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D Dormont

Publications and source records attributed to D Dormont.

At least 127 records · Page 7Linked to original sources
PubMed1999

Incubation period of Creutzfeldt-Jakob disease in human growth hormone recipients in France.

OBJECTIVE: To estimate the statistical distribution of the incubation period of Creutzfeldt-Jakob disease (CJD) in human growth hormone (hGH) recipients in France. BACKGROUND: Published papers suggest that the median incubation period of hGH-related CJD is approximately 15 years, but there are as yet no statistical data that support this assertion. METHODS: Of the 1,361 hGH recipients who were included in this study, 55 had developed CJD at the time of the study. Individual data on hGH treatment history were available. Different mathematical models were used to estimate the statistical distribution of the incubation period. One main feature of the models was to take into account the occurrence of future CJD cases. RESULTS: Models showed that the mean incubation period was 9 to 10 years, and the 95th percentile of the distribution was 15 to 16 years. Data and models indicated that the incubation period was significantly shorter in homozygotes at codon 129 of the prion protein gene than in heterozygotes. CONCLUSIONS: The short mean incubation period of CJD in French hGH recipients may be due to high infectivity in hormone lots. Estimates of the 95th percentile indicate that the number of hGH-related CJD cases may continue to increase in the coming years.

Creutzfeldt-Jakob Syndrome↗
PubMed1999

[Biology of the transmissible agent responsible for subacute spongiform encephalopathies].

Transmissible spongiform encephalopathies, also called prion diseases, are brain degenerative ailments. These diseases, that are either infectious, or genetic, or sporadic in origin, are characterised by the accumulation of a host protein, the prion protein. Although the disease mainly implicates the brain, the immune system is involved in the propagation of the infectious agent which is always associated with the prion protein. This protein presents a normal structure in healthy brain but changes its conformation in association with the disease. It has been possible to reproduce some characteristics of this conversion in vitro. The protein only hypothesis is grounded on this conformational change which is correctly simulated by physico-chemical models. This hypothesis can explain most of the characteristics of prion diseases but the existence of an other element associated with infection cannot be ruled out.

Animals↗
PubMed1999

Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines.

The scrapie isoform of the prion protein (PrPres) induces neurodegeneration and gliosis in the central nervous system. These features may be reproduced in vitro on exposure of neuronal and glial cultures to PrPres and the peptide HuPr P106-126. In the present study, we investigated the role of microglial cells and astrocytes in the pathological process by studying their molecular response to PrP 106-126 exposure. PrP 106-126 elicited a specific overproduction of pro-inflammatory cytokines IL1beta and IL6 in microglial cells (but not increased expression of TNFalpha, IL10, and TGFbeta1) and over-expression of GFAP in astrocytes. These effects were strictly dependent on the ability of the peptide to form amyloid fibrils. These data strongly suggest that microglial cells contribute to prion-related neurodegenerative processes by producing proinflammatory cytokines in the brain areas of amyloid PrP deposition.

Animals↗
PubMed1999

RANTES, IFN-gamma, CCR1, and CCR5 mRNA expression in peripheral blood, lymph node, and bronchoalveolar lavage mononuclear cells during primary simian immunodeficiency virus infection of macaques.

Primary infection of macaques with pathogenic isolates of simian immunodeficiency virus (SIV) (as a model of HIV infection in humans) represents a unique opportunity to study early lentivirus/host interactions. We sought to determine whether there is a temporal relationship linking SIV replication and dissemination and the expression of the chemokine RANTES (regulated upon activation normal T cell expressed and secreted) and the SIV/HIV coreceptor CCR5 in different tissues during acute SIV infection of macaques. Four cynomolgus macaques were inoculated intravenously with a pathogenic primary isolate of SIVmac251. RT-PCR was used to monitor the expression of RANTES and CCR5 mRNA in fresh isolated mononuclear cells from blood, lymph node, and bronchoalveolar lavages. These expressions were compared to those of IFN-gamma as an indicator of the development of the immune response and to another receptor for RANTES, CCR1, which is not described as a coreceptor for SIV/HIV-1 entry. An enhancement of CCR1/CCR5 mRNA expression was noticed during primary SIVmac251 infection of macaques, mainly in tissue. In the three different compartments investigated, IFN-gamma and RANTES overexpression was noticed by the time of systemic viral replication containment. Our results put CCR5 and RANTES mRNA expression back in the context of inflammatory and immune responses to SIV primary infection.

