[Visceral leishmaniasis: a new oral treatment?].
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Antiprotozoal Agents↗
Biomedical subjects
J M Garnier
Publications and source records attributed to J M Garnier.
[Imported pediatric malaria in Marseille].
UNLABELLED: Imported malaria is frequently observed in pediatric practices within geographical areas which have a migrant population. MATERIAL AND METHODS: All the pediatric malaria cases of a university children's hospital (Marseilles, southern France) had been studied retrospectively. The period of the study was from January 1987 to December 1997. Inclusion criteria were based on clinical diagnosis criteria established by WHO. RESULTS: Three hundred and fifteen clinical cases were observed. Ninety-nine percent were confirmed by blood smears. Eighty-six percent of the patients came from the archipelago of the Comoro Islands in the Indian Ocean. Twenty percent were not given chemoprophylaxis, and 77% of the patients with chemoprophylaxis were not compliant. Fever (92%), splenomegaly (61%), vomiting and/or diarrhea (50%) were frequently observed. Neurological signs (23%), especially headaches (15%), were noted. The causative species was Plasmodium falciparum in 76%; coinfections with two species were observed in 9%. Halofantrine was commonly used for therapy (64%), but relapses were noted with this drug. No death was observed during the study. DISCUSSION: Imported pediatric malaria is rare in France. Clinical signs may lead to misdiagnosis when splenomegaly is not obvious, or when vomiting and/or diarrhea, cough or otitis occur. Diagnosis relies on blood smears. Curative medications are chloroquine or halofantrine, with special attention to heart troubles. Mefloquine is rarely used in children. Quinine is reserved for serious attacks. Concerning chimioprophylaxy, medical prescriptions should be adapted to the stay abroad, and patient compliance to medications could be improved.
Adolescent↗
Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.
Thirty newly detected mutations in the PHEX gene are reported, and pooled with all the previously published mutations. The spectrum of mutations displayed 16% deletions, 8% insertions, 34% missense, 27% nonsense, and 15% splice site mutations, with two peaks in exon 15, and 17. Since 32.8% of PHEX amino acids were conserved in the endopeptidases family, the number of missense mutations detected at non-conserved residues was smaller than expected, whereas the number of nonsense mutations observed at non-conserved residues was very close to the expected number. Compared with conserved amino acids, the changes in non-conserved amino acids may result in benign polymorphisms or possibly mild disease that may go undiagnosed.
Exons↗
Cloning of a rat brain succinic semialdehyde reductase involved in the synthesis of the neuromodulator gamma-hydroxybutyrate.
The gamma-hydroxybutyrate biosynthetic enzyme succinic semialdehyde reductase (SSR) was purified to homogeneity from rat brain. Peptides were generated by tryptic cleavage and sequenced. PCR primers were designed from the amino acid sequences of two of the peptides showing a similarity (75-85%) to a mitochondrial aldehyde dehydrogenase. A PCR-amplified DNA fragment was generated from recombinant plasmids prepared by a mass excision procedure from a rat hippocampal cDNA library and used as a probe to screen this cDNA library. One cDNA of 1341 bp had an open reading frame encoding a protein of 447 residues with a deduced molecular mass of 47967 Da. The enzyme was expressed in Escherichia coli. Immunoblotting analysis revealed the existence of a protein with the same electrophoretic mobility as the SSR purified from rat brain and with an estimated molecular mass of 45 kDa. Northern blot experiments showed that this enzyme was not expressed in the kidney or in the liver. In the brain tissue, a single but rather broad band was labelled under high stringency conditions, suggesting the presence of more than one messenger species coding for SSR. Hybridization in situ performed on brain tissue slices showed specific labelling of the hippocampus, the upper cortex layer, the thalamus, the substantia nigra, the cerebellum, the pons medulla and the olfactory tract. The recombinant enzyme showed catalytic properties similar to those of the SSR purified from rat brain, particularly in regard to its substrate affinities and Ki for inhibition by phthalaldehydic acid. Valproic acid did not inhibit the cloned SSR. This enzyme had 20-35% identity in highly conserved regions involved in NADPH binding with four other proteins belonging to the aldo-oxo reductase family.
