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F Heitz

Publications and source records attributed to F Heitz.

At least 19 recordsLinked to original sources
PubMed2007

A non-covalent peptide-based strategy for siRNA delivery.

The major obstacle to clinical development of siRNAs (short interfering RNAs), like for most of the nucleic-acid-based strategies, is their poor cellular uptake and bioavailability. Although several viral and non-viral strategies have been proposed to improve siRNA delivery, their applications in vivo remain a major challenge. We have developed a new strategy, based on a short amphipathic peptide, MPG, that is able to form stable nanoparticles with siRNA. MPG-based particles enter the cell independently of the endosomal pathway and can efficiently deliver siRNA in a fully biologically active form into a variety of cell lines and in vivo. This short review will discuss the mechanism and the potency of the MPG strategy for siRNA delivery both in vitro and in vivo.

Animals↗
PubMed2006

Hidden Markov multiple event sequence models: A paradigm for the spatio-temporal analysis of fMRI data.

This paper presents a novel, completely unsupervised fMRI brain mapping method that addresses the three problems of hemodynamic response function (HRF) variability, hemodynamic event timing, and fMRI response non-linearity. Spatial and temporal information are directly taken into account into the core of the activation detection process. In practice, activation detection at voxel v is formulated in terms of temporal alignment between sequences of hemodynamic response onsets (HROs) detected in the fMRI signal at v and in the spatial neighborhood of v, and the input sequence of stimuli or stimulus onsets. Event-related and epoch paradigms are considered. The multiple event sequence alignment problem is solved within the probabilistic framework of hidden Markov multiple event sequence models (HMMESMs), a new class of hidden Markov models. Results obtained on real and synthetic data significantly outperform those obtained with the popular statistical parametric mapping (SPM2) method without requiring any prior definition of the expected activation patterns, the HMMESM mapping approach being completely unsupervised.

Adolescent↗
PubMed2006

Retrospective evaluation of a topology preserving non-rigid registration method.

This paper proposes a comprehensive evaluation of a monomodal B-spline-based non-rigid registration algorithm allowing topology preservation in 3-D. This article is to be considered as the companion of [Noblet, V., Heinrich, C., Heitz, F., Armspach, J.-P., 2005. 3-D deformable image registration: a topology preservation scheme based on hierarchical deformation models and interval analysis optimization. IEEE Transactions on Image Processing, 14 (5), 553-566] where this algorithm, based on the minimization of an objective function, was introduced and detailed. Overall assessment is based on the estimation of synthetic deformation fields, on average brain construction, on atlas-based segmentation and on landmark mapping. The influence of the model parameters is characterized. Comparison between several objective functions is carried out and impact of their symmetrization is pointed out. An original intensity normalization scheme is also introduced, leading to significant improvements of the registration quality. The comparison benchmark is the popular demons algorithm [Thirion, J.-P., 1998. Image matching as a diffusion process: an analogy with Maxwell's demons. Medical Image Analysis, 2 (3), 243-260], that exhibited best results in a recent comparison between several non-rigid 3-D registration methods [Hellier, P., Barillot, C., Corouge, I., Gibaud, B., Le Goualher, G., Collins, D.L., Evans, A., Malandain, G., Ayache, N., Christensen, G.E., Johnson, H.J., 2003. Retrospective evaluation of intersubject brain registration. IEEE Transactions on Medical Imaging, 22 (9), 1120-1130]. The topology preserving B-spline-based method proved to outperform the commonly available ITK implementation of the demons algorithms on many points. Some limits of intensity-based registration methods are also highlighted through this work.

Algorithms↗
PubMed2005

Cell-penetrating peptides: tools for intracellular delivery of therapeutics.

The main problem of therapeutic efficiency lies in the crossing of cellular membranes. Therefore, significant effort is being made to develop agents which can cross these barriers and deliver therapeutic agents into cellular compartments. In recent years, a large amount of data on the use of peptides as delivery agents has accumulated. Several groups have published the first positive results using peptides for the delivery of therapeutic agents in relevant animal models. These peptides, called cell-penetrating peptides (CPPs), are short peptides (fewer than 30 residues) with a net positive charge and acting in a receptor- and energy-independent manner. Here, we give an extensive review of peptide-mediated delivery systems and discuss their applications, with particular focus on the mechanisms leading to cellular internalization.

