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Biomedical subjects

M Pons

Publications and source records attributed to M Pons.

At least 19 recordsLinked to original sources
PubMed2006

Long-term improvement of slow-channel congenital myasthenic syndrome with fluoxetine.

We report on a 15-year-old patient who was diagnosed with congenital myasthenic syndrome (CMS) at the age of 7 months. At initial diagnosis, the CMS was not further characterized. The patient was treated for several years with the anticholinesterase drug (Mestinon), without clinical benefit. The patient deteriorated progressively and became dependent on home nocturnal ventilatory support, being unable to take part in daily life activities at age of 12 years. At age 14, the slow-channel syndrome mutation CHRNE L269F (805C>T) was detected and acetylcholinesterase inhibitor therapy was immediately stopped. Fluoxetine therapy was started and gradually increased over 2 months. The boy improved dramatically in strength and endurance and was taken off ventilatory support 1 month after the fluoxetine therapy was initiated. The clinical improvement was confirmed by functional respiratory and electrophysiological tests.

Adolescent↗
PubMed2006

Molecular biology of malignant melanoma and other cutaneous tumors.

Skin cancer is the most common cancer worldwide. Its incidence is doubling every 15-20 years likely because of an aging population, changes in behaviour towards sun exposure, and increased UV light fluency at the earth surface due to ozone depletion. In this review, we summarize the most important genetic changes contributing to the development of malignant melanoma, basal cell carcinoma and squamous cell carcinoma, the main tumor entities arising in the skin. While our understanding of the oncogenes and tumor suppressor genes involved in the development and progression of skin tumors is still fragmentary, recent advances have shown alterations affecting conserved signalling pathways that control cellular proliferation and viability. These pathways include INK4alpha/Rb, ARF/p53, RAS/MAPKs, and sonic hedgehog/Gli.

Animals↗
PubMed2005

Hydrodynamic models and computational methods for NMR relaxation.

Interpretation of NMR relaxation data of macromolecules is based on the analysis of their dynamic behavior in solution. For quasirigid molecules, in addition to a minor, separable contribution from local mobility, the main contribution corresponds to the overall rotational diffusion of the complete molecule. Therefore, theoretical descriptions and computational methodologies for hydrodynamic calculations, which yield the full, anisotropic rotational diffusion tensor of rigid molecules, are extremely helpful in the analysis of NMR relaxation. Recent approaches allow realistic predictions of the rotational diffusion tensor from structures at atomic detail. This enables measured relaxation rates and structural models to be compared. Such a comparison (1) provides an independent test of the structural model, (2) provides a framework for the interpretation of local motion, even for highly anisotropic systems, (3) provides a simple method for the detection of additional sources of relaxation, such as chemical exchange, and (4) provides a sensitive method for the detection of nonspecific aggregation or oligomer formation. Although hydrodynamic calculations usually assume a rigid structure, Brownian dynamics simulations extend their range of applications to flexible multidomain structures. Hydrodynamic applications are not restricted to globular proteins. Small DNA fragments, which could be otherwise considered cylindrical objects, can also be treated with atomic detail using the same methodology used for proteins.

Computational Biology↗
PubMed2004

Pulmonary involvement in tuberous sclerosis.

Tuberous sclerosis is a neurocutaneous syndrome involving many tissues. Pulmonary involvement is rare. Pulmonary cases are usually women of child-bearing age who present with spontaneous pneumothorax or progressive dyspnea. In childhood and, even more, in male patients, pulmonary involvement by tuberous sclerosis is exceptional. We report on a 4-year-old male patient diagnosed in the first months of life with tuberous sclerosis with predominantly respiratory symptoms (frequently with acute RDS criteria), in whom lung involvement was pathologically confirmed.

Child, Preschool↗
PubMed2004

Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation.

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.

Breast Neoplasms↗
PubMed2003

The importance of clinical factors in parenteral nutrition-associated hypertriglyceridemia.

