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Biomedical subjects

F Gray

Publications and source records attributed to F Gray.

At least 37 records · Page 2Linked to original sources
PubMed2000

Association of herpes simplex virus encephalitis and paraneoplastic encephalitis - a clinico-pathological study.

A 57 year-old woman developed acute limbic encephalitis and brainstem dysfunction. Anti-HU antibodies were repeatedly detected in serum and CSF. Postmortem examination showed necrotic and hemorrhagic lesions in the temporal lobes characteristic of herpes simplex virus encephalitis, which was confirmed by immunocytochemistry, and Purkinje cell loss with proliferation of Bergman glia and myelin loss in the external aspect of the dentate nuclei characteristic of paraneoplastic encephalitis. PCR-assay performed on temporal tissue extracts was positive for HSV-1. There was no identifiable neoplasm. This unusual association raises the possibility of a link between the two diseases.

Antibodies↗
PubMed2000

Corneal endothelial cell apoptosis in patients with Fuchs' dystrophy.

PURPOSE: To investigate whether apoptosis plays a notable role in degeneration of corneal endothelial cells in patients with Fuchs' dystrophy. METHODS: Forty-seven corneal buttons from 41 patients with Fuchs' dystrophy were studied. Nucleus labeling, transmission electron microscopy (TEM), and TdT-dUTP terminal nick-end labeling (TUNEL) were used to detect apoptosis. TEM and TUNEL were performed on sections of all 47 corneal buttons, and nucleus labeling was performed on the last 10 corneas. Seven human donor corneas, two corneal buttons from two patients with keratoconus, and one corneal button from a patient with interstitial keratitis were used as negative controls for detection of apoptotic endothelial cells. Negative controls were studied by means of nucleus labeling, TUNEL, and TEM. RESULTS: In the nucleus labeling assay, the average percentage of apoptotic endothelial cells was 2.65% in the Fuchs' dystrophy group (n = 10) and 0.23% in the control group (n = 10; P = 0.0003). In the TUNEL assay, labeling of some endothelial cells was observed on 42 of 47 corneas in the Fuchs' dystrophy group, whereas it was absent on most specimens of the control group. In TEM, most endothelial cell nuclei had a normal appearance, and apoptotic endothelial cells featuring condensed nucleus and decreased cell size could be observed exceptionally. Some apoptotic cells were found in the basal epithelial cell layer by means of nucleus labeling, TUNEL, and TEM in the Fuchs' dystrophy group but not in the control group. CONCLUSIONS: This study suggests that apoptosis plays an important role in endothelial cell degeneration in Fuchs' dystrophy. Because of a lack of conclusive evidence of increased endothelial apoptosis by TEM, further studies are needed to ascertain this finding.

Aged↗
PubMed1999

Increased peroxynitrite activity in AIDS dementia complex: implications for the neuropathogenesis of HIV-1 infection.

Oxidative stress is suggested to be involved in several neurodegenerative diseases. One mechanism of oxidative damage is mediated by peroxynitrite, a neurotoxic reaction product of superoxide anion and nitric oxide. Expression of two cytokines and two key enzymes that are indicative of the presence of reactive oxygen intermediates and peroxynitrite was investigated in brain tissue of AIDS patients with and without AIDS dementia complex and HIV-seronegative controls. RNA expression of IL-1beta, IL-10, inducible nitric oxide synthase, and superoxide dismutase (SOD) was found to be significantly higher in demented compared with nondemented patients. Immunohistochemical analysis showed that SOD was expressed in CD68-positive microglial cells while inducible nitric oxide synthase was detected in glial fibrillary acidic protein (GFAP)-positive astrocytes and in equal amounts in microglial cells. Approximately 70% of the HIV p24-Ag-positive macrophages did express SOD, suggesting a direct HIV-induced intracellular event. HIV-1 infection of macrophages resulted in both increased superoxide anion production and elevated SOD mRNA levels, compared with uninfected macrophages. Finally, we show that nitrotyrosine, the footprint of peroxynitrite, was found more intense and frequent in brain sections of demented patients compared with nondemented patients. These results indicate that, as a result of simultaneous production of superoxide anion and nitric oxide, peroxynitrite may contribute to the neuropathogenesis of HIV-1 infection.

AIDS Dementia Complex↗
PubMed1999

Upregulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection.

