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Biomedical subjects

C François

Publications and source records attributed to C François.

At least 19 recordsLinked to original sources
PubMed2007

Hepatitis C Virus p7 membrane protein quasispecies variability in chronically infected patients treated with interferon and ribavirin, with or without amantadine.

A clinical study was carried out to compare the response rate of two groups of non-responder (NR) hepatitis C virus (HCV) genotype 1 chronically infected patients treated with interferon and ribavirin, with or without amantadine. The viral load decreased more markedly in the group treated by tritherapy including amantadine, but the response rate at the end of treatment was not significantly different between bitherapy and tritherapy. As amantadine could have an antiviral effect on the ion channel activity of the p7 HCV protein, the p7 quasispecies was characterized by cloning and sequencing. Sequence data were analyzed to determine the pattern and significance of p7 genetic heterogeneity and a possible relationship with therapy. Subtype differences were confirmed between p7 HCV genotypes 1a and 1b, and quasispecies analysis showed a reduction of genetic diversity in subtype 1a, but not 1b, during tritherapy. However, the absence of changes at numerous positions, as well as the conservative changes at other positions, indicated the high conservation of the p7 structure. Residue His-17, proposed to interact with amantadine, was fully conserved in both subtypes 1a and 1b, independently of amantadine administration. In conclusion, although the analysis of the p7 sequences revealed a selective pressure during therapy, no specific residues appeared to be linked to the effect of amantadine on viral decline. These results suggest that the potential antiviral effect of amantadine might be non-specific and related to a reduction in endosomal acidification and therefore reduced viral entry of HCV via its pH-dependent pathway.

Adult↗
PubMed2005

An imported case of canine rabies in Aquitaine: investigation and management of the contacts at risk, August 2004-March 2005.

In August 2004, a case of rabies was diagnosed in a puppy that had been illegally imported from Morocco to Bordeaux (France). Because a great number of people and animals were thought to have come into contact with the puppy, extensive tracing measures were implemented, and an international alert was launched to trace and treat the contacts at risk. One hundred and eighty seven people received post-exposure treatment, eight of whom also received serovaccination, and 57 animals known to have been exposed to the puppy were tested. Six months after the death of the rabid animal, none of the people treated showed any signs of rabies, nor was any secondary animal case reported. The management of this crisis highlights the importance of the role of a rapid alert system at European level. Strict application of sanitary control regulations is essential for animals introduced into EU countries, and all necessary information must be made available to EU residents travelling to rabies enzootic areas.

Adolescent↗
PubMed2004

Positive effect of the hepatitis C virus nonstructural 5A protein on viral multiplication.

Hepatitis C virus infection (HCV), is a major cause of liver disease worldwide, and are frequently resistant to the interferon alpha treatment. The nonstructural (NS) 5A protein of HCV has been proposed to be involved in this resistance. Additional studies have pointed out a role for NS5A in several other cellular interactions as well as an important role of its adaptative mutations in HCV genome replication. However, no infectious system is available to assess the role of NS5A in the HCV life cycle. Thus, we have constructed a recombinant system directly demonstrating for the first time that the expression of NS5A confers a multiplicative advantage to Sindbis virus, a virus close to HCV. This advantage seemed to be related to an anti-apoptotic effect of the NS5A protein. At a later stage, a possible nuclear localization of NS5A was observed, likely due to apoptotic cleavages of this protein. The NS5A protein was also shown to induce the interleukin-8 (IL-8) mRNA and to activate the NF-kappaB pathway independently of the Sindbis virus. Together, our data suggest that the activation of NF-kappaB could lead to the anti-apoptotic activity of NS5A and explain the viral multiplicative advantage conferred by the expression of the NS5A protein.

Apoptosis↗
PubMed2003

A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor. Comparison of cost-effectiveness between escitalopram, citalopram, fluoxetine, and venlafaxine for the treatment of depression in Norway.