AIMS: The purpose of this study was to establish the relevance of several clinical factors associated with parenteral nutrition (PN) hypertriglyceridemia and to construct a predictive model for this complication. METHOD: This multicenter study included all patients with initial serum triglyceridemia <3 mmol and receiving a minimum of 7 days' PN therapy. The study ended for each patient when hypertriglyceridemia developed or PN was terminated. Two multivariate models were constructed, one to study the clinical factors and the second to predict plasma triglyceridemia. A total of 22 clinical factors studied as independent variables were included in the multiple-step regression models only when they showed a P-value over 0.1. Statistical significance was determined by the confidence interval of the odds ratio (OR) and the partial regression coefficient (b). RESULTS: The study included 260 patients from 14 hospitals. Lipid administration was 0.83+/-0.37 g/kg/day. Among the total, 68 patients (26.2%) showed hypertriglyceridemia. Variables included in both models were serum glucose (OR, 2.63; b, 0.06), renal failure (OR, 10.56; b, 1.70), corticoid administration >0.5 mg/kg (OR, 7.98; b, 0.97), pancreatitis (OR, 4.38; b, 0.64), sepsis (OR, 4.48; b, 0.24), lipids infused (OR, 3.03; b, 0.24) and heparin administration >3 mg/kg/day (OR, 0.11; b, -1.21). CONCLUSION: Although the rate of lipid infusion was low, certain clinical factors modified triglyceridemia. Nevertheless, relatively fast plasma clearance of lipids infused indicates that a reduction in lipid supply could be a quick, effective measure for controlling hypertriglyceridemia. Thus, careful monitoring of patients with clinical factors predicting risk in the model studied, with adjustment of lipid perfusion rates accordingly, is suggested to avoid hypertriglyceridemia.

Adult↗
PubMed2003

Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma. METHODS: After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 microg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or budesonide 1600 microg/day (n=441) for 12 weeks. RESULTS: Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1-3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" beta agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated. CONCLUSION: The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone.

Acetates↗
PubMed2002

Isolation and characterization of four isomers of a C(60) bisadduct with a TTF derivative. Study of their radical ions.

A family of triads composed of C(60) attached by a rigid spacer to two identical TTF moieties has been synthesized, and some of the isomers have been isolated and characterized by UV-vis spectroscopy, LDI-TOF-MS, and HMBC NMR spectroscopy. AM1 semiempirical calculations of the dipolar moments and the heats of formation of the different isomers have been carried out in order to verify their assignments. Oxidation and reduction of the triads affords the derived radical ion systems, TTF(+*)-C(60)-TTF(+*) and TTF-C(60)(-*)-TTF, which were studied by EPR spectroscopy. Spin density distributions of these radical cations and radical anions show that the unpaired electron is located mainly on the TTF and fullerene moieties, respectively. However, while the EPR signals obtained from the radical cations are very similar for all the isomers, the structured signals observed for the radical anions arising from the coupling of the unpaired electron with the hydrogen atoms of the methylene bridges in the spacer show that there is a strong influence of the isomerism on the spin distribution. Importantly, the theoretical calculations of the spin density distributions of the radical anions fit well with the experimental EPR results.

Journal Article↗
PubMed2002

Prevention of non-steroidal antiinflammatory drugs-induced gastropathy: follow up of protocol adherence.

OBJECTIVE: To reach a consensus on and evaluate the compliance of the protocol for the prophylaxis of gastropathy induced by non-steroidal anti-inflammatory drugs with 20 mg omeprazole per day. PATIENTS AND METHOD: Three transversal studies have been carried out on patients admitted to our hospital before establishing the protocol, immediately after and 6 months later. RESULTS: Between 16 and 24% of patients admitted to our hospital take non-steroidal anti-inflammatory drugs. Before the application of the protocol 34.7% of prescriptions coincided with this use. After its establishment adherence by the prescribing doctors improved to 51.8% (c2 = 5.27, p = 0.02) and at 6 months it reached 51.4% adherence, an improvement that continued being significative (c2 = 5.74, p = 0.01). The main reason for non-compliance was the use of ranitidine instead of omeprazole. One of the most useful methods for improving adhesion has been meeting with the medical services that most use the anti-inflammatory drugs, focussing specifically on the use of the protocol. CONCLUSIONS: The follow-up of the protocol shows an improvement in compliance after the establishment stage which is maintained after 6 months. Adherence by the prescribing doctors to the treatment, nevertheless, is lower than had been hoped.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

An analytical solution to the problem of the orientation of rigid particles by planar obstacles. Application to membrane systems and to the calculation of dipolar couplings in protein NMR spectroscopy.