Animals↗
PubMed1999

Macaque lymphocytes transduced by a constitutively expressed interferon beta gene display an enhanced resistance to SIVmac251 infection.

We are developing a method of gene therapy of HIV infection based on the low constitutive expression of an interferon beta (IFN-beta) gene in HIV target cells. Herein we report the first step in the development of a relevant animal model, provided by the macaque (Macaca fascicularis) infected with a pathogenic SIVmac251 isolate. To avoid the possibility of in vivo rejection of macaque lymphocytes expressing Hu IFN-beta, we have PCR-amplified and sequenced the Ma IFN-beta-coding sequence, and placed it under the control of a PstI-NruI 0.6-kb fragment of the murine H-2Kb gene promoter in the MFG-K(b)MaIFNbeta retroviral vector. Lymphocytic CEMX174 cells, transduced by coculture on packaging cells with this construct, harbored a mean of 0.07 to 1.2 copies of the IFN-beta transgene per cell, and were characterized by an IFN production ranging from 75 to 750 units per 5 x 10(5) cells per 3 days. The IFN-beta-transduced populations displayed an enhanced resistance against the pathogenic SIVmac251 isolate. Control experiments showed that the enhanced resistance could not be ascribed to the Ma IFN-beta released during the 3 days of coculture by the packaging cells, or to the mere transduction with a retroviral vector. Macaque lymphocytes transduced by the MFG-K(b)MaIFNbeta retroviral vector by coculture on packaging cells, acquired a mean number of IFN-beta transgene copies per cell ranging from 0.03 to 0.1. Such transduction led to the release of IFN-beta into the culture medium, ranging from 10 to 20 units per 5 x 10(5) cells per 3 days. This increased the anti-SIV resistance of the lymphocytes, as demonstrated by a decreased p27 antigen release into the culture medium, without affecting lymphocyte proliferation.

3T3 Cells↗
PubMed1999

Dopaminergic dysfunction in midbrain dystonia: anatomoclinical study using 3-dimensional magnetic resonance imaging and fluorodopa F 18 positron emission tomography.

OBJECTIVE: To determine the role of damage to neuronal systems, especially the dopaminergic system, in patients with symptomatic dystonia and mesencephalic lesions. DESIGN: Stereotaxic magnetic resonance imaging analysis and positron emission tomography after the administration of fluorodopa F 18. PATIENTS: Of a group of 48 patients with unilateral dystonia following a stroke, 7 patients with a well-defined midbrain lesion were selected. RESULTS: All patients had unilateral dystonic posture of an upper extremity and cerebellar dysmetria or hypotonia. Cerebellar tremor was present in 1 patient. Two patients had resting and postural tremor, which showed a marked improvement with treatment with levodopa. In patients with dystonia only, dopaminergic lesions were mostly confined to the ventromesial mesencephalon and red nucleus area, including the substantia nigra and nigrostriatal and cerebellothalamic fibers. Dystonia was severe and did not resolve with time in patients with lesions involving the nigrostriatal pathway, and the degree of dopaminergic denervation revealed by positron emission tomography was correlated with the severity of dystonia. In patients with resting and postural tremor, lesions of the dopaminergic structures were larger and located more laterally and dorsally in the pars compacta, the perirubral and retrorubral areas, and extending to the central tegmental tract. CONCLUSIONS: Dopaminergic dysfunction plays a role in the occurrence and severity of midbrain dystonia, and additional lesions to dopaminergic neurons in the perirubral and retrorubral areas result in tremor that responds to levodopa treatment.

Adolescent↗
PubMed1999

Is there a negative correlation between explicit memory and hippocampal volume?

The aim of this research was to study the relationship between explicit memory and hippocampal volume. Seventy healthy adults were administered one implicit memory test and one explicit memory (EM) test and underwent magnetic resonance imaging. The major finding was a negative correlation between the EM test and the right hippocampus/brain volume ratio (t = -0.25, P = 0.03) and the left hippocampus/brain volume ratio (t = -0.27, P = 0.02). This finding is not consistent with pathologic findings, which tend to show a relationship between decrease in memory performance and hippocampal atrophy. This discrepancy is discussed.

Adolescent↗
PubMed1999

Bilateral mesial temporal sclerosis: MRI with high-resolution fast spin-echo and fluid-attenuated inversion-recovery sequences.