This study compared the cost-effectiveness of escitalopram to that of citalopram,fluoxetine, and venlafaxine in the treatment of depression in Norway. A two-path decision analytic model with a 6-month horizon was used. Patients start at the primary path and are referred to specialist care in the secondary care path. Model inputs included drug-specific probabilities from comparative trial data, literature, and a panel of experts. The main outcome measure is success (remission), and costs of treatment (total and drug costs). Treatment with escitalopram yielded lower expected cost and greater effectiveness than citalopram, fluoxetine, and venlafaxine. The expected success rate was 64.2% with escitalopram,58.7% with citalopram, 58.7% with fluoxetine, and 62.1% with venlafaxine. Average expected total costs per patient were similar with escitalopram (19,661 Norwegian crowns) and venlafaxine (20,989) and somewhat higher with citalopram (22,379) and fluoxetine (22,558). Budgetary impact estimates a decrease in total health care budget of 72 million crowns. Escitalopram is therefore the most cost-effective alternative and its use would significantly reduce health care costs for the treatment of depression in Norway.

Journal Article↗
PubMed2003

Tremor-related activity of neurons in the 'motor' thalamus: changes in firing rate and pattern in the MPTP vervet model of parkinsonism.

The pathophysiology of parkinsonian tremor remains a matter of debate with two opposing hypotheses proposing a peripheral and a central origin, respectively. A central origin of tremor could arise either from a rhythmic activity of the internal segment of the globus pallidus (GPi) or from a structure such as the thalamus, outside the basal ganglia. In this study, single-unit recordings were performed in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys within the GPi and within three territories of the motor thalamus (delimited by their afferent inputs from the GPi, the substantia nigra and the cerebellum, respectively). For each recorded neuron, we compared the variations in firing rate and pattern in tremor and no tremor periods. Tremor either occurred spontaneously or was induced by external stimulation. When the animals entered into a tremor period we observed: (i) an increase in the mean firing rate in about half of the recorded neurons of the motor thalamus; and (ii), a change from an irregular to a rhythmic discharge within the range of tremor frequency (5-7 Hz) in about 10% of the recorded neurons of the motor thalamus (pallidal and cerebellar territories) and the GPi. Most of the thalamic neurons that exhibited a rhythmic discharge during tremor were found to be sensitive to external stimulation. Because the changes in firing rate occurred predominantly in the motor thalamus and not in the GPi, and because a fast rhythmic discharge of 10-15 Hz was frequently observed in the GPi and not in the motor thalamus, we conclude that thalamic activity is not a simple reproduction of basal ganglia output. Moreover, we suggest that thalamic processing of basal ganglia outputs could participate in the genesis of tremor, and that this thalamic processing could be influenced by sensory inputs and/or changes in attentional level elicited by external stimulation.

Action Potentials↗
PubMed2002

A pharmacoeconomic evaluation of zuclopenthixol compared with haloperidol and risperidone in the treatment of schizophrenia.

Zuclopenthixol and haloperidol are antipsychotic medications displaying different galenic forms, while risperidone is available on the market only in tablet form. The depot form presents advantages; the duration of action allows 3-4 weeks between administrations. A meta-analysis showed that zuclopenthixol patients had a higher response rate than haloperidol. A Markov model was developed to estimate the cost-effectiveness of the three antipsychotics in schizophrenia over a 5-year period. Model parameter estimates were based on a meta-analysis and literature. The viewpoint was that of the French National Health Insurance. When compared to haloperidol and risperidone, zuclopenthixol patients had additional 4 and 7 months without relapse correspondingly over a 5-year period. The estimated 5-year medical cost associated with zuclopenthixol was 800 and 1100 euros less than haloperidol and risperidone, respectively, per patient. Sensitivity analyses indicated that the results were robust to changes in key variables. The model indicates that the zuclopenthixol treatment strategy dominates haloperidol and risperidone.

