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P Dumas

Publications and source records attributed to P Dumas.

At least 19 recordsLinked to original sources
PubMed2004

Phasing in the presence of severe site-specific radiation damage through dose-dependent modelling of heavy atoms.

The case of a brominated RNA crystal structure determination in which standard three-wavelength MAD phasing was unsuccessful because of fast X-ray-induced debromination was reinvestigated [Ennifar et al. (2002), Acta Cryst. D58, 1262-1268]. It was found that if the data are kept unmerged and if a dose-stamp is associated with each reflection measurement, dose-dependent occupancies can be refined for the Br atoms. Such a parametrization has been implemented in the macromolecular phasing program SHARP. Refining such dose-dependent occupancies on an unmerged data set gave a dramatic improvement, even for SAD phases from only the first wavelength (peak), and resulted in a good electron-density map after solvent flattening. The adverse effect of radiation damage has been turned into a beneficial one. The crucial difference is made by the use of unmerged data: phasing power is generated through the intensity differences of symmetry-related reflections recorded at different doses, i.e. corresponding to different states of the X-ray-induced debromination. This approach should prove useful in all situations of experimental phasing where site-specific radiation damage occurs unavoidably and undesirably and not only in cases in which radiation damage is purposely being created in order to demonstrate its potential usefulness.

Binding Sites↗
PubMed2004

Imaging capabilities of synchrotron infrared microspectroscopy.

It has become increasingly clear that synchrotron infrared micro-spectroscopy is an extremely valuable analysis tool when determining the chemical composition of biological and biomedical samples, at the diffraction-limited spatial resolution. Highly resolved infrared micro-spectroscopy, together with the high signal-to-noise level of the recorded spectra, is essential in generating chemical and statistical (multivariate) images. This is illustrated in the case of individual cell and hair section studies. Unprecedented chemical images of lipid distribution and secondary structure relative concentration have been achieved using the synchrotron source. A comparison with a Focal plane Array imaging system, on the same hair section, shows that, despite the fast imaging processing and improved quality achieved with the focal plane array detectors, spectral quality is markedly superior in the case of the synchrotron source. It is clear that the two approaches could be very complementary if combined on the same sample area, in a synchrotron facility.

Algorithms↗
PubMed2004

New aspects of the alpha-helix to beta-sheet transition in stretched hard alpha-keratin fibers.

The putative transformation of alpha-helices into beta-sheets has been studied for more than 50 years in the case of hard alpha-keratin. In a previous study of stretched keratin fibers, we specified the conditions for beta-sheet appearance within horsehair: the formation of beta-sheets requires at least 30% relative humidity. However, this phenomenon was observed in the whole tissue. Then there was no clear chemical identification of the beta-sheets (keratin or matrix proteins) and the exact location of the beta-sheets across the fiber could not be specified. In this study, using wide-angle x-ray scattering and high spatial resolution infrared microspectroscopy, we could determine and characterize the structural elements across hair sections stretched in water, which provides new information about the aforementioned transition. Our results show that the process can be split into three steps: 1), unraveling of the alpha-helical coiled-coil domains, which starts at roughly 5% macroscopic strain; 2), further transformation of the unraveled coiled-coils into beta-sheet structures, which occurs above roughly 20% macroscopic strain; and 3), spatial expanding of the beta-structured zones from the sample center to its periphery.

Animals↗
PubMed2003

Microbeam synchrotron imaging of hairs from ancient Egyptian mummies.

Developments in microfocus synchrotron techniques have led to new results regarding the long-term alteration of archaeological samples of biological origin. Here, ancient hair samples from two Egyptian mummies have been analyzed using a conjunction of structural and elemental synchrotron methods. In this favored context of conservation, structural analysis revealed a remarkable preservation of keratin supramolecular organization at any observed length scale. Bulk keratin structure has therefore not been modified significantly over 2000 years. However, infrared spectroscopy indicated a partial disorganization of keratins close to the hair surface through polypeptide bond breakage. Elemental mapping showed a strongly heterogeneous distribution which can be related to mummification and cosmetic treatments.

Archaeology↗
PubMed2003

[Internal carotid artery dissection after Heimlich maneuver].

We report a case of cervical artery dissection following a Heimlich maneuver. Cervical artery dissections are at the present time well known and are sometimes associated with trivial traumas. However, to our knowledge, this complication of such maneuver was never reported in the literature. Pathophysiological mechanisms are discussed.

