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Biomedical subjects

F Gray

Publications and source records attributed to F Gray.

At least 19 recordsLinked to original sources
PubMed1996

HIV type 1 V3 sequences and the development of dementia during AIDS.

The most frequent neurological complication of AIDS is a dementia-like syndrome. Power and collaborators (J Virol 1994; 68:4643-4649) have reported an association between the clinical signs of AIDS dementia and the amino acid composition of two positions (305 and 329) within the V3 region of HIV-1 strains amplified from brain tissue. Similarly, we analyzed position 305 in the V3 region of HIV-1 present in the brain or cerebrospinal fluid of 25 nondemented subjects at different clinical stages of HIV-1 infection. Our results are, however, at variance with the findings presented by Power and colleagues. Histidine, found to be common among sequences derived from demented patients, was also present in the majority (16 of 25) of nondemented patients analyzed by us. In the hands of Power and colleagues, sequences derived from nondemented patients contained proline at position 305. None of our patients had proline in this position. We also asked the question whether the presence of a specific amino acid at position 305 of the V3 loop is linked to an increased capacity of HIV-1 isolates to infect primary microglial cells, the major target cell for HIV-1 infection in the brain. Primary HIV-1 isolates derived from blood and cerebrospinal fluid of five patients, two asymptomatic and three AIDS patients, were used to infect microglia cell cultures. Infection was monitored by syncytium formation and by p24 antigen release in the culture supernatant. All but one of the paired blood/CSF isolates replicated in human brain cultures. Replication occurred independently from the amino acid present at position 305 of the V3 region of the viral envelope. Our results indicate that the majority of HIV-1 isolates, even derived during the asymptomatic stage, have the capacity to infect microglial cells. The relevance of viral envelope sequences in determining tropism for microglial cells and development of neurological symptoms remains an open question.

AIDS Dementia Complex↗
PubMed1996

Analysis of ENV V3 sequences from HIV-1-infected brain indicates restrained virus expression throughout the disease.

The isolation of human immunodeficiency virus type 1 (HIV-1) from the cerebrospinal fluid (CSF) of asymptomatic virus carriers suggests that the viral infection spreading to the brain occurs early during infection. The aim of the present study was to investigate whether HIV-1 infection of the brain parenchyma also occurs during the early phase of infection. We also wished to compare the degree of replication of the virus in the brain at different clinical stages associated with HIV-1 infection. With the use of polymerase chain reaction (PCR), the viral genomes present in seven of eight brain specimens obtained from two asymptomatic HIV-1 carriers and six AIDS patients were amplified. Thereafter, the number of viral copies present in each brain specimen was quantified, the third variable region (V3) of the gp 120 glycoprotein was sequenced and these results compared with the histopathological findings in the tissue. The HIV-1 DNA genome was amplified from seven of the eight brain tissues, including the specimens obtained from the two asymptomatic carriers. An increased number of viral copies in the brain was found in association with histopathological findings of HIV-1 encephalitis. The analysis of the V3 sequences, however, revealed the presence of a homogeneous virus population in the brain at every clinical stage of the disease. These results suggest that, although entry of the virus in the parenchyma may occur early during infection, HIV-1 replication in the brain is constrained until the terminal phase of AIDS encephalitis.

Adult↗
PubMed1996

Investigation on the expression of major histocompatibility complex class II and cytokines and detection of HIV-1 DNA within brains of asymptomatic and symptomatic HIV-1-positive patients.

Among the various mechanisms proposed to explain the pathogenesis of cerebral lesions in human immunodeficiency virus (HIV)-induced encephalitis, a cytokine-mediated action has found most favour. Indeed, elevated expression of cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha), thought to be neurotoxic, has been found in AIDS patients. As a previous study had demonstrated the presence of HIV proviral DNA in brain tissue of a number of HIV-positive non-AIDS patients, we undertook this present investigation using morphological, immunohistochemistry (IHC) and polymerase chain reaction (PCR) methods to detect the expression of major histocompatibility complex (MHC) class II molecules, the presence of HIV-1 proviral DNA and of the cytokines TNF-alpha, IL-1 alpha, IL-4 and IL-6 in brains of the same group of individuals. The study included brains of 36 asymptomatic HIV-1 positive patients and the results were compared with those of AIDS patients either affected by HIV encephalitis (n = 8) or exempt from any neuropathological changes (n = 10) as well as of normal controls (n = 5). Results show that: HIV proviral DNA could be detected by PCR in 17 out of the 36 brains from HIV-positive pre-AIDS cases; most (15 of 17) of PCR-positive brains showed minimal to severe expression of MHC class II antigen; and cytokines could be detected predominantly within white matter even at this early stage. The data demonstrated that the state of immune activation described in AIDS is already present at the pre-AIDS stage and suggest that the presence of cytokines may already trigger the cascade of events leading to brain damage.

