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Biomedical subjects

C Petit

Publications and source records attributed to C Petit.

At least 109 records · Page 6Linked to original sources
PubMed1998

The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region.

Usher syndrome (USH) is an autosomal-recessive disease characterized by neurosensory deafness and progressive retinitis pigmentosa. So far, three clinical types of Usher syndrome have been defined, and are caused by defects at more than eight loci. We report the linkage analysis of seven Lebanese families with Usher syndrome, two with type I (USH1) and five with type II (USH2). We demonstrate that one family is linked to the USH1C locus, a rare form of USH1 only reported in the French Acadian population. Linkage analysis of the five USH2 families with recently mapped loci allowed us to reduce the USH2A candidate region to a very small interval flanked by D1S2646/D1S2629 and D1S2827. Furthermore, haplotype comparison between the different families suggests a founder effect for the USH2A mutation among the different Lebanese ethnic groups, while a genetic heterogeneity is noted for Usher syndrome type I.

Extracellular Matrix Proteins↗
PubMed1998

Treatment of ventilator-associated pneumonia with piperacillin-tazobactam/amikacin versus ceftazidime/amikacin: a multicenter, randomized controlled trial. VAP Study Group.

In a randomized trial conducted in 27 intensive care units, we compared the clinical efficacy and safety of piperacillin-tazobactam (TAZ; 4 g/0.5 g q.i.d.) and of ceftazidime (CAZ; 1 g q.i.d.), both combined with amikacin (7.5 mg/kg b.i.d.), as therapy for ventilator-associated pneumonia (VAP; acquired after > or =48 hours of mechanical ventilation). VAP was diagnosed with use of protected samples and quantitative cultures, and outcome was assessed blindly from treatment. Of 204 patients suspected of having VAP and randomized to a treatment arm of the study, 127 (64%) had bacteriologically confirmed infections, of which 37% were polymicrobial and 32% involved Pseudomonas aeruginosa; 115 patients (51 TAZ and 64 CAZ recipients) remained evaluable as per protocol. Clinical/bacteriologic cure rates (TAZ vs. CAZ, 51% vs. 36%; 95% confidence interval of difference, -0.2% to 30.2%), and 28-day mortality rates (16% vs. 20%) were similar; however, fewer bacteriologic failures occurred with TAZ (33% vs. 51%; P = .05). We conclude that the two regimens were of equivalent clinical efficacy in therapy for confirmed VAP.

Amikacin↗
PubMed1998

The fundamental and medical impacts of recent progress in research on hereditary hearing loss.

What would define real progress in the field of deafness research in fundamental and medical terms? In fundamental terms, progress would be measured by an improvement in our knowledge of the development and physiology of the ear. In medical terms, progress would lead to the division of the broad category of hearing defects into distinct clinical entities or subclasses, the collection of epidemiological data, the creation of molecular diagnostic tests, the improvement of genetic counselling services and the development of new therapeutics. In this review, we will introduce some general considerations on hereditary hearing loss and on the structure and function of the ear, present the rapidly emerging data on the molecular basis of syndromic and non-syndromic forms of hearing loss and comment on relevant recent progress in this field of research. Generally speaking, the isolation of genes underlying hereditary hearing loss has, as yet, had little impact on our understanding of the biology of the ear, whereas it has made major contributions to the medical field, in particular due to the recognition of two genes, Cx26 and mitochondrial 12S rRNA , as frequently underlying cases of non-syndromic hearing impairment.

Animals↗
PubMed1998

In-vivo therapeutic efficacy in experimental murine mycoses of a new formulation of deoxycholate-amphotericin B obtained by mild heating.