Amino Acid Sequence↗
PubMed2005

Fatty acyl moieties: improving Pro-rich peptide uptake inside HeLa cells.

In the field of drug delivery there has been a continuous study of powerful delivery systems to aid non permeable drugs in reaching their intracellular target. Among the systems explored are cell penetrating peptides (CPPs), which first garnered interest a decade ago when the interesting translocation properties of the pioneer CPPs Tat and Antp were described. A new family of CPPs has recently been described as non cytotoxic Pro-rich vectors with favorable profiles for internalization in HeLa cells. Fatty acyl moieties that can tune a peptide's interaction with the lipophilic environment of a cell membrane have been incorporated into the Pro-rich sequence. Improvements in cellular uptake of peptides modified with fatty acyl groups, as studied by confocal microscopy and flow cytometry, as well as the results obtained by the interaction of these peptides with a model dioleoylphosphatidylcholine (DOPC) membrane and transmission electron microscopy (TEM), illustrate the importance of the fatty acyl moieties for efficient internalization.

Drug Carriers↗
PubMed2004

Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression.

The design of potent systems for the delivery of charged and noncharged molecules that target genes of interest remains a challenge. We describe a novel technology that combines a new generation of peptide nucleic acids (PNAs), or HypNA-pPNAs, with a new noncovalent peptide-based delivery system, Pep-2, which promotes efficient delivery of PNAs into several cell lines. We have validated the potential of this technology by showing that Pep2-mediated delivery of an antisense HypNA-pPNA chimera directed specifically against cyclin B1 induces rapid and robust downregulation of its protein levels and efficiently blocks cell cycle progression of several cell lines, as well as proliferation of cells derived from a breast cancer. Pep-2-based delivery system was shown to be 100-fold more efficient in delivering HypNA-pPNAs than classical cationic lipid-based methods. Whereas Pep-2 is essential for improving the bioavailability of PNAs and HypNA-pPNAs, the latter contribute significantly to the efficiency and specificity of the biological response. We have found that Pep-2/HypNA-pPNA strategy promotes potent antisense effects, which are approximately 25-fold greater than with classical antisense oligonucleotide directed specifically against the same cyclin B1 target. Taken together, these data demonstrate that peptide-mediated delivery of HypNA-pPNAs constitutes a very promising technology for therapeutic applications.

Antisense Elements (Genetics)↗
PubMed2004

Effects of post-surgical cleansing protocols on early plaque control in periodontal and/or periimplant wound healing.

OBJECTIVE: The aim of this RCT was to evaluate early wound healing following specific post-surgical care protocols. MATERIAL AND METHODS: Following periodontal flap surgery, 60 patients were randomly assigned to follow one of two post-surgical protocols. Subjects smoking >20 cigarettes per day were excluded. Patients following the control protocol rinsed twice daily for 1 min with 0.1% of chlorhexidine (CHX) for 4 weeks. In addition to CHX rinsing, patients assigned to the test protocol applied CHX locally using a special very soft surgical toothbrush (Chirugia) from days 3 to 14, and a soft toothbrush (Ultrasuave) from days 14 to 28, twice daily. Baseline measurements included gingival crevicular fluid (GCF) flow rate, probing depth, probing attachment level, presence of bleeding on probing and full-mouth plaque score. Measurements were repeated at 1, 2 and 4 weeks after surgery. RESULTS: Both post-surgical protocols resulted in successful wound healing and optimal wound closure at 4 weeks. There were no statistical differences in the GCF flow rate between test and control protocols. There was a lower incidence of recession of > or =2 mm following the test protocol. CONCLUSION: The use of specific post-surgical cleansing protocols including the introduction of mechanical cleansing at day 3, using local application of CHX in addition to daily rinsing with CHX may be recommended.

Adult↗
PubMed2002

A systematic review of the effect of surgical debridement vs non-surgical debridement for the treatment of chronic periodontitis.

