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Biomedical subjects

I Simon

Publications and source records attributed to I Simon.

At least 55 records · Page 3Linked to original sources
PubMed1998

Rod models of DNA: sequence-dependent anisotropic elastic modelling of local bending phenomena.

Local bending phenomena can be predicted by elastic models that incorporate sequence-dependent anisotropic-bendability (SDAB). SDAB models consider DNA to be an initially straight, segmented, elastic rod, in which the flexibility of each segment is greater towards the major groove than it is in other directions. While local bending can be predicted by static-geometry models as well, SDAB models, in addition, qualitatively explain such phenomena as the affinity of protein binding and kinking. A set of prediction tools is available at http:/(/)www.icgeb.trieste.it/dna.

Animals↗
PubMed1998

Preschool stunting, age at menarche and adolescent height: a longitudinal study in rural Senegal.

OBJECTIVE: To study the impact of preschool stunting on adolescent height and age at menarche in rural West Africa. DESIGN: A longitudinal, population-based study. SETTING: The Niakhar study area in Central Senegal. SUBJECTS: 1650 children aged 12-17 y with known height-for-age at the age of 2-5 y. MAIN OUTCOME MEASURES: Adolescent height; mean age at menarche of girls estimated by the status quo method. RESULTS: The subjects were divided into three groups of preschool height-for-age: < -2, -2 to -1 and > -1 z-score of the NCHS reference. The mean height during adolescence differed significantly according to preschool height-for-age for both boys and girls (P < 0.001). Relative risk of adolescent stunting according to preschool stunting varied from 2.0-4.0 depending on age and sex. Estimated mean age at menarche was 17.2 (95% fiducial confidence interval: 16.6-18.7), 16.5 (16.1-17.2) and 15.6 (15.2-16.0) y, respectively, for the three groups of preschool height-for-age (P < 0.001). Mean increment from age 5 y to adolescence did not differ significantly among the boys according to preschool stunting, but among the girls aged 16-17 y, the increment was higher for those who had been stunted during preschool life (P < 0.01). CONCLUSION: Some evidence of catch-up growth between the ages of 5 and 17 y was found for stunted girls. The significant delay in sexual maturation of the stunted girls suggests that stunted children of both sexes have a possibility of catch-up growth after the age of 17 y.

Adolescent↗
PubMed1998

[Pharmaco-economics: a point of view of the mutualities].

In Belgium, the mutualities are responsible for their budgets. They are playing an important role in drug pricing and reimbursement procedures. This document aims at explaining our line of arguments for a critical evaluation and the place for a pharmacoeconomic evaluation in the Belgian social security system. The available economic data for each molecule or pathology are essential but insufficient. Economic evaluations could help to reveal the costs and benefits of different uses of medical therapies and could thereby enhance the resources allocation in a health care system. But this science is still in its infancy, and in practice, the methodological quality of this kind of study is often weak. Furthermore it is not easy to transfer those evaluations to the Belgian reimburse systems. The clinical efficacy and the transparency is price setting should remain the two most important criterions to build reimbursement rules in order to ensure right price, rational use of medicine and accessibility for all.

Belgium↗
PubMed1998

Socio-economic impact of chronic venous insufficiency. An underestimated public health problem.

BACKGROUND: Disease of the venous system is an underestimated public health problem affecting all Western industrialised countries. The prevalence of venous disease of the lower limb in the adult population is estimated at 40-50% for men and 50-55% for women, whereas visible varicose veins and chronic venous insufficiency are, respectively, present in 10-15% and 2-7% of the male population and 20-25% and 3-7% of the female population. In France the costs of venous disease represented 2.6% of the total health care budget in 1995, thus confirming other data from European studies and an early health survey in the USA. To evaluate the socio-economic impact of chronic venous insufficiency by measuring the health care cost. METHODS: Detailed information on diagnostic and therapeutic procedures for venous disease was obtained from the billing data of the compulsory health insurance system in Belgium. Total ambulatory and intramural treatment costs are calculated for varicose veins of the lower limb and for haemorrhoids during the 1988-1995 period. RESULTS: Medical care costs for chronic venous disease amount to 10 billion BEF, which is 2-2.5% of the 1995 total health care budget. Annual spending on venotropic drugs with 11.5 mean daily doses per 1,000 inhabitants amounted to one billion BEF in 1995 for ambulatory treatment only. CONCLUSIONS: In view of the major medical, social and economical consequences of venous pathology, research and prevention efforts are required in this area as part of a well-targeted and effective health policy.