Airway Obstruction↗
PubMed2003

Monitoring of umbilical cord blood lead levels and sources assessment among the Inuit.

Analyses completed on samples collected between 1993 and 1996 showed that about 7% of 475 Inuit newborns from northern Quebec (Canada) had a cord blood lead concentration equal to or greater than 0.48 micromol/l, an intervention level adopted by many governmental agencies. A comparison between the cord blood lead isotope ratios of Inuit and southern Quebec newborns showed that lead sources for these populations were different. Our investigation suggests that lead shots used for game hunting were an important source of lead exposure in the Inuit population. A cohort study conducted in three Inuit communities shows a significant decrease of cord blood lead concentrations after a public health intervention to reduce the use of lead shot. Lead shot ammunition can be a major and preventable source of human exposure to lead.

Cohort Studies↗
PubMed2002

X-ray-induced debromination of nucleic acids at the Br K absorption edge and implications for MAD phasing.

Multi-wavelength anomalous dispersion (MAD) using brominated derivatives is considered a common and convenient technique for solving chemically synthesized nucleic acid structures. Here, it is shown that a relatively moderate X-ray dose (of the order of 5 x 10(15) photons mm(-2)) can induce sufficient debromination to prevent structure determination. The decrease in bromine occupancy with radiation dose can be accounted for by a simple exponential, with an estimated rate constant at the absorption-peak wavelength, 7.4 (0.8) MGy, that is not significantly different from its value at the absorption-edge wavelength, 9.2 (2.6) MGy (the given e.s.d.s assess the relative closeness of the two values, not their absolute accuracy, which is probably worse). Chemically, these results (and others) are consistent with bromine cleavage resulting from direct photodissociation and/or from the action of free electrons, rather than from the action of hydroxyl radicals originating from water dissociation. The free bromine species (Br(-)) diffuse too quickly, even in amorphous ice around 100 K, to allow the determination of a diffusion coefficient. From a practical point of view, it is suggested that a single data collection with a crystal consisting of iodinated instead of brominated derivatives could provide both anomalous scattering and SIR phase information by the progressive cleavage of iodine.

Bromine↗
PubMed2002

Chromosomal mapping of HCaRG, a novel hypertension-related, calcium-regulated gene.

We recently identified a novel gene that is negatively regulated by extracellular calcium concentration with higher levels of transcripts in hypertensive animals (SHR). We named this gene HCaRG (Hypertension-related, Calcium-Regulated Gene). In this work we report the chromosomal localization of the HCaRG gene among different species. We identified a BglII RFLP between BN.lx and SHR rats. We then analysed the strain distribution pattern of this RFLP in 31 RIS, originating from BN.lx and SHR rats, and compared it to the segregation of 475 markers localized in the rat genetic map. Hcarg localizes to the rat chromosome 7 between the markers Mit3 and Mit4. This region is homologous to human chromosome 8q21-24. We identified three clones in Genbank that contain the sequence of HCaRG. It was therefore possible to narrow down the localization of human HCaRG to chromosome 8q24.3. Furthermore, a suggestive localization of mouse Hcarg based on conservation of linkage between human and mouse is on chromosome 15. We previously identified a putative calcium-binding motif (EF-Hand) and a nuclear receptor-binding domain (LxxLL) in the rat sequence of the HCaRG protein. Sequence comparison between five different species showed that these domains are highly conserved. Furthermore, a search of ESTs in Genbank for homologous sequences showed that HCaRG is expressed only in eukaryotes, particularly in mammals.

Adaptor Proteins, Signal Transducing↗
PubMed2002

[Hallucinations, delusions, and nocturnal events in 152 Parkinson's patients: a regional survey].

Parkinson's disease cannot be reduced to its motor symptoms. Psychological and behavioral disorders often accompany its development. Our study was conducted in June 1999 among 36 neurologists practicing in hospital or private clinic settings in the Poitou-Charentes area. Neurologists were requested to record hallucinations, delusions and nocturnal events observed in Parkinson's patients. A total of 152 reports were collected from 17 physicians. Fifty-three percent of the patients attended hospital clinics and 47p.100; were seen at the physician's office. Hallucinations were recorded in 23.1p.100; of the patients. The risk of hallucination symptoms was higher among patients seen at hospital clinics and who had more advanced disease. Only 7.2p.100; of the patients reported delusions, most often of a persecution type. Nocturnal events affected 49.3p.100; of the patients. The appearance of such symptoms was highly related to Hoehn and Yahr stage and was more frequent in hospital patients. Hallucinations, delusions, and nocturnal events affect patients with advanced Parkinson's disease, associated with long-term L-dopa treatment. Eighty-three percent of the patients had such symptoms and most of them used L-dopa. This long-term treatment is linked to these three symptoms. Hallucinations were increasingly reported for patients with increasing long-term medication with dopaminergic agonists. Nocturnal events, for patients on L-dopa, were associated with advanced disease, long-term treatment with L-dopa, and hospitalization. Psychic and behavioral disorders appear frequently in Parkinson's disease patients and are inter-related. Physicians should be aware of the relationship with treatment to avoid aggravation.