OBJECTIVE: To systematically review the evidence of effectiveness of surgical vs. non-surgical therapy for the treatment of chronic periodontal disease. METHODS: A search was conducted for randomized controlled trials of at least 12 months duration comparing surgical with non-surgical treatment of chronic periodontal disease. Data sources included the National Library of Medicine computerised bibliographic database MEDLINE, and the Cochrane Oral Health Group (COHG) Specialist Trials Register. Screening, data abstraction and quality assessment were conducted independently by multiple reviewers (L.H., F.H., L.T.). The primary outcome measures evaluated were gain in clinical attachment level (CAL) and reduction in probing pocket depth (PPD). RESULTS: The search provided 589 abstracts of which six randomized controlled trials were included. Meta-analysis evaluation of these studies indicated that 12 months following treatment, surgical therapy resulted in 0.6 mm more PPD reduction (WMD 0.58 mm; 95% CI 0.38, 0.79) and 0.2 mm more CAL gain (WMD 0.19 mm; 95% CI 0.04, 0.35) than non-surgical therapy in deep pockets (>6 mm). In 4-6 mm pockets scaling and root planing resulted in 0.4 mm more attachment gain (WMD -0.37 mm; 95% CI -0.49, -0.26) and 0.4 mm less probing depth reduction (WMD 0.35 mm; 95% CI 0.23, 0.47) than surgical therapy. In shallow pockets (1-3 mm) non-surgical therapy resulted in 0.5 mm less attachment loss (WMD -0.51 mm; 95% CI -0.74, -0.29) than surgical therapy. CONCLUSIONS: Both scaling and root planing alone and scaling and root planing combined with flap procedure are effective methods for the treatment of chronic periodontitis in terms of attachment level gain and reduction in gingival inflammation. In the treatment of deep pockets open flap debridement results in greater PPD reduction and clinical attachment gain.

Chronic Disease↗
PubMed2002

[Trichothiodystrophy and congenital heart disease in two sisters].

INTRODUCTION: Trichothiodystrophy refers to a heterogeneous group of autosomal recessive genodermatosis of unknown etiology. Patients with trichothiodystrophy have alopecia with typical hair dysplasia ("tiger-tail"), and abnormally low sulfur content. Numerous unrelated neuroectodermal defects have been observed in trichothiodystrophy. We report here trichothiodystrophy and congenital heart disease in two sisters. CASES REPORT: Two sisters were born as collodion babies and presented ichthyosis and alopecia. The diagnosis of trichothiodystrophy was confirmed by polarizing microscopy of hair and low sulfur content. Both had congenital heart disease. DISCUSSION: Cardiovascular defects have rarely been reported in trichothiodystrophy. The association trichothiodystrophy - congenital heart disease has never been described. The low incidence of both conditions suggests that these abnormalities are linked etiologically rather than by chance. Abnormal Notch signaling, or contiguous gene deletion syndrome could lead to combined phenotype as observed in our family.

Alopecia↗
PubMed2001

Lipid-induced pore formation of the Bacillus thuringiensis Cry1Aa insecticidal toxin.

After activation, Bacillus thuringiensis (Bt) insecticidal toxin forms pores in larval midgut epithelial cell membranes, leading to host death. Although the crystal structure of the soluble form of Cry1Aa has been determined, the conformation of the pores and the mechanism of toxin interaction with and insertion into membranes are still not clear. Here we show that Cry1Aa spontaneously inserts into lipid mono- and bilayer membranes of appropriate compositions. Fourier Transform InfraRed spectroscopy (FTIR) indicates that insertion is accompanied by conformational changes characterized mainly by an unfolding of the beta-sheet domains. Moreover, Atomic Force Microscopy (AFM) imaging strongly suggests that the pores are composed of four subunits surrounding a 1.5 nm diameter central depression.

Bacillus thuringiensis↗
PubMed2001

Reaction of canine plasminogen with 6-aminohexanoate: a thermodynamic study combining fluorescence, circular dichroism, and isothermal titration calorimetry.

The thermodynamics of the binding of 6-aminohexanoate (6-AH) to dog glu-plasminogen has been studied. Fluorescence titrations revealed four binding sites. Three yielded positive fluorescence changes on ligand binding; one yielded a negative fluorescence change. The fluorescence data gave no indication of cooperative interactions. Binding was studied using circular dichroism (CD). Near 295 nm there were small changes associated with binding ligand. These were magnified at 235 nm, a wavelength that is mainly associated with tryptophan bands. The dissociation constants obtained from the fluorescence were applied to the CD data and fit quite well. Below 220 nm, there were no significant differences between samples with or without 6-AH and, therefore, no substantial change in the secondary structure of the protein. Isothermal titration calorimetry was used in combination with the binding constants from fluorescence to study the enthalpy and entropy contributions to 6-AH binding. The enthalpies of association for the four sites are all negative. Their absolute values are small for the tight sites and large for the weakest. -TDeltaS is negative for the tight sites and positive for the weakest. The binding of 6-AH to plasminogen is entropically driven for the two tightest sites and enthalpically driven for the weakest site. The binding of 6-AH to lys-plasminogen has been studied and differs slightly from binding to glu-plasminogen. Most importantly, the binding of 6-AH for the weak site goes from enthalpy- to entropy-driven as is found with the other sites.