AIDS Dementia Complex↗
PubMed1995

Secretion capture and report web: use of affinity derivatized agarose microdroplets for the selection of hybridoma cells.

A novel assay is described which allows the entrapment and detection of the immunoglobulin secreted from individual viable hybridoma cells using a secretion capture and reporter web (SCRW). By encapsulating the cells in agarose microdroplets which have been derivatized to create a fluorescent antigen-specific sandwich assay, flow cytometry can be used to identify and sort productive cells from a heterogeneous population. Using agarase, the cells can be recovered from the microdroplets and clonally expanded after selection. The assay has been used to reclone rare secretors from hybridoma cultures and to enhance the production of cultures with poor producers. The assay is easily generalized for the detection of any secreted protein for which specific antibodies or other ligands are available.

Animals↗
PubMed1995

Creutzfeldt-Jakob disease after liver transplantation.

We report a 57-year-old woman who died from Creutzfeldt-Jakob disease 2 years after a liver transplantation. The liver donor had no history of neurological disease. In one albumin donor, possible Creutzfeldt-Jakob disease developed 3 years later. The patient initially had cerebellar symptoms. Neuropathology included "Kuru-type" plaques and prion protein (PrP) deposits involving the cerebellum predominantly. The patient was homozygote valine at codon 129 of the PrP gene while the liver was homozygote methionine. This observation raises the possibility of transmission of Creutzfeldt-Jakob disease by the graft itself or the associated albumin transfusions and, on a wider extent, by nonneural tissue.

Creutzfeldt-Jakob Syndrome↗
PubMed1995

Parkinsonism and dilatation of the perivascular spaces (état criblé) of the striatum: a clinical, magnetic resonance imaging, and pathological study.

Two men, 89 and 83 years of age, presented with predominantly axial parkinsonian signs. In both cases, magnetic resonance imaging of the brain showed numerous small foci, delineating the striatum. The lesions had the same signal as cerebral spinal fluid in both T1 and T2 sequences. Postmortem examination of the brain showed numerous lacunes due to dilatation of the perivascular spaces, frequently associated with alterations of the surrounding brain parenchyma. Typical changes of Parkinson's disease were associated in one case. Such vascular changes may produce, or modify, a parkinsonian syndrome.

Aged↗
PubMed1995

AIDS-associated progressive multifocal leukoencephalopathy revealed by new-onset seizures.

PURPOSE: To describe the clinical features of new-onset seizures in HIV-1-infected persons with progressive multifocal leukoencephalopathy (PML), and to discuss potential mechanisms. PATIENTS AND METHODS: Forty-nine consecutive HIV-1-infected patients with PML attended our institutions between January 1988 and September 1993. We retrospectively analyzed cases with seizures as the presenting symptom of PML. RESULTS: Twenty percent of the HIV-1-infected patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had a concomitant opportunistic infection. Their mean CD4 cell count was < 60/mm3. Brain magnetic resonance imaging showed areas of increased signal intensity on T2-weighted images in 9 cases, and atrophy in only 1 case. Lesions most often involved subcortical white matter in parieto-occipital or frontal lobes, but 2 patients had posterior fossa lesions. Image-guided stereotactic brain biopsies in 8 cases and postmortem examination in 2 confirmed the diagnosis of PML. Typical histological lesions were observed in all cases, and positive immunolabelling of oligodendroglial nuclei was obtained in all cases with the polyclonal antibody directed against late SV40 antigens. Putative causative factors for the seizures include demyelinated lesions adjacent to the cerebral cortex acting as irritative foci, axonal conduction abnormalities, or disturbances of the neuron-glia balance. CONCLUSION: These cases illustrate that PML should be considered as a possible cause of new-onset seizures in patients with HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Neuronal apoptosis in HIV infection in adults.