Adult↗
PubMed1997

The role of DNA bending in Cro protein-DNA interactions.

Binding energy of DNA-Cro protein complexes is analyzed in terms of DNA elasticity, using a sequence-dependent anisotropic bendability (SDAB) model of DNA, developed recently [M.M. Gromiha, M.G. Munteanu, A. Gabrielian and S. Pongor, J. Biol. Phys. 22(1996) 227-243.]. The protein is considered to bind aspecifically to DNA that reduces the freedom of movement in the DNA molecule. In cognate DNA, the Cro protein moves on to form specific interactions and bends DNA. A comparison of the experimental data [Y. Takeda, A. Sarai and V.M. Rivera, Proc. Natl. Acad. Sci. U.S.A. 86 (1989) 439-443.] with the calculated DNA stiffness data shows that delta G of the complex formation increases with stiffness of the ligand when the interactions are nonspecific ones, while an opposite trend is observed for specific binding. Both of these trends are in agreement with our approach using the SDAB model. A decomposition of the energy terms suggests that binding energy in the nonspecific case is used maily to compensate the free energy changes due to entropy lost by DNA, while the energy of specific interactions provide enough energy both to bend the DNA molecule and to change the conformation of the Cro protein upon ligand binding.

Base Sequence↗
PubMed1997

Stabilization centers in proteins: identification, characterization and predictions.

Methods are presented to locate residues, stabilization center elements, which are expected to stabilize protein structures by preventing their decay with their cooperative long range interactions. Artificial neural network-based algorithms were developed to predict these residues from the primary structure of single proteins and from the amino acid sequences of homologous proteins. The prediction accuracy using only single sequence information is 65%, but the incorporation of evolutionary information in the form of multiple alignments and conservation scores raises the efficiency by 3%. The composition, relative accessibility, number and type of interactions, conservation and the X-ray thermal factor of the identified stabilization center residues are different, not only from the whole data set but from the rest of the long range interacting residues as well. The most frequent stabilization center residues are usually found at buried positions and have a hydrophobic or aromatic side-chain, but some polar or charged residues also play an important role in the stabilization. The stabilization centers show significant difference in the composition and in the type of linked secondary structural elements compared with the rest of the residues. The performed structural and sequential conservation analysis showed the higher conservation of stabilization centers over protein families. The relation of the proposed stabilization centers to folding nuclei is also discussed.

Algorithms↗
PubMed1997

The role of long-range interactions in defining the secondary structure of proteins is overestimated.

MOTIVATION: Secondary structure predictions based on the properties of individual residues, and sometimes on local interactions, usually fail to exceed 65% efficiency. Therefore, non-local, long-range interactions seem to be a significant cause of this limitation. RESULTS: In this paper, we apply approaches to localize highly interacting residues and clusters of residues involved in multiple non-local interactions, and test various secondary structure predictions on this separate subset to assess the effect of long-range interactions on the prediction efficiencies. It was found that only a marginal part of the failure of secondary structure predictions results from the presence of long-range interactions. Alternative possibilities are also discussed.

Algorithms↗
PubMed1997

Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: the dense alignment surface method.

A new, simple method for predicting transmembrane segments in integral membrane proteins has been developed. It is based on low-stringency dot-plots of the query sequence against a collection of non-homologous membrane proteins using a previously derived scoring matrix [Cserzö et al., 1994, J. Mol. Biol., 243, 388-396]. This so-called dense alignment surface (DAS) method is shown to perform on par with earlier methods that require extra information in the form of multiple sequence alignments or the distribution of positively charged residues outside the transmembrane segments, and thus improves prediction abilities when only single-sequence information is available or for classes of membrane proteins that do not follow the 'positive inside' rule.