Journal Article↗
PubMed2002

Optimization of exopolysaccharide production by Tremella mesenterica NRRL Y-6158 through implementation of fed-batch fermentation.

In liquid culture conditions, the yeast-like fungus Tremella mesenterica occurs in the yeast state and synthesizes an exopolysaccharide (EPS) capsule, which is eventually released into the culture fluid. It is composed of an alpha-1,3-D-mannan backbone, to which beta-1,2 side chains are attached, consisting of D-xylose and D-glucuronic acid. Potato dextrose broth (PDB) seemed to be an excellent medium for both growth of the yeast cells and synthesis of the EPS. This medium is composed solely of an extract of potatoes to which glucose was added. Yet an important disadvantage of this production medium is the presence of starch in the potato extract, since Tremella cells are not capable of metabolizing this component; furthermore, it coprecipitates upon isolation of the polymer [3]. In this respect, it was essential to remove the starch in order to achieve high polysaccharide production and recovery. A good method was the removal of starch through ultrafiltration of the PDB medium before inoculation of the strain. This resulted in an excellent starch-free medium in which other components essential for polysaccharide production were still present [3]. Through implementation of single and cyclic fed-batch fermentations with glucose feed, 1.6- and 2.2-fold increases in EPS yield were obtained, respectively. Lowering the carbon source level by using a cyclic fed-batch technique might decrease the osmotic effect of glucose or any catabolite regulation possibly exerted by this sugar on enzymes involved in EPS synthesis.

Basidiomycota↗
PubMed2002

[Experimental models of Parkinson's disease].

Parkinson's disease is a neurodegenerative condition who is related to a large loss of nigral dopaminergic neurons leading to a depletion of dopamine in the striatum. Experimental research is required in order to increase our knowledge on the cellular mechanism and functional consequences of this degenerative process. These models allow investigations of new therapeutics in order to improve the treatment of patients or to test new drugs able to protect any remaining dopaminergic neurons. It is relatively easy to obtain animal models of this disease since the target structure and the neuronal population are clearly defined. Two neurotoxic compounds are available for inducing animal models of Parkinson's disease, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A new one, rotenone, requires further investigations. Each of the neurotoxic compounds requires a specific protocol which can be used either with rodents or non-human primates. Progressive lesioning, using MPTP on green african monkeys (Cercopithecus aethiops sabaeus) provides the most reliable model of the idiopathic disease.

Animals↗
PubMed2001

Simultaneous quantitation of nucleoside HIV-1 reverse transcriptase inhibitors by short-end injection capillary electrochromatography on a beta-cyclodextrin-bonded silica stationary phase.

As part of our on-going study of the analysis and quantitation of anti-HIV nucleosides, a capillary electrochromatography (CEC) method has been developed for the simultaneous quantitation of nucleoside HIV reverse transcriptase inhibitors (NRTIs), i.e. zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC). CEC on chiral stationary phase has mainly been dedicated to the separation of enantiomers. However, this paper explores an original application of a beta-cyclodextrin-bonded silica packed column, taking advantage of the internal hydrophobicity of the polysaccharide to separate the NRTIs. The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed2000

Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson's disease patients.

The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.

Aged↗
PubMed2000

Improving accuracy in the grading of renal cell carcinoma by combining the quantitative description of chromatin pattern with the quantitative determination of cell kinetic parameters.