Nonspherical particles or molecules experience an ordering effect in the presence of obstacles due to the restrictions they place on the orientation of those molecules that are in their proximity. Obstacles may be the limits of a membrane in which the molecule is embedded, oriented mesoscopic systems such as bicelles, or membrane fragments used to induce weak protein alignment in a magnetic field. The overall shape of most proteins can be described to a good approximation by an ellipsoidal particle. Here we describe and solve analytically the problem of the orientation of ellipsoidal particles by planar obstacles. Simple expressions are derived for the orientational distribution function and the order parameter. These expressions allow the analytical calculation of the residual dipolar couplings for a protein of known three-dimensional structure oriented by steric effects. The results are in good agreement with experiment and with the results of previously described simulations. However, they are obtained analytically in a fraction of the time and therefore open the possibility to include the optimization of the overall shape in the determination of three-dimensional structures using residual dipolar coupling constraints. The equations derived are general and can also be applied to problems of a completely different nature. In particular, previous equations describing the orientation of particles embedded in membranes are verified and generalized here.

Membrane Proteins↗
PubMed2001

Self-assembly of the amphipathic helix (VHLPPP)8. A mechanism for zein protein body formation.

gamma-Zein, a maize storage protein with an N-terminal proline-rich repetitive domain (gamma-ZNPRD), is located at the periphery of protein bodies. This domain appears to be indispensable for the aggregation of the protein on the surface of the organelle. The peptide (VHLPPP)8, spanning the gamma-ZNPRD, adopts a polyproline II (PPII) conformation that gives an amphipathic helix different from the alpha-helix. We used atomic force microscopy to study the surface organisation of the octamer, and transmission electron microscopy to visualise aggregates of the peptide in aqueous solution. We consider two self-assembly patterns that take account of the observed features. The micellar one fits best with the experimental results presented. Moreover, we found that this peptide has properties associated with surfactants, and form micelles in solution. This spontaneous amphipathic arrangement of the gamma-ZNPRD suggests a mechanism of gamma-zein deposition inside maize protein bodies.

Amino Acid Sequence↗
PubMed2001

Evidence for the Involvement of annexin 6 in the trafficking between the endocytic compartment and lysosomes.

Annexins are a family of calcium-dependent phospholipid-binding proteins, which have been implicated in a variety of biological processes including membrane trafficking. The annexin 6/lgp120 prelysosomal compartment of NRK cells was loaded with low-density lipoprotein (LDL) and then its transport from this endocytic compartment and its degradation in lysosomes were studied. NRK cells were microinjected with the mutated annexin 6 (anx6(1-175)), to assess the possible involvement of annexin 6 in the transport of LDL from the prelysosomal compartment. The results indicated that microinjection of mutated annexin 6, in NRK cells, showed the accumulation of LDL in larger endocytic structures, denoting retention of LDL in the prelysosomal compartment. To confirm the involvement of annexin 6 in the trafficking and the degradation of LDL we used CHO cells transfected with mutated annexin 6(1-175). Thus, in agreement with NRK cells the results obtained in CHO cells demonstrated a significant inhibition of LDL degradation in CHO cells expressing the mutated form of annexin 6 compared to controls overexpressing wild-type annexin 6. Therefore, we conclude that annexin 6 is involved in the trafficking events leading to LDL degradation.

Animals↗
PubMed2001

Activation of Raf-1 is defective in annexin 6 overexpressing Chinese hamster ovary cells.

Annexin 6 is a Ca2+-dependent phospholipid-binding protein involved in membrane trafficking. In this study we demonstrate the association of Raf-1 with recombinant rat annexin 6. Raf-annexin 6 interaction was shown to be independent of cell activation by epidermal growth factor (EGF) or phorbol esters (12-O-tetradecanoyl-phorbol-13-acetate (TPA)). A stable Chinese hamster ovary (CHO)-anx6 cell line overexpressing annexin 6 was established to examine the function of annexin 6. In these cells, no increase of Ras-GTP levels, induced by EGF or TPA, was detected. In addition, the activity of Raf was completely inhibited, whereas the mitogen-activated protein kinase-P was unaffected.

Animals↗
PubMed2001

Stereoisomerism of molecular multipropellers. 1. Static stereochemistry of bis- and tris-triaryl systems.