Cell Membrane↗
PubMed1997

Segmentation algorithms for detecting microcalcifications in mammograms.

The presence of microcalcification clusters in mammograms contributes evidence for the diagnosis of early stages of breast cancer. In many cases, microcalcifications are subtle and their detection can benefit from an automated system serving as a diagnostic aid. The potential contribution of such a system may become more significant as the number of mammograms screened increases to levels that challenge the capacity of radiology clinics. Many techniques for detecting microcalcifications start with a segmentation algorithm that indicates all candidate structures for the subsequent phases. Most algorithms used to segment microcalcifications have aspects that might raise operational difficulties, such as thresholds or windows that must be selected, or parametric models of the data. We present a new segmentation algorithm and compare it to two other algorithms: the multi-tolerance region growing algorithm that operates without the aspects mentioned above, and the active contour model that has not been applied previously to segment microcalcifications. The new algorithm operates without threshold or window selection, or parametric data models, and it is more than an order of magnitude faster than the other two.

Algorithms↗
PubMed1997

Interresidue interactions in protein classes.

The free energy difference between folded and unfolded state is about the same for most proteins and it is not more than the energy of a few noncovalent interactions. In addition to the numerous noncovalent interactions, some proteins contain one or more disulfide bonds, which, as covalent crosslinks, significantly stabilize their tertiary structure. Correlation between the presence of disulfide bond(s), and the number noncovalent interresidue interactions of various kinds is analyzed here. The number of interactions per residue is almost the same for all protein. Also the number of long-range interactions per residue is the same in all proteins. Proteins with S--S bond(s) (extracellular proteins) have more medium-range and fewer short-range interactions than those without S--S bonds. However, the difference is independent of the number of these covalent crosslinks. We concluded that the different distributions of the various kinds of noncovalent interaction reflect the needs of proteins in the different environments, the extracellular and the intracellular ones, rather than the presence of the disulfide bond(s). We also pointed out that the observed differences in the distributions of short- and medium-range interactions are in good agreement with different secondary structure compositions of extracellular and intracellular proteins.

Amino Acids↗
PubMed1997

[Value of helical CT scan in the preoperative assessment of the ureteropelvic junction syndrome].

INTRODUCTION: The search for anatomical variants of the renal blood supply is an important element in the choice of surgical technique for the treatment of ureteropelvic junction syndrome. MATERIAL AND METHODS: Prospective study of 17 patients (mean age: 33 years), assessed by spiral CT with acquisition of overlapping thin sections during the arterial phase. The renal blood supply anatomical findings were then compared with operative findings in all patients. RESULTS: We observed a solitary renal artery in 8 cases, a lower pole pedicle crossing the junction in 9 cases and vascular abnormalities in 4 cases. All of these radiological findings were confirmed intraoperatively. Spiral CT, with rapid acquisition during the arterial phase and overlapping thin sections, allows accurate analysis of the renal blood supply. Axial sections are sufficient to provide the necessary anatomical information. Three dimensional reconstructions allow a better spatial visualization of the various structures. CONCLUSION: This examination allows visualization of a possible lower pole artery associated with UPJ syndrome, with identical accuracy to that of renal arteriography, but constitutes a less invasive and less expensive investigation.

Adolescent↗
PubMed1996

Conservation of amino acids in multiple alignments: aspartic acid has unexpected conservation.

