of eight consecutive isolates were sequenced and analyzed by a new statistical method called polygram, which allowed the deduction of amino acid sequence motifs of gp160 which were specific for SIVcpz-ant isolates belonging to the same isolate neutralization clusters. Changes in specific amino acid quadruplets in V1, V2, C3, V4, V5, and CD4 domains of gp120 and gp40 were seen to correlate with the neutralization clusters with most of the specific changes occurring in the V4 region. This method of analysis may facilitate an understanding of the study of the dynamic interplay between human immunodeficiency virus (HIV) and host neutralization responses as well as providing possible insights into mechanisms of persistence of HIV-1-related lentiviruses in their natural hosts.

Amino Acid Sequence↗
PubMed1996

Susceptibilities of Candida spp. to antifungal agents visualized by two-dimensional scatterplots of relative growth.

The growth of 811 clinical yeast isolates in the presence of single concentrations of antifungal agents was measured spectrophotometrically and expressed as a percentage of growth in inhibitor-free control cultures. Two-dimensional scatterplots of the relative growth data allowed for the simple visual determination of some susceptibility trends, including correlations in relative growth between different agents and in relative susceptibilities between different yeast species. A positive susceptibility correlation was found for relative growth results with the azole antifungal agents fluconazole, itraconazole, and ketoconazole for 504 Candida albicans isolates. The relative growth scatterplots for fluconazole versus itraconazole showed that 50 (9.9%) of 504 C. albicans isolates were outliers with respect to the 95% confidence limits for a line of correlated relative growth established with an initial test panel of 59 isolates of this species. The outlying isolates were relatively less susceptible to fluconazole than to itraconazole under the conditions of the test. Most of the outliers were received in 1993 and 1994; only 3.9% of the isolates received in 1991 and 1992 and 1.7% of the isolates received before 1991 showed this differential susceptibility. In addition, most of the outliers came from patients with human immunodeficiency virus infections. The relative growth scatterplots confirmed the known high susceptibility of most Candida parapsilosis isolates to both fluconazole and itraconazole and the specifically low susceptibility of Candida krusei isolates to fluconazole. The scatterplots also illustrated a tendency towards lower (and correlative) relative growth among oral isolates obtained from AIDS patients who responded to azole antifungal treatment than among isolates from clinical nonresponders.

AIDS-Related Opportunistic Infections↗
PubMed1996

Multivariate analysis of human immunodeficiency virus type 1 neutralization data.

We report on the use of spectral map analysis of the inter- and intraclade neutralization data of 14 sera of human immunodeficiency virus type 1 (HIV-1)-infected individuals and 16 primary isolates, representing genetic clades A to H in group M and group O. This multivariate analysis has been used previously to study the interaction between drugs and receptors and between viruses and antiviral compounds. The analysis reveals the existence of neutralization clusters, not correlated with the known genetic clades. The structural factors that have been identified may correlate with the most important neutralization epitopes. Three key primary HIV-1 isolates, which allow discrimination of sera that are likely or unlikely to neutralize primary isolates from most of the genetic clades, were identified. Our method of analysis will facilitate the evaluation as well as the design of suitable HIV-1 vaccines, which induce high-titer interclade cross-neutralizing antibodies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Further prospective evidence of a circadian variation in the frequency of call for sudden cardiac death. Belgian Cardiopulmonary Cerebral Resuscitation Study Group.

OBJECTIVE: To determine whether in a larger data base call for sudden cardiac death exhibits a specific circadian rhythm similar to that recently demonstrated by Levine et al. DESIGN AND SETTING: The time of the day of calls received for out-of-hospital cardiac arrests (OOHCA) prospectively registered between 1983 and '90 by 7 major Belgian pre-hospital EMS-MICU services. Chrono-biologic assessment was made by two-harmonic linear regression analysis of the data tabulated by hour of the day. The hourly distribution of calls for OOHCAs was subjected to Fourier transformation resulting in a periodogram. PATIENTS: 3471 OOHCAs with presumed cardiac etiology and age of more than 18 years versus 2007 inpatients registered in the same period. MEASUREMENTS AND RESULTS: Significant and remarkably similar circadian patterns were found (R-square = 0.84) for the cardiac origin OOHCAs and the ventricular fibrillation OOHCAs. There is a low incidence during the night and an increased incidence from 6 a.m. until noon with an additional early afternoon-peak. The data were always better fitted when applying sinusoids with periods of 8 and 24 h instead of 12 and 24 h. Our observed circadian distribution resembles the reported circadian variation of ischaemic episodes, ventricular tachycardia and acute myocardial infarction in the awake hours. The time distribution of OOHCA (cardiac origin) differs significantly from OOHCA (non-cardiac origin) and from in-hospital cardiac arrests. The in-hospital CA pattern shows less deviation. The age dependent variation in the incidence of cardiac origin OOHCAs, was not obvious for the ventricular fibrillation subgroup. CONCLUSION: Knowledge about the cyclical nature of incidence of cardiac arrests is useful to improve intersystem comparisons and make sound decisions about prophylaxis, treatment and allocation of resources.

Circadian Rhythm↗
PubMed1995

Does age have an effect on the time of occurrence of cardiac arrest of presumed cardiac etiology? Belgian Cardiopulmonary-Cerebral Resuscitation Study Group.