Aldehyde Reductase↗
Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators.
NSD1, a novel 2588 amino acid mouse nuclear protein that interacts directly with the ligand-binding domain (LBD) of several nuclear receptors (NRs), has been identified and characterized. NSD1 contains a SET domain and multiple PHD fingers. In addition to these conserved domains found in both positive and negative Drosophila chromosomal regulators, NSD1 contains two distinct NR interaction domains, NID-L and NID+L, that exhibit binding properties of NIDs found in NR corepressors and coactivators, respectively. NID-L, but not NID+L, interacts with the unliganded LBDs of retinoic acid receptors (RAR) and thyroid hormone receptors (TR), and this interaction is severely impaired by mutations in the LBD alpha-helix 1 that prevent binding of corepressors and transcriptional silencing by apo-NRs. NID+L, but not NID-L, interacts with the liganded LBDs of RAR, TR, retinoid X receptor (RXR), and estrogen receptor (ER), and this interaction is abrogated by mutations in the LBD alpha-helix 12 that prevent binding of coactivators of the ligand-induced transcriptional activation function AF-2. A novel variant (FxxLL) of the NR box motif (LxxLL) is present in NID+L and is required for the binding of NSD1 to holo-LBDs. Interestingly, NSD1 contains separate repression and activation domains. Thus, NSD1 may define a novel class of bifunctional transcriptional intermediary factors playing distinct roles in both the presence and absence of ligand.
Amino Acid Sequence↗
Pediatric visceral leishmaniasis in southern France.
PURPOSE: The purposes of this study were to describe the characteristics of pediatric visceral leishmaniasis in southern France and to evaluate a new scheme of therapy. METHODS: Hospital records of 59 children with visceral leishmaniasis were retrospectively reviewed. The period of the study was from 1981 to 1997. RESULTS: All children but one lived or had previously dwelled in the south of France. None was coinfected with human immunodeficiency virus or known to be immunocompromised. The mean age was 31 months; 10 children were younger than 1 year when admitted to the hospital. The male:female ratio was 0.73. Fever and splenomegaly were present in 90 and 100%, respectively. Anemia, leukopenia and thrombocytopenia were commonly observed, especially in the youngest patients. Hypergammaglobulinemia was noted in 64%. A biopsy sample of the bone marrow was always performed, but direct microscopic examination failed to identify Leishmania in 13 (22%) cases. In these patients specific serology and genomic amplification with polymerase chain reaction were useful tools for the diagnosis. All patients were initially treated with meglumine antimonate (Glucantime). Twenty-six (44%) patients receiving the drug experienced at least one adverse event during treatment. Treatment failure occurred in six children (10%), who were subsequently cured with liposomal amphotericin B. Three additional children were treated with liposomal amphotericin B. All the children were finally cured and no death was observed. CONCLUSION: Our experience suggests that liposomal amphotericin B is effective therapy for visceral leishmaniasis in children.
Amphotericin B↗
Ligand-dependent interaction between the estrogen receptor and the human homologues of SWI2/SNF2.
The human SNF2alpha (or hbrm) and SNF2beta (or BRG1) proteins have previously been shown to enhance transcriptional activation by nuclear receptors (NRs) in cultured human cells, and to be present in SWI/SNF complexes which are thought to be involved in control of transcription by facilitating remodelling of chromatin templates. Using the yeast two-hybrid system, we now demonstrate that the N-terminal regions of hSNF2alpha and hSNF2beta, preceding the DNA-dependent ATPase domain, specifically interact with the region of the estrogen receptor (ER) which includes the ligand binding domain and the ligand-dependent activation function AF-2. These interactions are increased by estrogen, but not by the ER AF-2 antagonist hydroxytamoxifen. Furthermore, mutants of ER that lack AF-2 activity are unable to interact with hSNF2alpha and -beta. These results suggest that the human homologues of the yeast SWI2/SNF2 protein may participate in the enhancement of transcription by the ER in vivo through interactions with the AF-2 activating domain, thus leading to ligand-dependent remodelling of chromatin templates.