The determination of grade and stage in renal cell carcinomas (RCCs) often fails to predict the actual clinical outcome for individual patients. The aim of the present work was to investigate whether it is possible to significantly improve the prognostic accuracy of the grading system by using the combination of two independent computer-assisted microscopy techniques. The first technique relates to the quantitative description of morphonuclear and nuclear DNA content features by means of the image analysis of Feulgen-stained cell nuclei, and the second quantitatively characterizes tumor growth by means of different cell kinetic parameters. These parameters consist of a duplication of a time-related parameter determined by means of the technique of using silver-stained proteins in interphase nucleolar organizer regions (AgNOR), a proliferation index determined by means of MIB-1 immunohistochemistry, and an apoptotic index determined by means of the terminal dUTP nick end labeling technique. The prognostic value of these quantitative features was investigated in a series of 60 RCCs. The quantitative analysis of Feulgen-stained nuclei made it possible to identify subgroups of patients with significantly different prognoses in both grade II and grade III RCCs. We labeled the RCCs associated with the most favorable prognoses as grade II- and III- and those with the least favorable ones as grade II+ and III+. The two most important kinetic variables to identify patients with different clinical outcomes were the MIB-1 index and the mean AgNOR area in the MIB-1-positive cells. Three significantly different survival curves were obtained for the 53 grade II and III RCC patients. Our results show that conventional RCC grading can be significantly improved by the quantitative analysis of Feulgen-stained nuclei, by cell kinetic parameter determination, and, more importantly, by combining the proliferation index with the mean AgNOR area parameter.

Antigens, Nuclear↗
PubMed2000

Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Adolescent↗
PubMed2000

Metabolic effects of nigrostriatal denervation in basal ganglia.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.

Basal Ganglia↗
PubMed2000

Big prolactin 60 kDa is overexpressed in salivary glandular epithelial cells from patients with Sjögren's syndrome.

Characterization of endogenous synthesis of prolactin (PRL) proteins and their cellular localization in labial salivary glands of patients with Sjogren's syndrome (SS) were achieved. PRL, PRL-receptors (PRL-R), and S100A6 protein were detected by immunohistochemistry. In situ prolactin synthesis was investigated in controls and SS patients by ex vivo incubation of minor salivary glands biopsies and immunoprecipitation assay. Increased PRL-immunoreactivity was found in cytoplasmic acinar epithelial cells in SS patients compared with normal subjects. PRL-R was distributed only in ductal epithelial cells in which S100A6 protein (a PRL-R-associated protein) was also present. PRL, PRL-R, or S100A6-immunoreactivity was not detected in infiltrating mononuclear cells. Immunoprecipitation demonstrated that PRL synthesis occurred in minor salivary glands with increased synthesis of two distinct PRL-like proteins (one major band at 60 kDa and a minor at 16 kDa) in SS glands compared with normal glands. Expression of PRL gene was demonstrated in SS salivary glands using RT-PCR. A positive correlation was found between the presence of PRL-like proteins in acinar epithelial cells of SS patients and clinical extraglandular manifestations. The presence of anti-Ro and anti-La antibodies also positively correlated with a higher percentage of PRL in acinar epithelial cells. In conclusion, PRL-like proteins are synthetized and overexpressed in glandular epithelial cells of labial salivary glands from SS patients and correlate with the aggressiveness of the disease.

Adult↗
PubMed2000

Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis.

Hepatitis C virus (HCV) of genotype 1 is the most resistant to interferon (IFN) therapy. Here, we have analyzed the response to IFN of the human cell line UHCV-11 engineered to inducibly express the entire HCV genotype 1a polyprotein. IFN-treated, induced UHCV cells were found to better support the growth of encephalomyocarditis virus (EMCV) than IFN-treated, uninduced cells. This showed that expression of the HCV proteins allowed the development of a partial resistance to the antiviral action of IFN. The nonstructural 5A (NS5A) protein of HCV has been reported to inhibit PKR, an IFN-induced kinase involved in the antiviral action of IFN, at the level of control of protein synthesis through the phosphorylation of the initiation factor eIF2alpha (M. Gale, Jr., C. M. Blakely, B. Kwieciszewski, S. L. Tan, M. Dossett, N. M. Tang, M. J. Korth, S. J. Polyak, D. R. Gretch, and M. G. Katze, Mol. Cell. Biol. 18:5208-5218, 1998). Accordingly, cell lines inducibly expressing NS5A were found to rescue EMCV growth (S. J. Polyak, D. M. Paschal, S. McArdle, M. J. Gale, Jr., D. Moradpour, and D. R. Gretch, Hepatology 29:1262-1271, 1999). In the present study we analyzed whether the resistance of UHCV-11 cells to IFN could also be attributed to inhibition of PKR. Confocal laser scanning microscopy showed no colocalization of PKR, which is diffuse throughout the cytoplasm, and the induced HCV proteins, which localize around the nucleus within the endoplasmic reticulum. The effect of expression of HCV proteins on PKR activity was assayed in a reporter assay and by direct analysis of the in vivo phosphorylation of eIF2alpha after treatment of cells with poly(I)-poly(C). We found that neither PKR activity nor eIF2alpha phosphorylation was affected by coexpression of the HCV proteins. In conclusion, expression of HCV proteins in their biological context interferes with the development of the antiviral action of IFN. Although the possibility that some inhibition of PKR (by either NS5A or another viral protein) occurs at a very localized level cannot be excluded, the resistance to IFN, resulting from the expression of the HCV proteins, cannot be explained solely by inhibition of the negative control of translation by PKR.