Productive infection of the central nervous system by HIV predominantly involves the white matter and basal ganglia. Involvement of the cerebral cortex with neuronal loss is also described in AIDS patients but not in asymptomatic HIV-positive patients. The mechanism of neuronal damage is unknown. To enquire whether neuronal loss in AIDS may be due to an apoptotic process, we examined the cerebral cortex from 12 patients who died from AIDS using two different methods: in situ end labelling and gel electrophoresis of DNA to demonstrate DNA fragmentation. None of the patients had cerebral opportunistic infection or tumour. Four patients had no significant neuropathological changes, eight patients had variable cerebral atrophy and four of them also had productive HIV infection of the brain. These patients were compared with four HIV-positive asymptomatic patients, five seronegative asymptomatic controls, and two seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in the cortex in all AIDS patients, as well as in the Alzheimer's patients. Apoptosis was not observed in the asymptomatic cases whether seropositive or seronegative. Neuronal apoptosis was more severe in atrophic brains, and did not directly correlate with productive HIV infection, suggesting an indirect mechanism of neuronal damage is most likely.

Adult↗
PubMed1995

Low susceptibility of resident microglia to simian immunodeficiency virus replication during the early stages of infection.

To assess the susceptibility of resident microglia to simian immunodeficiency virus (SIV) infection, we analysed the brains of rhesus macaques after intracerebral (i.c.) inoculation of the virus into the central region at 7 days, 1, 2 and 3 months post-inoculation (p.i.). The brains of animals showed the same moderate neuropathological changes in central, frontal and parietal regions of the brain, characterized by gliosis, microglial nodules, perivascular infiltrates and occasional white matter pallor and similar low numbers of infected cells detected by in situ hybridization. These results, showing that i.c. inoculation did not lead to preferential infection of brain tissue, even near the inoculation point at 7 days p.i., provide evidence for the low susceptibility of resident microglia to SIV replication during the early stages of infection.

Animals↗
PubMed1995

[Early cerebral lesions in HIV infection. Postmortem radio-pathologic correlations in non-AIDS asymptomatic seropositive patients].

In order to evaluate the diagnostic and prognostic value of MRI in the very early stages of HIV infection, we have compared the results of postmortem brain MRI and neuropathological studies in 7 asymptomatic HIV seropositive individuals, 8 seronegative controls with similar cause of death and 6 patients who died of AIDS in the absence of focal cerebral changes (opportunistic infection or tumour). Cerebral atrophy was consistently evaluated by both techniques. Seropositive asymptomatic cases were significantly more atrophic than the seronegative controls and significantly less atrophic than AIDS patients. Small high signal intensity areas in the white matter and basal ganglia were not significantly more frequent in seropositives than in seronegatives. No corresponding lesion was found at neuropathological examination. Diffuse myelin pallor of the cerebral white matter on myelin preparation was somewhat more severe in seropositive asymptomatic cases than in seronegative controls and less than in AIDS cases. However, these differences were not statistically significant. No significant correlation could be found between neuropathological myelin pallor and diffuse signal abnormalities of the white matter on MRI. We conclude that brain abnormalities are present at the early asymptomatic stage of HIV infection. These include vasculitis with opening of the blood brain barrier and consequent myelin pallor and gliosis of the white matter, and moderate brain atrophy. However MRI correlates are discrete or non specific on post mortem examination, and some probably correspond to scars of transient vascular inflammation. It is very unlikely that MRI examination has any diagnostic or prognostic value at the early stages of the disease.

AIDS Dementia Complex↗
PubMed1995

[Imagery of human immunodeficiency virus (HIV) encephalitis].

The authors present the different aspects of HIV encephalitis in CT and MR in a series of 15 patients with anatomopathological proof. Atrophy was the most commonly found lesion (12 patients) and could rapidly be evolutive. White matter lesions (9 patients) were more of ten nodular than diffuse. They were better demonstrated by MRI and did not enhance after intra-venous injection of DOTA-gadolinium. A frequent association with opportunistic infections (toxoplasmosis: 10 patients, CMV:2 patients), lymphoma (4 patients), or PML (3 patients) was observed which emphasized the low specificity of brain imaging in patients with HIV encephalitis.

AIDS Dementia Complex↗
PubMed1995

[CMV and VZV encephalitis in AIDS].