Binding Sites↗
Human connective tissue growth factor is expressed in advanced atherosclerotic lesions.
BACKGROUND: Atherosclerosis affects certain but not all vascular beds of the human circulation. Its molecular mechanisms are only partially understood. Human connective tissue growth factor (hCTGF) is a novel cysteine-rich, secreted polypeptide. hCTGF is implicated in connective tissue formation, which may play an important role in atherosclerosis. METHODS AND RESULTS: By using a differential cloning technique, we isolated a cDNA clone from a human aorta cDNA library, which is identical to hCTGF. Northern analysis shows that hCTGF mRNA was expressed at 50- to 100-fold higher levels in atherosclerotic blood vessels compared with normal arteries. In vascular smooth muscle cells, high-level expression of hCTGF mRNA was induced by transforming growth factor-beta 1. Using in situ hybridization and immunohistochemistry, we found that all advanced atherosclerotic lesions of human carotid arteries (eight patients; mean age, 69; age range, 57 to 85 years) and femoral arteries (two patients; mean age, 71.5 years) that we tested expressed high levels of both hCTGF mRNA and protein. hCTGF expression was localized mainly to smooth muscle cells in the plaque lesions that are negative for proliferating cell nuclear antigen staining. In addition, some CD-31-positive endothelial cells of plaque vessels expressed high levels of hCTGF mRNA and protein. hCTGF-positive cells were found predominantly in areas with extracellular matrix accumulation and fibrosis. In contrast, in normal arteries, we were unable to detect either hCTGF mRNA or immunoreactive hCTGF protein. CONCLUSIONS: In the present study, we have shown for the first time that both hCTGF mRNA and protein are expressed in human arteries in vivo and that hCTGF may represent a novel factor expressed at high levels specifically in advanced lesions and may play a role in the development and progression of atherosclerosis.
Adult↗
Neurologic onset of Behçet's disease: a diagnostic enigma in childhood.
Neuro-Behçet's disease, which is uncommonly reported in childhood, encompasses a wide variety of clinical features since any part of the neuraxis may be involved. It carries a serious prognosis and represents a leading cause of death or severe disability. Neuro-Behçet's disease may occur in 5% to 50% of adults with Behçet's disease and is usually subsequent to other systemic manifestations. In this report, we express the possibility of a primary neurologic presentation of Behçet's disease in childhood with pseudotumor cerebri and meningoencephalitis as exclusive initial features. We focus on diagnostic problems when major features of Behçet's disease are missing at the outset. We emphasize the high sensitivity of magnetic resonance imaging to make the diagnosis of cerebral vasculitis or thrombosis with a good reliability to clinical features.
Adolescent↗
Role of the retinoic acid receptor beta (RARbeta) during mouse development.
Homozygous RAR beta mutants are growth-deficient, but are fertile and have a normal longevity. They display homeotic transformations and malformations of cervical vertebrae and a retrolenticular membrane. This latter abnormality arises from the persistence and hyperplasia of the primary vitreous body. In contrast, we found that abnormalities of cranial nerves IX and X which were previously proposed to be specific features of the RAR beta mutant phenotype (Luo et al., Mech. Dev. 53: 61-71, 1995) occur with the same low penetrance in wildtype littermates. Although the RAR beta protein is expressed at high levels in the striatum and interdigital mesenchyme, the brain and limbs of RAR beta mutants appear morphologically normal. RAR alpha/RAR beta double mutants display numerous visceral abnormalities, most of which are incompatible with post-natal life. The majority of these abnormalities was previously detected in RAR alpha/RAR beta2 mutants with the notable exceptions of agenesis of the stapedial (2nd aortic arch-derived) artery, thymic and spleen agenesis and abnormal inferior vena cava. RAR beta/RAR gamma double mutants show major ocular defects including a shortening of the ventral retina and pre-natal retinal dysplasia, both of which represent the only abnormalities of the fetal vitamin-A deficiency (VAD) syndrome not previously detected in RAR beta2/RAR gamma compound mutants. In addition, RAR beta is apparently functionally redundant with either RAR alpha or RAR gamma for the formation of a small subset of craniofacial skeletal elements, as well as for eyelid development and digit separation. We also provide evidence that, at least in some instances, this phenomenon of functional redundancy between RARs may be an artifactual consequence of gene knock-out.