Analysis of the relationship between surface accessibility and amino acid conservation in multiple sequence alignments of homologous proteins confirms expected trends for hydrophobic amino acids, but reveals an unexpected difference between the conservation of Asp, Glu and Gln. Even when not in an active site, Asp is more highly conserved than Glu. There is a clear preference for conserved and buried Asp to be present in coil, but there is no tendency for Asp to conserve phi/psi in the ++ region of the Ramachandran map. Glu does not show any preference to be conserved in a particular secondary structure. Analysis of recently derived substitution matrices (e.g. BLOSUM) confirms that Glu tends to substitute more frequently with other amino acids than does Asp. Analysis of relative accessibility versus relative conservation for individual amino acid positions in alignments shows a negative correlation for all amino acid types. With the exception of Arg, Lys, Gly, Glu, Asp and Tyr, a relative conservation of > 2 suggests the amino acid will have a relative accessibility of < 50%. Observation of conserved Cys, Gly or Asp in a reliable multiple alignment suggests a position important for the structure of the protein. Furthermore, the Asp is likely to be involved in polar interactions through its side chain oxygen atoms. In contrast, Gln is the least conserved amino acid overall.

Amino Acid Sequence↗
PubMed1996

GTPase activity of Rab5 acts as a timer for endocytic membrane fusion.

The GTPase cycle is a versatile regulatory mechanism directing many cell functions, and Rab family members use it to regulate intracellular transport. Current models propose that GTP hydrolysis by Rab proteins is either required for membrane fusion or occurs afterwards to allow recycling of the protein. To measure the GTPase activity of Rab5 in endocytic membrane fusion, we engineered a mutant that preferentially binds xanthosine 5'-triphosphate (XTP),Rab5(D136N) and monitored the kinetics of [alpha(32)P]-XTP hydrolysis in situ during endosome fusion in vitro. Surprisingly, nucleotide hydrolysis occurred even in the absence of membrane fusion, indicating that membrane-bound Rab5 undergoes futile cycles of GTP(XTP) binding and hydrolysis. Nucleotide triphosphate hydrolysis by Rab5 is not conditional on membrane fusion and is reduced by its effector Rabaptin-5. Our data reveal that the GTP cycle of Rab proteins differs from that of other GTPases (for example, EF-Tu) and indicate that GTP hydrolysis acts as a timer that determines the frequency of membrane docking/fusion events.

ADP-Ribosylation Factors↗
PubMed1996

Kinetics of interaction of Rab5 and Rab7 with nucleotides and magnesium ions.

We describe here the kinetics of the interaction of GTP and GDP with the small GTP-binding proteins Rab5 and Rab7. It was possible to make use of the intrinsic fluorescence of these proteins, since Rab5 contains two and Rab7 three tryptophan residues, respectively. With both enzymes, there is a significant decrease in fluorescence on binding GTP and an increase on binding GDP. As with the small GTP-binding protein Ha-Ras p21 and with EF-Tu, nucleotide binding occurs in at least two steps and is describable in terms of a relatively weak initial interaction followed by a highly irreversible isomerization of the protein-nucleotide complex, which results in a change in the fluorescence properties. Dissociation of GDP and GTP could be followed in a time-dependent manner using fluorescently labeled GDP (methylanthraniloyl GDP) as displacing agent and taking advantage of substantial fluorescent energy transfer from tryptophan to the nucleotide. Fluorescence techniques could also be used to quantitate the interaction of Mg2+ ions with the GTP and GDP forms of Rab7, and it was shown that the metal ion was bound approximately 1000-fold more strongly to the GTP than the GDP form. The rate of GTP cleavage by the two proteins differed by a factor of approximately 20 (2 x 10(-3)s-1 for Rab5 and 9 x 10(-4)s-1 for Rab7 at 37 degrees C). Both proteins showed significant discrimination against xanthosine 5'-O-diphosphate (Kd approximately 10(3)-fold higher than that of GDP) and dramatic discrimination against ADP or ATP (Kd approximately 10(6)-fold higher than that of GDP). The results demonstrate a high degree of mechanistic similarity between the Rab proteins and other GTP-binding proteins, which have been examined in detail, including Ha-Ras p21, Ran, and EF-Tu.

Adenosine Diphosphate↗
PubMed1996

Biochemical and biological consequences of changing the specificity of p21ras from guanosine to xanthosine nucleotides.