We report a retrospective analysis of MRI in 206 patients with intractable seizures and describe the findings in bilateral mesial temporal sclerosis (MTS) on fast spin-echo (FSE) and fast fluid-attenuated inversion-recovery (fFLAIR) sequences. Criteria for MTS were atrophy, signal change and loss of the digitations of the head of the hippocampus. In patients with bilateral MRI signs of MTS, correlation with clinical electro, volumetric MRI data and neuropsychological tests, when available, was performed. Bilateral MTS was observed in seven patients. Bilateral loss of the digitations and signal change on fFLAIR was seen in all seven. In three, bilateral atrophy was obvious. In two patients, mild bilateral atrophy was observed and in two others, the hippocampi were: asymmetrical, with obvious atrophy on only one side. Volumetric data confirmed bilateral symmetrical atrophy in five patients, and volumes were at the lowest of the normal range in the other two. The EEG showed temporal abnormalities in all patients, unilateral in five and bilateral in two. All patients had memory impairment and neuropsychological data confirmed visual and verbal memory deficits; two patients failed the Wada test on both sides. High-resolution T2-weighted FSE and fFLAIR sequences allow diagnosis of bilateral MTS, which has important therapeutic and prognostic implications.

Adult↗
PubMed1999

Agents that cause transmissible subacute spongiform encephalopathies.

Transmissible spongiform encephalopathies (TSE) are characterised by a long incubation period which precedes clinical symptoms related to the degeneration of the central nervous system (CNS). The nature of their etiologic agents (TSA/prions) remains unknown, although there exists strong experimental data supporting the prion hypothesis. This hypothesis suggests a key role for the host derived protein (the prion protein, PrP) as the transmissible agent. In infected individuals, PrP accumulates proportionally to infectivity titre and resists proteinase K treatment (PrP-res). Iatrogenic Creutzfeldt-Jakob disease (CJD) cases have been described in humans after neurosurgery, treatment with pituitary derived hormones, and cornea and dura mater grafting. TSA-associated infectivity is dependent upon the nature of the organ in a given infected individual, though the CNS has the highest infectivity rate. In vitro, TSA/prions do not replicate easily: only cells of neuronal origin are susceptible, and the replication rate is very low. TSA/prions have unconventional properties; in particular, they resist to almost all the chemical and physical processes which inactivate conventional viruses. Only autoclaving at 134/136 degrees C for 1 h or treatment with either 1N NaOH or sodium hypochlorite (2% Cl) during 1 h at room temperature are considered to give inactivation that is compatible with public health criteria. In vivo, the distribution of infectivity is dependent upon strain and host, for a given inoculum injected by a given route. Although supported by numerous experimental data, the prion only hypothesis has not yet been convincingly demonstrated.

Humans↗
PubMed1999

Secretion of beta-chemokines by bronchoalveolar lavage cells during primary infection of macaques inoculated with attenuated nef-deleted or pathogenic simian immunodeficiency virus strain mac251.

Primary infection of macaques with simian immunodeficiency virus (SIV) as a model of human immunodeficiency virus (HIV) infection represents a unique opportunity to investigate early lentivirus-host interactions. In order to gain insight into immunopathogenic events taking place in the lung during lentiviral infection, we analysed lymphocyte expansion in the lung and chemokine secretion by mononuclear cells obtained by bronchoalveolar lavage (BALMCs) during primary infection by a pathogenic and a non-pathogenic SIV. Two groups of cynomolgus macaques were inoculated intravenously with a fully pathogenic isolate of SIVmac251 or with an attenuated, nef-deleted, molecular clone of SIVmac251. Spontaneous MIP-1alpha, MIP-1beta and RANTES production was assessed by ELISA in supernatants of short-term cultured BALMCs. Kinetics of haematological, virological and immunological parameters were investigated simultaneously. All 11 inoculated animals became infected. Monkeys inoculated with the nef-deleted SIV clone exhibited a significantly reduced plasma virus load and a less pronounced accumulation of lymphocytes in the lung compared to monkeys infected with the pathogenic SIVmac251 isolate. Compared to pre-infection levels, we observed an increase in the levels of RANTES, MIP1-alpha and MIP1-beta production in the two groups of monkeys, by the time of peak viraemia. Strikingly, a greater enhancement of RANTES and MIP-1alpha production was detected in monkeys infected with the attenuated virus. Given the potential influence of beta-chemokines on the immune response and virus replication, such results suggest that RANTES, MIP1-alpha and MIP1-beta could contribute to the singular features of the immune response elicited during infection of macaques with an attenuated SIV.