Aminocaproic Acid↗
PubMed2001

Conformation and ion channel properties of a five-helix Bundle protein.

The primary amphipathic peptide Ac-Met-Gly-Leu-Gly-Leu-Trp-Leu-Leu-Val-Leu10-Ala-Ala-Ala-Leu-Gln-Gly-Ala-Lys-Lys-Lys20-Arg-Lys-Val-NH-CH2-CH2-SH called SPM was able to induce formation of ion channels into planar lipid bilayers with main conductance values of 75 and 950 pS in 1 M KCl. The 75 pS value can be attributed to an aggregate composed of five monomers since the corresponding five-unit bundle (5-SPM) also presented a 70 pS channels under the same conditions. The upper 950 pS level would be generated by a hexameric aggregate. Ion channels induced by both SPM and its pentameric bundle are slightly cation selective but not voltage-dependent. The structural studies showed that the SPM and 5-SPM possess mainly an alpha-helical structure (approximately 40%) and are strongly embedded in the bilayer. This behaviour and the strong hydrophobic interactions occurring between helices in the bundle induce a strong stabilization of 5-SPM in the bilayer and would be responsible for the stepwise current fluctuations observed during the incorporation of 5-SPM into the membrane.

Algorithms↗
PubMed2001

Domain formation in models of the renal brush border membrane outer leaflet.

The plasma membrane outer leaflet plays a key role in determining the existence of rafts and detergent-resistant membrane domains. Monolayers with lipid composition mimicking that of the outer leaflet of renal brush border membranes (BBM) have been deposited on mica and studied by atomic force microscopy. Sphingomyelin (SM) and palmitoyloleoyl phosphatidylcholine (POPC) mixtures, at molar ratios varying from 2:1 to 4:1, were phase-separated into liquid condensed (LC) SM-enriched phase and liquid expanded (LE) POPC-enriched phase. The LC phase accounted for 33 and 58% of the monolayers surface for 2:1 and 4:1 mixtures, respectively. Addition of 20-50 mol % cholesterol (Chl) to the SM/POPC (3:1) mixtures induced marked changes in the topology of monolayers. Whereas Chl promoted the connection between SM domains at 20 mol %, increasing Chl concentration progressively reduced the size of domains and the height differences between the phases. Lateral heterogeneity was, however, still present at 33 mol % Chl. The results indicate that the lipid composition of the outer leaflet is most likely responsible for the BBM thermotropic transition properties. They also strongly suggest that the common maneuver that consists of depleting membrane cholesterol to suppress rafts does not abolish the lateral heterogeneity of BBM membranes.

Animals↗
PubMed2001

Three-dimensional segmentation of anatomical structures in MR images on large data bases.

In this paper an image-based method founded on mathematical morphology is presented in order to facilitate the segmentation of cerebral structures over large data bases of 3D magnetic resonance images (MRIs). The segmentation is described as an immersion simulation, applied to the modified gradient image, modeled by a generated 3D-region adjacency graph (RAG). The segmentation relies on two main processes: homotopy modification and contour decision. The first one is achieved by a marker extraction stage where homogeneous 3D-regions are identified. This stage uses contrasted regions from morphological reconstruction and labeled flat regions constrained by the RAG. Then, the decision stage intends to precisely locate the contours of regions detected by the marker extraction. This decision is performed by a 3D extension of the watershed transform. The method has been applied on a data base of 3D brain MRIs composed of fifty patients. Results are illustrated by segmenting the ventricles, corpus callosum, cerebellum, hippocampus, pons, medulla and midbrain on our data base and the approach is validated on two phantom 3D MRIs.

Databases as Topic↗
PubMed2001

A peptide carrier for the delivery of biologically active proteins into mammalian cells.