The D119N mutation of p21ras was prepared by site-directed mutagenesis. Its nucleotide binding properties were investigated using fluorescently labelled guanosine and xanthosine nucleotides. Its affinity for guanosine nucleotides is severely reduced, with a concomitant increase in the affinity for xanthosine nucleotides, which leads to an almost complete reversal of base specificity. The protein is a GTPase as well as a XTPase and the hydrolysis reaction can be efficiently stimulated by GAP. Dissociation of XDP from the mutant is stimulated by the guanine nucleotide exchange factor Cdc25Mm in a similar manner to that of GDP from wildtype. The interaction of the mutant with the effector domain of c-Raf kinase or Ral-GEF is normal. In microinjection experiments in PC12 and NIH3T3 cells the protein behaves as an oncogenic mutant due to its high dissociation rate for GDP. However, when the protein is loaded with XDP before microinjection the onset of the oncogenic signal can be efficiently retarded. Thus, the protein behaves initially as wildtype and later as an oncogenic protein.

3T3 Cells↗
PubMed1996

[Effect of S9788, cyclosporin A and verapamil on intracellular accumulation of doxorubicin, daunorubicin and daunorubicinol in primary rat hepatocyte culture].

The aim of this study was to compare the effect of three MDR modulators, cyclosporine A, S9788 and verapamil on the efflux of two anthracyclines, doxorubicin and daunorubicin and of daunorubicinol, the C-13 alcohol metabolite of daunorubicin. Rat hepatocyte primary cultures were used as a model of P-gp expression. They allow to study MDR at different levels of P-gp expression which increases in parallel with culture time. Furthermore, hepatocytes are able to metabolize drugs and enable determination of the role of P-gp on metabolite efflux. Hepatocytes grown for 4 or 48 hours were incubated for 6 hours in the presence of a combination of each modulator and one of the two anthracyclines (0.5 microM). Modulator concentrations used were 1, 5 and 15 microM when associated with DOX, and 1 and 15 when associated with DNR. In fresh hepatocytes, the three MDR modulators did not induce an increase in intracellular retention of the two anthracyclines compared to controls without MDR modulators. At 48 hours of culture, the three tested drugs increased intracellular accumulation of DOX. However, daunorubicin retention was not modified but that of its metabolite was increased. The activity rank order was cyclosporine A > S9788 > verapamil. Cyclosporine A and S9788 were active in simultaneous as well as in sequential combinations with anthracyclines. Verapamil was only effective when co-incubated with anthracyclines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

[Diagnostic value of various echo- and Doppler echocardiography methods in quantifying mitral valve stenosis].

UNLABELLED: Two-dimensional and Doppler echocardiography have been widely used for noninvasive determination of valve area in patients with mitral stenosis. Recent studies have indicated that the Doppler-echocardiographic pressure half-time method (PHT) does not accurately predict mitral orifice area (MOA). Therefore, applications of the continuity equation and the Gorlin formula have been used additionally to the PHT for Doppler-echocardiographic assessment of MOA. In a prospective study of 34 patients MOA determined by two-dimensional and Doppler echocardiography was compared with MOA measured by cardiac catheterization (range 0.40 to 1.90 cm2, mean 1.08 +/- 0.37 cm2). There was a moderate correlation between two-dimensional echocardiographic and invasive measurements (r = 0.65, SEE = 0.20 cm2). MOA calculated by the PHT showed only poor correlation with cardiac catheterization (r = 0.38 SEE = 0.37 cm2). We found better correlations for the continuity equation (r = 0.73, SEE = 0.35 cm2) and Doppler-echocardiographic application of the Gorlin formula (r = 0.81, SEe = 0.27 cm2). Doppler-echocardiographic use of the Gorlin formula yielded the best prediction of the severity of mitral valve stenosis (concordance with invasive measurement in 82%). CONCLUSION: Pressure half-time is only a poor predictor of the severity of mitral valve stenosis. More accurate results are obtained by Doppler-echocardiographic applications of the continuity equation and especially the Gorlin formula.

Adult↗