Aged↗
PubMed2002

[Aphasic hypergraphy in the course of a bilateral hemispheric glioblastoma].

A 68-year old patient, suffering from a left temporal and right frontal multifocal glioblastoma, initially presented Wernicke's aphasia with abnormal behavior. After a stereotaxic biopsy of his right frontal lesion, the patient developed an activity of ceaseless writing associated with mutism. This hypergraphic behavior was accompanied with a production of numerous aphasic paragraphics contrasting with the mutism. Such association could evoke the rise of a suppressive activity of the right hemisphere on graphic functions linguistically organized by the left hemisphere.

Aged↗
PubMed2001

A genomic-systems biology map for cardiovascular function.

With the draft sequence of the human genome available, there is a need to better define gene function in the context of systems biology. We studied 239 cardiovascular and renal phenotypes in 113 male rats derived from an F2 intercross and mapped 81 of these traits onto the genome. Aggregates of traits were identified on chromosomes 1, 2, 7, and 18. Systems biology was assessed by examining patterns of correlations ("physiological profiles") that can be used for gene hunting, mechanism-based physiological studies, and, with comparative genomics, translating these data to the human genome.

Animals↗
PubMed2001

Detailed analysis of RNA-protein interactions within the ribosomal protein S8-rRNA complex from the archaeon Methanococcus jannaschii.

The crystal structure of ribosomal protein S8 bound to its target 16 S rRNA from a hyperthermophilic archaeon Methanococcus jannaschii has been determined at 2.6 A resolution. The protein interacts with the minor groove of helix H21 at two sites located one helical turn apart, with S8 forming a bridge over the RNA major groove. The specificity of binding is essentially provided by the C-terminal domain of S8 and the highly conserved nucleotide core, characterized by two dinucleotide platforms, facing each other. The first platform (A595-A596), which is the less phylogenetically and structurally constrained, does not directly contact the protein but has an important shaping role in inducing cross-strand stacking interactions. The second platform (U641-A642) is specifically recognized by the protein. The universally conserved A642 plays a pivotal role by ensuring the cohesion of the complex organization of the core through an array of hydrogen bonds, including the G597-C643-U641 base triple. In addition, A642 provides the unique base-specific interaction with the conserved Ser105, while the Thr106 - Thr107 peptide link is stacked on its purine ring. Noteworthy, the specific recognition of this tripeptide (Thr-Ser-Thr/Ser) is parallel to the recognition of an RNA tetraloop by a dinucleotide platform in the P4-P6 ribozyme domain of group I intron. This suggests a general dual role of dinucleotide platforms in recognition of RNA or peptide motifs. One prominent feature is that conserved side-chain amino acids, as well as conserved bases, are essentially involved in maintaining tertiary folds. The specificity of binding is mainly driven by shape complementarity, which is increased by the hydrophobic part of side-chains. The remarkable similarity of this complex with its homologue in the T. thermophilus 30 S subunit indicates a conserved interaction mode between Archaea and Bacteria.

Amino Acid Sequence↗
PubMed2001

Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors. PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status < or = 2, were entered. The starting dose of DX-8951f was 0.15 mg/m(2); the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred. RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m(2) and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m(2), grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m(2), three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m(2), DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively. CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m(2). DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m(2) for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.

Adult↗
PubMed2001

[Anterior compartment syndrome of the forearm caused by exercise: unusual cause of recurrent episodes of acute effort rhabdomyolysis].

INTRODUCTION: An effort-related compartmental syndrome is well known in the leg, but may be present infrequently, acutely or chronically in the anterior compartment of the forearm. EXEGESIS: We report a case of a 32-year-old man who presented four times after climbing exercises a bilateral compartment of the forearm, unusual because of the observation of rhabdomyolysis, but without irreversible damage. Clinical information and follow-up on two acute and 14 chronic cases were reexamined, showing a homogenous presentation. He refused fasciotomy because he stopped athletic activities. Measurement of intramuscular pressure after exertion was useful for diagnosis. CONCLUSION: A local effort-related pain must call to mind a chronic compartment syndrome of the forearm, which may risk incurring the acute form, with irreversible lesions of muscle and nerve, and possibly renal failure because of rhabdomyolysis.