Animals↗
A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors.
Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate complex effects on development, differentiation and homeostasis. They regulate the transcription of their target genes through binding to cognate DNA sequences as homodimers or heterodimers. The molecular mechanisms underlying transcriptional activation by NRs are still poorly understood, although intermediary factors (mediators) appear to be involved in mediating the transactivation functions of NRs. TIF1 has been identified previously as a protein that interacts specifically with the ligand binding domain of several nuclear receptors, both in yeast and in vitro. The characteristics of these interactions have led us to suggest that TIF1 might be a mediator of the NR ligand-inducible activation function AF-2. Using a two-hybrid screening in yeast, we have now identified two TIF1-binding proteins, mHP1 alpha and mMOD1, that are mouse homologues of the Drosophila heterochromatinic protein 1. Using mHP1 alpha as a bait in a second two-hybrid screening, we have isolated cDNAs encoding proteins that are also very likely to be involved in chromatin structure and function, as well as a protein structurally and functionally related to TIF1 (renamed TIF1 alpha), which was named TIF1 beta. Here we discuss how the function of members of the TIF1 family in the control of transcription could be exerted at the level of the structure of the chromatin template.
Amino Acid Sequence↗
[Vaccination against type B Haemophilus influenzae in the Bouches du Rhône district. Value and practice].
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Child, Preschool↗
Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1.
Using a yeast two-hybrid system we report the isolation of a novel mouse protein, mSUG1, that interacts with retinoic acid receptor alpha (RAR alpha) both in yeast cells and in vitro in a ligand- and AF-2 activating domain (AF-2 AD)-dependent manner and show that it is a structural and functional homologue of the essential yeast protein SUG1. mSUG1 also efficiently interacts with other nuclear receptors, including oestrogen (ER), thyroid hormone (TR), Vitamin D3 (VDR) and retinoid X (RXR) receptors. By comparing the interaction properties of these receptors with mSUG1 and TIF1, we demonstrate that: (i) RXR alpha efficiently interacts with TIF1, but not with mSUG1, whereas TR alpha interacts much more efficiently with mSUG1 than with TIF1, and RAR alpha, VDR and ER efficiently interact with mSUG1 and TIF1; (ii) the amphipathic alpha-helix core of the AF-2 AD is differentially involved in interactions of RAR alpha with mSUG1 and TIF1; (iii) the AF-2 AD cores of RAR alpha and ER are similarly involved in their interaction with TIF1, but not with mSUG1. Thus, the interaction interfaces between the different receptors and either mSUG1 or TIF1 may vary depending on the nature of the receptor and the putative mediator of its AF-2 function. We discuss the possibility that mSUG1 and TIF1 may mediate the transcriptional activity of the AF-2 of nuclear receptors through different mechanisms.
Adenosine Triphosphatases↗
[Hypoglossia-hypodactylia syndrome: apropos of a case with maxillo-mandibular synostosis, glossopalatine ankylosis and cleft palate].