The development of peptide drugs and therapeutic proteins is limited by the poor permeability and the selectivity of the cell membrane. There is a growing effort to circumvent these problems by designing strategies to deliver full-length proteins into a large number of cells. A series of small protein domains, termed protein transduction domains (PTDs), have been shown to cross biological membranes efficiently and independently of transporters or specific receptors, and to promote the delivery of peptides and proteins into cells. TAT protein from human immunodeficiency virus (HIV-1) is able to deliver biologically active proteins in vivo and has been shown to be of considerable interest for protein therapeutics. Similarly, the third alpha-helix of Antennapedia homeodomain, and VP22 protein from herpes simplex virus promote the delivery of covalently linked peptides or proteins into cells. However, these PTD vectors display a certain number of limitations in that they all require crosslinking to the target peptide or protein. Moreover, protein transduction using PTD-TAT fusion protein systems may require denaturation of the protein before delivery to increase the accessibility of the TAT-PTD domain. This requirement introduces an additional delay between the time of delivery and intracellular activation of the protein. In this report, we propose a new strategy for protein delivery based on a short amphipathic peptide carrier, Pep-1. This peptide carrier is able to efficiently deliver a variety of peptides and proteins into several cell lines in a fully biologically active form, without the need for prior chemical covalent coupling or denaturation steps. In addition, this peptide carrier presents several advantages for protein therapy, including stability in physiological buffer, lack of toxicity, and lack of sensitivity to serum. Pep-1 technology should be extremely useful for targeting specific protein-protein interactions in living cells and for screening novel therapeutic proteins.

3T3 Cells↗
PubMed2001

A joint physics-based statistical deformable model for multimodal brain image analysis.

A probabilistic deformable model for the representation of multiple brain structures is described. The statistically learned deformable model represents the relative location of different anatomical surfaces in brain magnetic resonance images (MRIs) and accommodates their significant variability across different individuals. The surfaces of each anatomical structure are parameterized by the amplitudes of the vibration modes of a deformable spherical mesh. For a given MRI in the training set, a vector containing the largest vibration modes describing the different deformable surfaces is created. This random vector is statistically constrained by retaining the most significant variation modes of its Karhunen-Loève expansion on the training population. By these means, the conjunction of surfaces are deformed according to the anatomical variability observed in the training set. Two applications of the joint probabilistic deformable model are presented: isolation of the brain from MRI using the probabilistic constraints embedded in the model and deformable model-based registration of three-dimensional multimodal (magnetic resonance/single photon emission computed tomography) brain images without removing nonbrain structures. The multi-object deformable model may be considered as a first step toward the development of a general purpose probabilistic anatomical atlas of the brain.

Anatomy, Cross-Sectional↗
PubMed2001

In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions.

Tegaserod is a selective 5-HT(4) receptor partial agonist with promotile activity in the gastrointestinal tract. This study was designed to describe the metabolic pathways of tegaserod in the human liver and small intestine in vitro, to identify the enzymes involved in tegaserod metabolism, and to investigate the effect of tegaserod on CYP-catalyzed reactions involving other compounds. Tegaserod was metabolized in human liver microsomes to O-desmethyl tegaserod at a low rate. This metabolite was also formed by cDNA expressed CYP2D6, and the reaction in human liver microsomes was inhibited by quinidine. In human liver slices, direct N-glucuronidation of tegaserod at the guanidine nitrogens (M43.2, M43.8, and M45.3) was found, with M43.8 being the major metabolite. Human small intestine slices also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism. 5-Methoxyindole-3-carboxylic acid (M29.0), the main metabolite in human plasma, was generated in vitro by a sequence of reactions starting with nonenzymatic acid-catalyzed hydrolysis, followed by enzymatic oxidation and conjugation with glucuronic acid. Tegaserod inhibited CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A only to a small extent with IC(50) values >30 microM. Tegaserod more effectively inhibited CYP1A2 and CYP2D6 with K(i) values of 0.84 and 0.85 microM, respectively. However, these K(i) values are approximately 140-fold greater than the maximal tegaserod plasma concentrations following the clinically relevant 6-mg oral dose given to healthy volunteers. M29.0, the main circulating metabolite, did not demonstrate any inhibitory potential toward cytochrome P450 enzymes in vitro. Therefore, clinically relevant metabolic drug interactions with tegaserod seem unlikely.

Biotransformation↗