Apoptosis of neurons and glial cells has been shown to occur in the brain of patients with the acquired immune deficiency syndrome (AIDS) and was postulated as contributing to brain atrophy and white matter damage in these patients. Since apoptotic events may be induced by the Fas-Fas ligand (FasL) system, we analyzed the relevance of these molecules to cell depletion in eight brains from HIV-1-infected patients and nine HIV-1-negative controls all of whom were analyzed histopathologically. The presence of Fas and FasL in brain tissue was analyzed by PCR amplification using Fas- and FasL-specific oligonucleotide primers and immunohistochemistry. The visualization of DNA fragmentation was used to evaluate apoptosis. Fas transcripts were detected in brains from each of four AIDS patients, each of three asymptomatic HIV-1 carriers and each of two HIV-1-negative controls. In the brains from AIDS patients the level of Fas expression was higher than in asymptomatic carriers and uninfected controls. FasL transcripts were seen in three of seven HIV-1-infected brains, two AIDS cases and one asymptomatic HIV-1 carrier. The predominant Fas-expressing cells were reactive astrocytes seen in each of two AIDS patients and one pre-AIDS case, but not in HIV-1-negative controls. Occasional Fas-positive oligodendrocyte-like cells were also seen in AIDS and pre-AIDS cases. No significant expression of Fas and FasL was seen in neurons. Fas-positive reactive astrocytes were more frequent in foci of HIV-1 encephalitis (HIVE). In the same area reactive apoptotic astrocytes were seen in close vicinity to FasL-expressing CD3 T lymphocytes, suggesting that apoptosis of astrocytes is mediated by Fas-FasL. The Fas expression on glial cells in asymptomatic HIV-1 infection may indicate apoptosis already in the asymptomatic stage of HIV-1 disease. In AIDS brains expression of Fas and FasL may contribute to the loss of glial cells and indirectly to the loss of neurons.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Histological demonstration of haemosiderin deposits in lungs and liver from victims of chronic physical child abuse.

In the context of chronic physical child abuse, two entities have been described based on macroscopical and radiological criteria: the battered baby syndrome and the shaken baby syndrome. However, in some autopsy cases, clinico-radiological information may not be available. In these cases, histological examinations are necessary to look for sequelae of repeated haemorrhages, particularly in organs likely to have suffered traumatisms such as the lungs, or in organs belonging to the mononucleated macrophage resorption system, such as the liver and the spleen. We examined a series of 15 young children who died from proven chronic child abuse and compared them with 15 sex and age-matched control subjects who died from natural causes with no history of child abuse. Using Perl's stain for iron, we identified haemosiderin deposits in pulmonary, hepatic and splenic samples and the deposits were evaluated qualitatively and quantitatively. Haemosiderin deposits were significantly (P < 0.001) more abundant in the lungs and liver of the chronic abuse victims than in those of the control subjects. However, they were not significantly more abundant in the spleens of child abuse victims than in controls. We conclude that haemosiderin deposits in lungs and liver could be proposed as a marker for chronic physical child abuse. This study stresses the importance of systematic histological examination to look for pulmonary and hepatic haemosiderin deposits in cases in which chronic child abuse is suspected.

Battered Child Syndrome↗
PubMed1999

Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage.

To characterize the distribution of apoptotic neurons and their relationships with the stage of disease, a history of HIV-dementia, and the degree of productive HIV infection, microglial activation and axonal damage, we examined the brains of 40 patients. Samples of frontal and temporal cortex, basal ganglia and brain stem were taken post-mortem from 20 patients with AIDS (including three with HIV-dementia, and eight with cognitive disorders that did not fulfil the criteria for HIV-dementia), 10 HIV-positive asymptomatic cases and 10 seronegative controls. Neuronal apoptosis was demonstrated by in situ end labelling in 18 AIDS cases and two pre-AIDS cases; a single apoptotic neuron was present in the temporal cortex of a control. Semiquantitative evaluation showed that the severity of neuronal apoptosis in the cerebral cortex correlated with the presence of cerebral atrophy, but not with a history of HIV dementia. There was no global quantitative correlation between neuronal apoptosis and HIV encephalitis or microglial activation. However, there was some topographical correlation between these changes. In the basal ganglia, apoptotic neurons were much more abundant in the vicinity of multinucleated giant cells and/or p24 expressing cells. Microglial activation was constantly present in these areas. Axonal damage was identified using beta-amyloid-precursor protein (betaAPP) immunostaining in 17 AIDS and eight pre-AIDS brains. Although no global quantitative correlation could be established between axonal damage and neuronal apoptosis there was an obvious topographic correlation supporting the view that axonal damage, either secondary to local microglial activation or due to the intervention of systemic factors, may also contribute to neuronal apoptosis.