Heat-induced 'superaggregation' of deoxycholate-amphotericin B (AmB-DOC, Fungizone) was shown previously to reduce the in-vitro toxicity of this antifungal agent. We compared AmB-DOC with the formulation obtained by heating the commercial form (Fungizone, Bristol Myers Squibb, Paris, France) for 20 min at 70 degrees C, in the treatment of murine infections. An improvement of antifungal activity was obtained with heated AmB-DOC formulations due to a lower toxicity which allowed the administration of higher drug doses than those achievable with the commercial preparation. Single intravenous injections of heated AmB-DOC solutions were demonstrated to be two-fold less toxic than unheated ones to healthy mice. For mice infected with Candida albicans, the maximum tolerated dose was higher with heated than with unheated AmB-DOC solutions. In the model of murine candidiasis, following a single dose of heated AmB-DOC 0.5 mg/kg, 85% of mice survived for 3 weeks, whereas at this dose the immediate toxicity of the standard formulation in infected mice restricted the therapeutic efficacy to 25% survival. Both formulations were equally effective in increasing the survival time for murine cryptococcal pneumonia and meningoencephalitis. Injection of heated AmB-DOC solutions at a dose two-fold higher than the maximal tolerated dose observed with the unheated preparation (1.2 mg/kg) increased the survival time by a factor of 1.4 in cryptococcal meningoencephalitis. These results indicate that mild heat treatment of AmB-DOC solutions could provide a simple and economical method to improve the therapeutic index of this antifungal agent by reducing its toxicity on mammalian cells.

Amphotericin B↗
PubMed1998

Two cases of Townes-Brocks syndrome with previously undescribed anomalies.

Townes-Brocks syndrome is characterized by the association of anorectal, radial ray and outer ear malformations and deafness. We describe two patients affected with several typical clinical signs of Townes-Brocks syndrome in addition to growth and puberty delays and vertebral anomalies not previously reported.

Abnormalities, Multiple↗
PubMed1998

Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients.

We have studied the phenotypic impact of adaptative Gag cleavage site mutations in patient-derived human immunodeficiency virus type 1 (HIV-1) variants having developed resistance to the protease inhibitor ritonavir or saquinavir. We found that Gag mutations occurred in a minority of resistant viruses, regardless of the duration of the treatment and of the protease mutation profile. Gag mutations exerted only a partial corrective effect on resistance-associated loss of viral fitness. Reconstructed viruses with resistant proteases displayed multiple Gag cleavage defects, and in spite of Gag adaptation, several of these defects remained, explaining the limited corrective effect of cleavage site mutations on fitness. Our data provide clear evidence of the interplay between resistance and fitness in HIV-1 evolution in patients treated with protease inhibitors.

Amino Acid Sequence↗
PubMed1998

Anosmin-1 underlying the X chromosome-linked Kallmann syndrome is an adhesion molecule that can modulate neurite growth in a cell-type specific manner.

Anosmin-1 is an extracellular matrix glycoprotein which underlies the X chromosome-linked form of Kallmann syndrome. This disease is characterized by hypogonadism due to GnRH deficiency, and a defective sense of smell related to the underdevelopment of the olfactory bulbs. This study reports that anosmin-1 is an adhesion molecule for a variety of neuronal and non-neuronal cell types in vitro. We show that cell adhesion to anosmin-1 is dependent on the presence of heparan sulfate and chondroitin sulfate glycosaminoglycans at the cell surface. A major cell adhesion site of anosmin-1 was identified in a 32 amino acid (32R1) sequence located within the first fibronectin-like type III repeat of the protein. The role of anosmin-1 as a substrate for neurite growth was tested on either coated culture dishes or monolayers of anosmin-1-producing CHO cells. In both experimental systems, anosmin-1 was shown to be a permissive substrate for the neurite growth of different types of neurons. Mouse P5 cerebellar neurons cultured on anosmin-1 coated wells developed long neurites; the 32R1 peptide was found to underly part of this neurite growth activity. When the cerebellar neurons were cultured on anosmin-1-producing CHO cells, neurite growth was reduced as compared to wild-type CHO cells; in contrast, no difference was observed for E18 hippocampal and P1 dorsal root ganglion neurons in the same experimental system. These results indicate that anosmin-1 can modulate neurite growth in a cell-type specific manner. Finally, anosmin-1 induced neurite fasciculation of P5 cerebellar neuron aggregates cultured on anosmin-1-producing CHO cells. The pathogenesis of the olfactory defect in the X-linked Kallmann syndrome is discussed in the light of the present results and the recent data reporting the immunohistochemical localisation of anosmin-1 during early embryonic development.

Amino Acid Sequence↗
PubMed1998

[Etiological diagnosis of sensorineural deafness in children: a year-long review of genetic counseling for deaf people].