MATERIAL AND METHODS: Eighty patients were followed up prospectively. Histological correlation was obtained in 25 cases. All MRI examinations were performed on at 0.5 Tesla in T1-weighted sequences with and without gadolinium injection, and in axial or frontal T2-weighted spin echo sequences. Histological confirmation was obtained 30 days on average after the last MRI examination. Immunohistochemical stainings were performed in search of CMV, VZV, toxoplasma, HIV antigen and lymphoma. RESULTS: CMV meningoencephalitis was found in 6 cases. In 3 of these it was manifested by atrophy, either isolated or associated with high signal intensity punctiform areas. Histology detected cortical or subcortical microglial nodules. In 2 cases MRI displayed abnormalities of subependymal nodular signals without enhancement, associated with punctiform abnormalities of subcortical signals. Histology showed subependymal foci of necrosis and abnormalities of white matter. In one case, MRI showed a ventriculitis confirmed by histology. VZV meningoencephalitis was diagnosed in 2 cases. MRI displayed abnormal basal ganglia related to meningitis (n = 1). All abnormalities were confirmed at histology. CONCLUSION: Some images (ventriculitis, infarction in basal ganglia, abnormal subependymal signal) would suggest VZV and CMV encephalitis. Other images (abnormalities of punctiform signals or atrophy) are not specific.

AIDS-Related Opportunistic Infections↗
PubMed1995

[Extracerebral metastases of a glioblastoma, in the absence of surgery].

A 50 y.o. male presented with a right parietal tumor which was a glioblastoma on stereotactic biopsy. He was treated by radiation and steroids, with clinical improvement. Four months later, he presented with a left preauricular mass and cervical lymphadenopathy. CT scan showed destruction of the left mastoid and filling of the left tympanic cavity. One month later, he suffered progressive dyspnea. Chest X ray showed a mediastinal mass on the right side and numerous bilateral interstitial opacities in the lungs. A bronchial biopsy was inconclusive. His general condition worsened, and he died. Postmortem showed continuous neoplastic infiltration of the left part of the base of skull, extending into the neck. Numerous metastases were present in mediastinal lymph nodes, lung parenchyma, pleura and pleural aspect of the diaphragm. There were no subdiaphragmatic metastases. Neuropathological examination confirmed a poorly differentiated highly malignant glioblastoma with severe necrosis involving the internal part of the parietal lobe extending to the dura mater of the convexity and falx cerebri with invasion of the superior longitudinal sinus which was entirely occluded. The biopsy scar was not infiltrated. Visceral tumors were morphologically identical to the brain tumor. They were strongly GFAP positive and cytokeratin negative. Extraneural metastases of glioblastoma in the absence of surgery are uncommon in adults. Involvement of the dura mater and/or superior longitudinal sinus is an almost constant feature. In our case, this may have led to invasion of the base of skull and secondary regional, lymphatic, and hematogenous spread.

Brain Neoplasms↗
PubMed1994

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178-->Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein.

Codon↗
PubMed1994

Creutzfeldt-Jakob disease and cerebral amyloid angiopathy.

An 83-year-old female with no personal or familial neurological history developed progressive gait and speech disturbance and left motor deficit. She suffered intractable seizures and died 3 months after the onset of neurological signs. Neuropathology showed severe spongiosis and gliosis in the cortex and basal ganglia, and diffuse cerebral amyloid angiopathy. Immunostaining for prion protein (PrP) showed intense PrP positivity in areas of confluent spongiosis and some granular staining in astrocytes. The cortical vessel walls stained positively for beta/A4 amyloid but not for PrP amyloid. Both types of amyloid were only observed in pericapillary parenchyma, in areas with severe spongiosis. There were only a few tangles and neuritic plaques in the temporal cortex; amyloid plaques were not present either by silver stains or immunostains. There was neither arteriopathic leukoencephalopathy nor cerebral hemorrhage. Immunoblot analysis of brain extracts revealed an abnormal proteinase K-resistant isoform of PrP. Association of Creutzfeldt-Jakob disease and Cerebral amyloid angiopathy in the absence of Alzheimer changes in unusual. The association of PrP and beta/A4 amyloid deposits could have been fortuitous in an 83-year-old patient. An etiopathogenic relationship between beta/A4 amyloid deposition and PrP accumulation may also be considered.

Aged↗