2',5'-Oligoadenylate Synthetase↗
PubMed2000

Dopaminergic innervation of the pallidum in the normal state, in MPTP-treated monkeys and in parkinsonian patients.

The aim of the present study was to characterize the dopaminergic innervation of the pallidum in primates (humans and Cercopithecus aethiops). Firstly, in monkeys, biotin dextran amine was injected into dopaminergic areas, and the anterogradely labelled axons were reconstructed from serial sections and analysed in the pallidum. Secondly, in parkinsonian patients and MPTP-treated monkeys, the dopaminergic innervation of the pallidum was studied using tyrosine hydroxylase-positive fibre quantification. Our study revealed that dopaminergic areas A8 and A9 innervated the two pallidal segments. Individual axonal arborizations displayed a great heterogeneity. Some dopaminergic axons crossed the pallidum without branching, other axons made small terminal arborizations in a restricted region of one pallidal segment, whereas others developed dense arborizations covering extended areas in the two pallidal segments. This heterogeneous organization suggests that dopamine could directly modulate the pallidum using either a point-to-point or a diffuse projection pattern. A statistically significant loss of dopaminergic fibres in the internal (-43%) and external pallidum (-39.6%) of humans, and in the internal (-54.3%) and external pallidum (-59%) of monkeys was revealed in parkinsonian states. The consequences of this alteration are still unknown but it might participate in the triggering of motor symptoms observed in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Dopaminergic cell group A8 in the monkey: anatomical organization and projections to the striatum.

The first part of the study was a quantitative analysis of the distribution of A8 neurons compared with that of A9 and A10 neurons by means of tyrosine hydroxylase and calbindin-D(28K) immunohistochemistry and image analysis in monkeys. Then the striatal projection of A8 neurons was studied using retrograde and anterograde tracing methods. It was compared with that originating in cell groups A9 and A10 by performing injections of the retrograde tracer wheat germ agglutinin conjugated to horseradish peroxidase into different regions of the striatum. Ten percent of all mesencephalic dopaminergic neurons are located in cell group A8. This cell group, along with A10 and the dorsal part of A9, constitutes the dorsal tier, which accounts for 28% of mesencephalic dopaminergic neurons. Double-staining experiments showed that the neurons located in the dorsal tier were calbindin positive, whereas those from the ventral tier were not. In terms of anatomical projection, the dorsal tier mainly projects to the ventral part of the associative striatum, with preferential projections of A8 neurons to the ventrocaudal putamen, of A10 neurons to the nucleus accumbens, and of dorsal A9 neurons to both. Conversely, the main targets of the ventral tier of mesencephalic neurons (ventral part of A9) are the sensorimotor putamen and the associative caudate nucleus. In conclusion, each mesencephalic cell group projects primarily to one specific striatal region but also participates, albeit to a lesser extent, in the innervation of all the remaining striatal parts.

Animals↗