From February 1996 to January 1997, 74 patients from 53 sibships underwent genetic counselling for sensorineural deafness at the Pasteur Hospital, Paris, France. Genetic counselling was based on the etiological diagnosis of the hearing impairment, by an audiological and non-audiological examination program. At the first examination, 31 families presented with a familial deafness and 22 families with apparently one affected individual. However, familial audiological examinations revealed familial deafness in 5 of these 22 families. Consequently, a total of 36 families had hereditary hearing impairment and the etiological groups showed the following distribution: non-syndromic deafness (14 families), syndromic deafness (12 families), probable syndromic deafness (5 families), and incomplete assessment (5 families). Out of the remaining 17 families in which affected individuals were sporadic cases, the etiological groups were as follows: acquired deafness (2 families), probable syndromic deafness (5 families), unknown cause (5 families), and incomplete assessment (5 families). Etiological assessment is discussed, with reference to the cost-effectiveness of this examination program. In light of this preliminary report, we present a model of assessment for the etiological diagnosis of sensorineural deafness in children and young adults.

Adolescent↗
PubMed1997

Otogelin: a glycoprotein specific to the acellular membranes of the inner ear.

Efforts to identify the specific components of the mammalian inner ear have been hampered by the small number of neuroepithelial cells and the variety of supporting cells. To circumvent these difficulties, we used a PCR-based subtractive method on cDNA from 2-day-old mouse cochlea. A cDNA encoding a predicted 2910-amino acid protein related to mucin has been isolated. Several lines of evidence indicate, however, that this protein does not undergo the O-glycosylation characteristic to mucins. As confirmed by immunocytochemistry and biochemical experiments, this protein is specific to the inner ear. Immunohistofluorescence labeling showed that this protein is a component of all the acellular membranes of the inner ear: i.e., the tectorial membrane of the cochlea, the otoconial and accessory membranes of the utricule and saccule, the cupula of the semicircular canals, and a previously undescribed acellular material covering the otoconia of the saccule. The protein has been named otogelin with reference to its localization. A variety of nonsensory cells located underneath these membranes could be identified as synthesizing otogelin. Finally, this study revealed a maturation process of the tectorial membrane, as evidenced by the progressive organization of otogelin labeling into thick and spaced radial fiber-like structures.

Amino Acid Sequence↗
PubMed1997

JL 13, a potential successor to clozapine, is less sensitive to oxidative phenomena.

The oxidation behaviour of JL 13, a promising antipsychotic, was investigated in comparison with clozapine and loxapine, by measuring their direct "radical scavenging" abilities and their efficacies in inhibiting the lipid peroxidation. In the lipid peroxidation system, the reactivity of these compounds with free radicals produced by gamma-irradiation of linoleic acid may be presented as follows: JL 13 = loxapine < clozapine. In two enzymatic systems (HRP/GSH and HRP/H2O2/ GSH) which generate the thiyl free radicals, clozapine produces a strong enhancement of the thiyl-radical EPR signal intensity while JL 13 and loxapine exhibit no or minimal effect on this signal. The redox potential values for the three derivatives confirm the spectro-photometric and EPR results. Following this study, we show that JL 13, although presenting a preclinical clozapine-like profile, appears less sensitive to oxidation than clozapine.

Antipsychotic Agents↗
PubMed1997

Cloning of the genes encoding two murine and human cochlear unconventional type I myosins.

Several lines of evidence indicate a crucial role for unconventional myosins in the function of the sensory hair cells of the inner ear. We report here the characterization of the cDNAs encoding two unconventional type I myosins from a mouse cochlear cDNA library. The first cDNA encodes a putative protein named Myo1c, which is likely to be the murine orthologue of the bullfrog myosin I beta and which may be involved in the gating of the mechanotransduction channel of the sensory hair cells. This myosin belongs to the group of short-tailed myosins I, with its tail ending shortly after a polybasic, TH-1-like domain. The second cDNA encodes a novel type I myosin Myo1f which displays three regions: a head domain with the conserved ATP- and actin-binding sites, a neck domain with a single IQ motif, and a tail domain with the tripartite structure initially described in protozoan myosins I. The tail of Myo1f includes (1) a TH-1 region rich in basic residues, which may interact with anionic membrane phospholipids; (2) a TH-2 proline-rich region, expected to contain an ATP-insensitive actin-binding site; and (3) a SH-3 domain found in a variety of cytoskeletal and signaling proteins. Northern blot analysis indicated that the genes encoding Myo1c and Myo1f display a widespread tissue expression in the adult mouse. Myo1c and Myo1f were mapped by in situ hybridization to the chromosomal regions 11D-11E and 17B-17C, respectively. The human orthologuous genes MYO1C and MYO1F were also characterized, and mapped to the human chromosomal regions 17p18 and 19p13.2-19p13.3, respectively.