AIDS Dementia Complex↗
PubMed1999

Neuronal apoptosis in Creutzfeldt-Jakob disease.

Neuronal loss is a salient feature of prion diseases; however, its causes and mechanisms are unclear The possibility that it could occur through an apoptotic process has been postulated and is consistent with the lack of inflammation in prion disorders as supported by experimental studies. In order to test this hypothesis in humans, we examined samples of frontal and temporal cerebral cortex, striatum, thalamus, and cerebellum from 16 patients who died from Creutzfeldt-Jakob disease. They included 5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant. These were compared with age and sex matched controls. Using in situ end labelling, we identified apoptotic neurons in all the cases of Creutzfeldt-Jakob disease. A single labelled neuron was found in the eldest control. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. This supports the view that apoptosis of neurons is a feature of prion diseases and may contribute to the neuronal loss which is one of the main characteristics of these conditions. Neuronal apoptosis also correlated well with microglial activation, as demonstrated by the expression of major histocompatibility complex class II antigens, and axonal damage, as identified by beta-amyloid protein precursor immunostaining. In contrast, we found no obvious relationship between the topography and severity of neuronal apoptosis and the type, topography, and abundance of prion protein deposits as demonstrated by immunocytochemistry.

Adult↗
PubMed1999

Primary brain lymphoma cell turnover differs in patients with and without AIDS: relationships to bcl-2 expression and host cell reaction.

Primary central nervous system lymphomas (PCNSLs) are more resistant to radiotherapy and chemotherapy in AIDS (A-PCNSLs) than in non-AIDS patients (NA-PCNSLs). We investigated 23 A-PCNSLs and 24 NA-PCNSLs. Lymphoma cell kinetics (i.e. proliferation [mitotic index, MIB-1 and PCNA labeling indices], apoptosis and turnover) were determined and compared with bcl-2 and LMP-1 expression, and to the percentage of tumor-infiltrating T-lymphocytes (T-TILs) and macrophages. A-PCNSLs showed lower proliferation (p < 0.005), less apoptosis (p < 0.0001) and slower cell-turnover (p < 0.0001) than NA-PCNSLs. LMP-1 was detected in 90% of A-PCNSLs and 5% of NA-PCNSLs, a finding correlating positively with bcl-2 expression (p < 0.0007). In contrast, T-TIL counts and CD4/CD8 T-TIL ratios were similar in A-PCNSLs and NA-PCNSLs. T-TIL counts correlated negatively with proliferation indices (from p < 0.05 to p < 0.0005) in NA-PCNSLs, but not in A-PCNSLs. Macrophage counts correlated positively with apoptosis in both groups. We concluded the following: (i) A-PCNSLs are characterized by accumulation of slow-cycling, long-lived cells that might be protected from apoptosis by LMP-1 induced bcl-2 expression, and independently from the host response; (ii) NA-PCNSLs are characterized by a faster cell turnover associated with an insufficient antiproliferative host response; and (iii) A-PCNSLs and NA-PCNSLs constitute 2 entities with distinctive morphology and different kinetic profiles that could account for different responses to therapy.

Apoptosis↗
PubMed1999

Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals.

There is overwhelming evidence that invasion of the central nervous system (CNS) by HIV-1 takes place at an early stage of the infection. It has been demonstrated that HIV-1 DNA is present in brains of asymptomatic individuals. Evidence of immune activation and increased expression of cytokines suggested that neuropathological changes and neuronal and axonal damage could be the effect of the presence of the virus. The purpose of the study is to ascertain whether target cells for HIV-1 in brain of patients at early stage of the infection are the same as those found in AIDS sufferers or if the distribution seen in AIDS patients results from the late spreading of the infection from cells considered traditionally the reservoir of the virus, i.e. microglial cells. Eighteen brains, all HIV-1 DNA positive, as shown by nested polymerase chain reaction (PCR), were selected among the group of HIV-1 positive asymptomatic cases. In 6 of them, HIV-1 DNA was detected by PCR in situ. Positive cells included astrocytes and endothelial cells, in addition to microglial cells. We conclude that astrocytes and endothelial cells are already infected at an early (asymptomatic) stage of the infection and suggest that they might contribute to the damage of the CNS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Cytokine profiles of AIDS patients are similar to those of mice with disseminated Cryptococcus neoformans infection.