Animals↗
PubMed1999

MS-8209, a water-soluble amphotericin B derivative, affects both scrapie agent replication and PrPres accumulation in Syrian hamster scrapie.

Amphotericin B (AmB) has been shown to delay hamster scrapie. Infectivity studies have been performed previously using AmB in order to understand the relationship between the accumulation of an abnormal isoform (PrPres) of the prion protein and 263K scrapie agent replication in the brain. The first study reported that AmB had no effect upon agent replication, although it delayed the development of both clinical signs and PrPres accumulation. However, subsequent experiments using the same model showed a significant effect both on agent replication and PrPres accumulation early in infection. This fundamental discrepancy was assumed to be linked to differences in experimental protocols. In order to unravel the issue, a new experiment has been performed encompassing different protocols and using an AmB derivative, MS-8209, that can be used at higher doses because of its lower toxicity. The findings of this study exclude the suspected differences in the protocols as the reason for previous conflicting results, and suggest strongly that these discrepancies were due to a low dose of AmB causing a 'threshold effect'. Overall, this study indicates that, in this model, PrPres cannot be dissociated from infectivity by polyene antibiotics.

Amphotericin B↗
PubMed1999

Inhibiting scrapie neuroinvasion by polyene antibiotic treatment of SCID mice.

The polyene antibiotic MS-8209 is currently one of the most effective drugs in the treatment of experimental scrapie. However, its mechanism of action and its site of intervention in the pathogenetical process of scrapie infection are largely unknown. It has been shown previously that the infection of immunodeficient SCID mice by the peripheral route provides a reliable model for direct scrapie neuroinvasion, bypassing the lymphoreticular system. Indeed, a proportion of SCID mice develop scrapie after a similar time to immunocompetent mice, despite their severe immune impairment. This model is now used to clarify the targets of MS-8209. In SCID mice, MS-8209 treatment protected against infection but did not prolong survival time. In SCID mice immunologically reconstituted prior to inoculation, the drug delayed the disease without an effect on the attack rate. These findings strongly suggest that MS-8209 acts by hampering the first step of the neuroinvasion process, i.e. the uptake of the infectious agent by peripheral nerve endings. The mechanism leading to the inhibition of agent propagation to nervous cells is discussed with regard to the properties of polyene antibiotics.

Amphotericin B↗
PubMed1999

Vertical transmission of HIV: parameters which might affect infection of placental trophoblasts by HIV-1: a review. Biomed Group on the Study of in Utero Transmission of HIV 1.

PROBLEM: To understand the mechanisms preventing and/or facilitating maternofetal transmission of human immunodeficiency virus (HIV)-1 across the placenta during pregnancy. METHODS OF STUDY: Current experimental data were reviewed. RESULTS AND CONCLUSIONS: The data about the production of cytokines by placental cells and explants, taken together with information indicating selective passage of certain HIV-1 variants across the placental trophoblast, suggest an intricate regulatory network operating at the fetomaternal interface. The data show a differential differentiation of early and late trophoblasts, as far as HIV entry routes are concerned. We believe this explains the relative predominance of the early infection window, as far as in utero infection is concerned. Whether such a differentiation state can be transiently induced on term placental trophoblasts by several differentiation agents, including cytokines, is being investigated. Whatever the results may be, it is obvious that infection of placental cells is an excellent model of passage infection by HIV of/through a mucosal barrier.

Chemokines↗
PubMed1999

Yield of fluid-attenuated inversion recovery in drug-resistant focal epilepsy with noninformative conventional magnetic resonance imaging.

PURPOSE: To determine the role in presurgical assessment and evaluate the yield of fast fluid-attenuated inversion recovery (FLAIR) sequences for patients with intractable partial epilepsy for whom conventional magnetic resonance imaging (MRI) was normal. MATERIAL AND METHODS: Forty patients were selected. Conventional MRI including spin echo T1-weighted sagittal images and fast spin echo T2-weighted axial images was normal in 33 patients and showed noninformative lesions in 7. Fast FLAIR and T2-weighted sequences were performed perpendicularly to the hippocampal long axis. RESULTS: Additional abnormalities were found in 40%. They were correlated with electroclinical data in 13 patients (32.5%) and not correlated or doubtful in 3 (7.5%). CONCLUSION: Fast FLAIR sequences brought congruent additional information in 32.5% cases and seemed useful in presurgical evaluation.

Adolescent↗