Amino Acid Sequence↗
PubMed1997

Expression of myosin VIIA during mouse embryogenesis.

The gene encoding myosin VIIA is responsible for the mouse shaker-1 phenotype, which consists of deafness and balance deficiency related to cochlear and vestibular neuroepithelial defects. In humans, a defective myosin VIIA gene is responsible for Usher syndrome type IB, which associates congenital deafness, vestibular dysfunction and retinitis pigmentosa. In an attempt to progress in the understanding of the function(s) of myosin VIIA, we studied the expression of the myosin VIIA gene during mouse embryonic development. Embryos from day 9 (E9) to E18 were analyzed by in situ hybridization and immunohistofluorescence. The myosin VIIA mRNA and protein were consistently detected in the same embryonic tissues throughout development. Myosin VIIA was first observed in the otic vesicle at E9, and later in a variety of tissues. The olfactory epithelium and the liver express it as early as E10. In the retinal pigment epithelium, choroid plexus, adrenal gland and tongue, expression begins at E12 and in the testis and the adenohypophysis at E13. In the small intestine, kidney and hair follicles of the vibrissae, expression of myosin VIIA starts only at E15. Myosin VIIA expression was observed only in epithelial cell types, most of which possess microvilli or cilia. Interestingly, myosin VIIA expression seems to be concomitant with the appearance of these structures in the epithelial cells, suggesting a role for this myosin in their morphogenesis. The cellular location of myosin VIIA within sensory hair cells and olfactory receptor neurons also argues for a role of this protein in the synaptic vesicle trafficking.

Adrenal Glands↗
PubMed1997

A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.

A candidate gene for Branchio-Oto-Renal (BOR) syndrome was identified at chromosome 8q13.3 by positional cloning and shown to underlie the disease. This gene is a human homologue of the Drosophila eyes absent gene (eya), and was therefore called EYA1. A highly conserved 271-amino acid C-terminal region was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern is indicative of a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches.

Adult↗
PubMed1997

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Adult↗
PubMed1997

The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene.

Hereditary non-syndromic profound deafness affects about 1 in 2000 children prior to language acquisition. In 80% of the cases, the mode of transmission is autosomal recessive. The number of genes involved in these recessive forms of isolated deafness (DFNB genes) has been estimated to between 30 and 100. So far, ten DFNB genes have been mapped to human chromosomes, one of which has been isolated. By linkage analysis of a single family whose members were affected with profound deafness, some of them presenting with vestibular dysfunction, DFNB2 has been mapped to chromosome 11q13 (ref. 3). The gene responsible for a form of Usher syndrome type I, USH1B, has been assigned to the same chromosomal region. Usher syndrome associates profound congenital deafness and vestibular dysfunction with retinitis pigmentosa. In the homologous murine region are located the shaker-1 mutations responsible for deafness and vestibular dysfunction. It has been demonstrated that the murine shaker-1 and human USH1B phenotypes result from mutations in the gene encoding myosin-VIIA. Based on mapping data as well as on the similarities between the phenotypes of DFNB2-affected patients and shaker-1 mouse mutants, we have proposed that a defective myosin-VIIA may also be responsible for DFNB2 (ref. 1). Sequence analysis of each of the coding exons of the myosin-VIIA gene (MYO7A) was thus undertaken in the DFNB2-affected family. In the last nucleotide of exon 15, a G to A transition was detected, a type of mutation that is known to decrease the efficiency of splicing. Accordingly, this result shows that different mutations in MYO7A result in either an isolated or a syndromic form of deafness.

Alleles↗