BACKGROUND: The hypoglossia-hypodactylia syndrome, a combination of limb hypogenesis and micrognathia is exceptionally associated with glossopalatine ankylosis and cleft palate. CASE REPORT: A twin girl from monochorionic pregnancy had hypoglossia and micrognathia with anterior maxillo-mandibular fusion, glossopalatine ankylosis and cleft palate. Her left foot was amputated distal to the talus and calcaneous; her right foot had only one phallange. The second phallange of the second finger was hypoplastic on her right hand. There was no abnormality on left hand. Her sister was unaffected. The maxillo-mandibular fusion was divided on second day. The infant was able to suckle on the tenth day. Episodes of airway obstruction occurred on cardiorespiratory recording and the patient was further monitored at home. CONCLUSION: This case suggests that the hemodynamic disorders due to multiple vascular connections from monochorionic pregnancies may have induced ischemic lesions of hypoglossia-hypodactylia. Other malformations and signs of brain stem dysfunction should be detected.
Abnormalities, Multiple↗
[Resistance of Leishmania infantum to Glucantime: risk factors and therapeutic management].
BACKGROUND: Resistance to antimonial drugs is rarely observed in immunocompetent patients. CASE REPORT: A 1-year-old girl was admitted suffering from persistent fever. A diagnosis of visceral leishmaniasis was made. The patient was given two courses of meglumine antimoniate (Glucantime) (60 mg/kg/d for 15 days) and one course of 12 injections of pentamidine (4 mg/kg). She relapsed 8 months later and failed to respond to Glucantime. Immunological tests performed during the relapse showed a suppression of the T cell response to Leishmania antigen and no production of interferon gamma. The patient was then successfully given liposomal amphotericin B (3 mg/kg/d for 10 days). She was asymptomatic 9 months later and had acquired specific cellular immunity against Leishmania. CONCLUSION: Deficient cell-mediated immunity and interferon gamma production are some factors responsible for decreased sensitivity to antimonial drugs. The WHO recommendations treating visceral leishmaniasis with prolonged administration of Glucantime may prevent relapses. Liposomal amphotericin B could be an alternative treatment.
Animals↗
Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.
Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.
Adolescent↗
A screening method to identify genes commonly overexpressed in carcinomas and the identification of a novel complementary DNA sequence.
We describe a differential screening method for cDNA libraries which used a combination of subtracted and PCR-amplified cDNA probes, and which can be applied to the selection of genes expressed in multiple tissues. This technique was used to identify genes commonly overexpressed in breast and basal cell carcinomas. These represent stromally dependent, invasive tumors with and without metastatic capacity. Thus, this screening sought to identify genes involved in the early stages of tumor progression. We identified a total of 16 genes, including c-erbB-2 and tissue inhibitor of metalloproteinases 3 whose products have been implicated in tumorigenesis or invasion. We also identified a novel sequence (D52) showing little homology with others described in any species, which maps to the human chromosomal band 8q21. In situ RNA hybridizations of breast carcinoma sections indicated that the D52 gene was expressed in cancer cells, whereas other genes identified in the differential screening were expressed in fibroblastic or inflammatory cells within the tumor stroma. Thus, the procedure developed in this study selected genes expressed in a diversity of cell types, indicating its potential usefulness in other systems.
Amino Acid Sequence↗
The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18.
Nuclear receptors (NRs) bound to response elements mediate the effects of cognate ligands on gene expression. Their ligand-dependent activation function, AF-2, presumably acts on the basal transcription machinery through intermediary proteins/mediators. We have isolated a mouse nuclear protein, TIF1, which enhances RXR and RAR AF-2 in yeast and interacts in a ligand-dependent manner with several NRs in yeast and mammalian cells, as well as in vitro. Remarkably, these interactions require the amino acids constituting the AF-2 activating domain conserved in all active NRs. Moreover, the oestrogen receptor (ER) AF-2 antagonist hydroxytamoxifen cannot promote ER-TIF1 interaction. We propose that TIF1, which contains several conserved domains found in transcriptional regulatory proteins, is a mediator of ligand-dependent AF-2. Interestingly, the TIF1 N-terminal moiety is fused to B-raf in the mouse oncoprotein T18.
Amino Acid Sequence↗