Cryptococcosis is an hematogenously disseminated meningoencephalitis during which the relationship between the disease severity and the immune response remains unclear. We thus analyzed, by enzyme-linked immunosorbent assay, proinflammatory (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and anti-inflammatory (IL-10) cytokine levels in plasma at the time of diagnosis in 51 AIDS patients with culture-proven cryptococcosis. We used a murine model to determine the correlation between cytokine levels and fungal burden in blood and tissues and the kinetics of the immune response and of the formation of cerebral lesions. In AIDS patients, plasma TNF-alpha and IL-10, but not IL-6, levels were significantly higher in the case of fungemia or disseminated infection than in their absence, whereas the presence of meningitis had no influence on these levels. In mice, none of these cytokines were detected within the first day after inoculation. Later on, TNF-alpha and IL-10, but not IL-6, levels in plasma correlated significantly with the fungal burden in the blood and spleen but not the brain. In the brain, cytokine levels were low compared to those in other compartments, and tissue lesions and a degree of infection similar to those observed in humans were seen, further suggesting the relevance of this experimental model. Thus, AIDS patients with cryptococcosis produce an immune response that reflects the dissemination but not the meningeal involvement. This murine model of disseminated cryptococcosis can be used to investigate the pathophysiology of cryptococcosis and new therapeutic approaches.

AIDS-Related Opportunistic Infections↗
PubMed1999

Viral load and neuropathology in the SIV model.

To investigate neuropathological processes involved in HIV infection, a longitudinal analysis of central nervous system (CNS) changes was performed using the SIV-infected macaque model. Five animals were studied during the early phase and 13 during the asymptomatic and symptomatic phases. Histopathological analyses were performed on one cerebral fixed hemisphere whereas on the other frozen hemisphere in situ hybridisation, immunohistochemistry and RT-PCR were performed. Viral load was quantified by in situ hybridisation, CD4 and CD8 T cell infiltration by immunohistochemistry and mRNA cytokine expression (IL1beta, IL2, IL6, TNFalpha, IFNgamma and TGF-beta1) by semiquantitative RT-PCR. As reported for HIV-infected humans, the neuropathological analysis of SIV infected animals revealed four distinct lesion profiles: minimal changes, early encephalitis, leukoencephalopathy and encephalitis. No relationship was found between neuropathological findings, numbers of SIV replicating cells and T cell infiltration. CNS infection was found to be an early event characterised by glial activation, an increase in the level of IL1beta, TNFalpha and IL6 mRNA expression. During the asymptomatic and symptomatic phases, IL6 and IL1beta mRNAs increase coincided with gliosis and the development of myelin lesions. The absence of relationship between neuropathological findings and viral load suggests that cerebral lesions are caused by an indirect mechanism. Inflammatory cytokine pattern associated with severe lesions show the key role of glial activation in the SIV neuropathological process.

AIDS Dementia Complex↗
PubMed1999

[Neuronal apoptosis in human prion diseases].

Neuronal loss is a salient feature of prion diseases; however, its causes and mechanisms are unclear. The possibility that it could occur through an apoptotic process has been postulated and this is consistent with the lack of inflammation in prion disorders as supported by experimental studies. In order to test this hypothesis in humans, we examined samples of frontal and temporal cerebral cortex, striatum, thalamus and cerebellum from 26 patients who died from prion diseases. They included 16 cases of Creutzfeldt-Jakob disease (5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant), and 10 cases of fatal familial insomnia including 8 homozygotes methionine/methionone at codon 129 of the prion protein gene and 2 heterozygotes. These were compared with age and sex matched controls. Using in situ end labelling, we identified apoptotic neurons in all the cases of Creutzfeldt-Jakob disease. A single labelled neuron was found in the eldest control. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. This supports the view that apoptosis of neurons is a feature of prion diseases and may contribute to the neuronal loss which is one of the main characteristics of these conditions. Neuronal apoptosis also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II antigens and axonal damage as identified by beta-amyloid protein precursor immunostaining. In contrast, we found no obvious relationship between the topography and severity of neuronal apoptosis and the type, topography and abundance of prion protein deposits as demonstrated by immunohistochemistry.