To assess possible age-related differences in the time of occurrence (hour of the day, day of the week, month of the year) of cardiopulmonary collapses of presumed cardiac etiology, 3,305 out-of-hospital patients registered by the Belgian Cardiopulmonary-Cerebral Resuscitation Study Group between 1983 and 1990 were studied. Occurrence of call-time was separately tabulated for patients less than versus above 60 years of age and tested for differences with the Kolmogorov-Smirnov two-sample test. Only the circadian patterns of all out-of-hospital cardiac arrests of presumed cardiac etiology showed a significant difference between the two age-groups; the prominent morning peak (6 a.m.-10 a.m.) in incidence was less pronounced in the younger age-group. The overall incidence is lower in the summer and during mid-week. These trends are similar for both age-groups.

Adolescent↗
PubMed1989

Pre-CPR conditions and the final outcome of CPR. The Cerebral Resuscitation Study Group.

Outcome of cardiac arrest (CA) is very much influenced by pre-CPR conditions. To assess the importance of these pre-CPR factors, an analysis of the Belgian CPCR registry was made according to some pre-CPR conditions. In this registry, several variables related to pre-arrest, arrest, CPR and post CPR period have been recorded in 4548 patients. The pre-CPR conditions studied were: age, witnessed event or not, pre-arrest health state, underlying disease, site of cardiac arrest, type of respiratory arrest and type of cardiac arrest. Age did not influence outcome significantly. The importance of witnessing is very significant. Severe pre-arrest disability reduces chances on long-term survival (LTS) to half and overall health status longterm survivors is clearly less. Intoxication and metabolic origin of CA have good prognosis (LTS, 21%). Trauma/exsanguination, drowning, SIDS and sepsis have bad prognosis (LTS, 1-3%). Cardiac (LTS, 12%) and respiratory (LTS, 14%) origin have similar outcome, although significant difference exists in occurrence of cerebral failure, suggesting that post-ischemic encephalopathy is more severe in respiratory than in cardiac origin. The most frequent site of CA, the home of the patient, has poor outcome results (LTS, 5%). Gasping is significantly related to successful outcome. In the out-of-hospital setting the type of CA was 25% VF (LTS, 77%), 65% asystole (LTS, 4%) and 10% EMD (LTS, 3%). Outcome of the subgroup out-of-hospital, witnessed, VF is comparable to other reports. This sub-group seems to us the most appropriate for clinical trials.

Adult↗
PubMed1989

Use of topical ketanserin in the treatment of skin ulcers: a double-blind study.

The use of a 2% ointment formulation of ketanserin, an S2-serotoninergic blocking agent, was investigated in a randomized double-blind clinical trial for its effect on the healing of wounds of patients with decubitus, venous, and ischemic skin ulcers. The result demonstrates a significant difference in favor of the ketanserin-treated group (35 patients) versus the placebo-treated group (37 patients) on the basis of two factors: formation of granulation tissue and epithelialization. In addition, a significant difference of 150% in the initial velocity of wound closure was observed in favor of the patients treated with ketanserin. This effect was persistent during the entire study period.

Administration, Cutaneous↗
PubMed1984

Multivariate analysis of angiographic, histologic, and electrocardiographic data in patients with coronary heart disease.

In 61 consecutive patients undergoing aortocoronary bypass grafting, angiographic and electrocardiographic (ECG) changes were studied. Histologic delineation of myocardium was obtained by analysis of transmural biopsy specimens acquired at the time of surgery. The use of principal-component analysis revealed three definite groups of patients. Group I comprised patients with histologic findings associated with severe left anterior descending coronary artery (LAD) stenosis, without abnormal wall motion or ejection fraction. ECG abnormalities were limited to ST changes. Group II comprised patients with severe myocardial cell degeneration with only modest fibrosis associated with severe LAD stenosis and severely impaired wall motion. The incidence of infarction on the ECG was low. Group III patients had important myocardial cell degeneration with severe fibrosis associated with severe LAD stenosis, severely depressed wall motion, and significantly impaired ejection fraction. In this group there was a high incidence of infarction apparent on the ECG. Postoperative follow-up (24 months) showed a total survival of 94.4% in group I, 92.8% in group II, and only 72.7% in group III. This identification of subtypes of coronary artery disease seems to be helpful in estimating patient prognosis after coronary surgery.

Adult↗
PubMed1976

On-line computation of cardiac output with the thermodilution method, using a digital minicomputer.

In the present study, several techniques for calculating cardiac output were evaluated in order to find an accurate technique suitable for on-line digital computation. The thermodilution method was evaluated by different calculation techniques and by comparing these techniques with electromagnetic flowmeter values. Comparison of thermal dilution curves, manually calculated by the log-normal and the exponential assumption, showed a correlation coefficient of 0.978 between the two methods, the former values being 11% higher. The exponential method correlated very well with the technique, using a correction factor for injection errors (r = 0.999). Since the exponential technique correlated well with the electromagnetic values (r = 0.84) and since it was less complicated than the technique, using correction factors, this technique was chosen for automation. Comparison of exponential calculated thermodilution values with a digital computer and manually, showed a correlation coefficient of 0.991. Therefore, it was concluded that on-line computation of thermodilution curves improves the applicability of the termodilution techniques as a means of measuring cardiac output.

Animals↗
PubMedDate not supplied

Protein-protein interactions: mechanisms and modification by drugs.

Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures, properties of contact surfaces, and forces involved in protein-protein interactions. The properties of protein contact surfaces depend on their functions. The characteristics of contact surfaces of short-lived protein complexes share some similarities with the active sites of enzymes. The contact surfaces of permanent complexes resemble domain contacts or the protein core. It is reasonable to consider protein-protein complex formation as a continuation of protein folding. The contact surfaces of the protein complexes have unique structure and properties, so they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations have been undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or on the other hand, induce protein dimerization.

Animals↗