The static stereoisomerism of bis- and tris-triaryl systems has been analyzed by a systematic stereochemical analysis, and the resulting theoretical predictions have been experimentally confirmed by using reversed-phase HPLC and ESR and (1)H NMR spectroscopies with a family of seven distinct polychlorinated aromatic multipropellers. To analyze the static stereochemistry of these molecules, we have developed a specific procedure that uses a symmetry-adapted symbolic notation, allowing the theoretical prediction of both the number and symmetry of the isomers of the investigated molecules. Due to the steric hindrance introduced by the presence of bulky chlorine substituents, (all) conformational isomers can be characterized experimentally by several independent techniques confirming the theoretical stereochemical predictions. The different propeller moieties that constitute the molecule appear to be nearly independent of each other. Consequently, most of the observed isomers show comparable populations in solution at room temperature.

Journal Article↗
PubMed2001

Stereoisomerism of molecular multipropellers. 2. Dynamic stereochemistry of bis- and tris-triaryl systems.

The dynamic stereochemistry of bis- and tris-triaryl systems, the most simple "molecular multipropellers", is discussed on the basis of an extension of a systematic stereochemical analysis based on a symmetry-adapted symbolic notation developed specifically for these molecules. A suitable theoretical basis for our study is provided by the classical hypotheses concerning the dynamics of simple triaryl systems as formulated by Mislow and co-workers (J. Am. Chem. Soc. 1973, 95, 1535-1547), which, once applied to molecular multipropellers, show the existence of two modes of rearrangement for each propeller. Interconversion graphs for all molecules under study, covering a wide span of structural complexity, are presented. A complete NMR study of a two- and a three-propeller molecule indicates that all experimentally observable exchange pathways are indeed predicted by theoretical analysis. Moreover, quantitative analysis of 2D-EXSY experiments affords the activation energy of the subset of pathways that give rise to observable interconversions on the NMR time scale. Assuming that two-ring flips are the threshold mechanism for individual propeller interconversion, the experimental evidence indicates a preference for the flip of the central ring and one of the outer rings over the flip of two outer rings.

Journal Article↗
PubMed2001

Wine phenolic antioxidants inhibit AP-1 transcriptional activity.

Some of the beneficial effects of moderate wine consumption may be related to the antioxidant properties of polyphenolic compounds containing tannins, flavonoids, and phenolic acids. Cellular actions have recently been reported and may involve the modulation of transcriptional factors such as AP-1 (activator protein-1), which controls the expression of various genes implicated in inflammation processes, cell differentiation, and proliferation. The aim of this study was to evaluate the modulation of AP-1 activity by the phenolic acids (gallic, caffeic, protocatechic, paracoumaric, sinapic, and ferulic acids) that are present in wine and to compare their modulating pathways to those of lipophilic or hydrophilic "chain-breaking" antioxidants (such as DL-alpha-tocopherol or trolox) vitamin C, nitric oxide, and reduced glutathione. AP-1 response was studied on a cell line (MTLN) derived from MCF-7 cells transfected with luciferase gene under TRE sequence control. After stimulation by phorbol 12-myristate 13-acetate (PMA; 100 nM, 6 h, 10(-7) M), luciferase activity was determined by a luminescence method in the presence of luciferine/coenzyme A solution using a luminometer (LKB 1251, Finland). Antioxidants to be tested were incubated with cells in the presence or absence of PMA. Stimulation with PMA resulted in an AP-1-mediated increase in luciferase gene expression corresponding to an 8-fold increase in luciferase activity. After stimulation by PMA, a dose-dependent inhibition of AP-1 was observed with the six phenolic acids in the 20 nM-20 microM concentration range: gallic acid > caffeic > protocatechic, paracoumaric, sinapic acids > ferulic acid. Inhibition was more pronounced with phenolic acids than with DL-alpha-tocopherol (IC(50) = 5 +/- 4.5 microM for gallic acid vs 85 +/- 11 microM for vitamin E). None of the hydrophilic antioxidants inhibited PMA-induced AP-1 activation. None of the antioxidants tested in the absence of PMA stimulation induced any activation or inhibition of AP-1. Our results suggest that phenolic acids may act directly on cell signaling via inhibition of AP-1 transcriptional activity. In addition to preventing LDL oxidation in the arterial wall, our observations indicate that phenolic acids have a cell-mediated capacity to prevent some of the processes involved in atherosclerosis in a plasma concentration range compatible with nutritional intakes.

Antioxidants↗