Acute Disease↗
PubMed2001

Crystal structures of coaxially stacked kissing complexes of the HIV-1 RNA dimerization initiation site.

We describe the crystal structures of the RNA dimerization initiation sites (DIS) of HIV-1 subtypes A and B. Both molecules adopt a hairpin conformation, with loop sequences consisting of 272-AGGUGCACA-280 and 272-AAGCGCGCA-280, respectively. This includes a six-base self-complementary stretch (underlined) that allows homodimerization through the formation of a loop-loop, or 'kissing-loop', complex. The DISs for the two sequences have identical conformations, and the two interacting hairpins show a perfect coaxial alignment. The conserved purines, A272 and R273, are stacked in a bulged-out conformation and symmetrically join the upward and downward strands of each hairpin by crossing the helix major groove. There is good agreement between these structures and previous results from chemical probing in solution, as well as with differences in magnesium dependence for dimerization. The overall shape of the kissing-loop complex is very similar to that of the previously determined subtype A DIS duplex form. Unexpectedly, the purine R273 is the only base seen at a different position and is responsible for the difference in topology between the two forms. We propose that the transition from kissing-loop duplex could occur by a recombination mechanism based on symmetrical chain cleavage at R273 of each hairpin and subsequent cross-religation, rather than by base-pair melting and subsequent reannealing.

Base Pairing↗
PubMed2001

Outcome after combined reperfusion therapy for acute myocardial infarction, combining pre-hospital thrombolysis with immediate percutaneous coronary intervention and stent.

BACKGROUND: Primary therapies in acute myocardial infarction (thrombolysis and angioplasty) have inherent limitations which may be overcome by combining them. So far, no trial has demonstrated a clinical benefit in combining mechanical and pharmacological treatment strategies. METHODS: From January 1995 to December 1999, out of 1010 patients admitted to our institution for acute myocardial infarction, 148 had received pre-hospital full dose thrombolysis within 12 h of onset. One hundred and thirty-one patients were included and underwent immediate angioplasty and stenting when suitable, independent of the infarct-artery patency (TIMI grade flow 0-3). In-hospital outcome was assessed and clinical information was collected for a mean (+/-SD) of 2+/-1 years. RESULTS: Ninety-minute angiography revealed a patent (TIMI grade 3) infarct artery in 65 patients (49%). Immediate angioplasty was performed in 119 patients (91%) with stent implantation in 114 (96%). Angioplasty achieved TIMI 2, 3 flow in 98%, and complete patency (TIMI 3 flow) in 92%. Six other patients underwent deferred revascularization (surgery in one patient, angioplasty in five) and six received medical treatment. Stent thrombosis and reinfarction occurred in three patients (2.3%). In-hospital death occurred in six patients (4.6%), including four patients presenting with cardiogenic shock. Major bleeding was observed in 2.3% of cases. No patient had emergency surgery. Freedom from death and reinfarction at 2 years was 90% and freedom from death, reinfarction and target vessel revascularization was 83%. CONCLUSION: A strategy of combined reperfusion using full dose pre-hospital thrombolysis and immediate angioplasty with stent implantation in a non-selected acute myocardial infarction population is safe and achieves high and early patency rates. This preliminary experience suggests that a combined strategy in acute myocardial infarction may have a significant impact on both early and long-term outcomes.

Angioplasty, Balloon, Coronary↗
PubMed2001

An efficient method for solving RNA structures: MAD phasing by replacing magnesium with zinc.

The structure of a 46-nucleotide RNA complex has been successfully solved using multi-wavelength anomalous dispersion (MAD) at the zinc K edge. Taking advantage of the eight magnesium-binding sites, it has been shown that for five of them magnesium could be replaced by zinc. This resulted in an excellent 2.0 A MAD electron-density map. Zinc, in common with some other transition metals, is able to replace magnesium in RNA structures, but zinc has the advantage of its K edge being ideally located at 1.284 A. As most RNA molecules contain magnesium-binding sites, it is suggested that this method could be a valuable alternative to the use of bromo derivatives of bases, which is limited to chemically synthesizable and thus rather short RNA sequences.

Crystallography, X-Ray↗