Adult↗
PubMed1999

Prion disease with octapeptide repeat insertion.

OBJECTIVE: About 8% of prion disease cases are familial and a few are due to an octapeptide repeat insertion (OPRI) in the prion protein gene. A suitable neuropathological examination has been performed in 20 cases from 9 families and in 3 isolated cases. The number of OPRI ranges from 4 to 9 multiples of 24 base-pair. METHODS: Results from routine histopathological preparations and from immunohistochemistry performed after special tissue pretreatment were compared with those of molecular genetic investigation. RESULTS: Eight cases with 4 to 7 multiples of OPRI exhibited characteristic elongated deposits in the cerebellar molecular layer, which were visible on slides prepared with antibodies against the prion protein only. Conversely, 6 cases with 8 or 9 multiples of OPRI presented typical plaques already obvious on routine preparations. CONCLUSIONS: These variable modifications in the cerebellar molecular layer deserve to be underlined, in particular the elongated deposits which are characteristic for cases presenting 4 to 7 OPRI.

Adult↗
PubMed1999

[Fatal familial insomnia].

Since its description in 1986, Fatal Familial Insomnia (FFI) became the third most common inherited prion diseases (23 described families, 3 isolated cases). It is characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. Insomnia, dysautonomia, disruption of circadian rhythms and motor dysfunctions (myoclonus, ataxia, dysarthria, spasticity) are the main clinical symptoms in the homozygote patients (met/met at codon 129). Heterozygotes have motor dysfunctions from onset and cognitive changes. Pheno-typic variability does not appear to be strictly related to codon 129 polymorphism as recently stressed in some reports. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially in the medio-dorsal and antero-ventral nuclei, without any amyloïd deposits. Some spongiosis may be seen essentially in the cerebral cortex, in patients with longer duration disease. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease. However, in these two phenotypically different diseases, two protease resistant fragments of the pathogenic PrP (PrPres) are accumulated. They differ in molecular mass. In FFI PrPres, the unglycosylated form is underrepresented. This particularity does not result from the preferential conversion of the glycosylated forms but from an inaccessibility of non glycosylated form to conversion. PrPres has been shown to be form allelic origin. Neuronal apoptosis was found to contribute to neuronal loss in FFI. Its presence correlates with neuronal loss, being invariably noticed in the thalamus and medullary nuclei. It is not correlated with PrPres accumulation. The quantity of deposits is globally low in FFI brains and rarely immunohistochemically detected. Pathogenesis of lesions and clinical signs remain to be assessed. Protein dysfunction could be hypothesized according to some clinical and experimental data as well as to the discordance between protein accumulation and programmed cell death. Neurotoxicity is also postulated. Studies on this pathology led to consider the existence of "strains" in human prion diseases. Despite remarkable advances, many issues remain unsolved in this non spongiform prion disease.

Amino Acid Substitution↗
PubMed1999

[A process of programmed cell death as a mechanisms of neuronal death in prion diseases].

Neuronal loss is a salient feature of prion diseases; however, its cause and mechanism, particularly its relationship with the accumulation of the pathogenic, protease resistant isoform PrPres of the cellular prion protein PrPc, are still unclear. A number of studies suggest that it could occur through a process of programmed cell death which is consistent with the lack of inflammation in these conditions. In this paper, we review the different techniques used to identify apoptosis of neurons, and analyse the studies demonstrating neuronal apoptosis in prion diseases, either experimentally, in animal or in human. Apoptosis of rat hippocampal neurons, in cultures exposed to a synthetic peptide homologous to the prion protein, has been identified on morphological criteria after staining by a fluorescent marker of DNA and by gel electrophoresis of neuronal DNA. Apoptosis of neurons has also been identified in vivo using in situ end labelling and electron microscopy in scrapie infected mice. In human, apoptotic neurons were identified by in situ end labelling in Creutzfeldt-Jakob Disease and in Fatal Familial Insomnia. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. Neuronal apoptosis also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II, antigens, and with axonal damage as identified by beta-amyloid protein precursor immunostaining. In contrast, there was no clear correlation between the topography and severity of neuronal apoptosis and the type, topography and abundance of prion protein deposits as demonstrated by immunohistochemistry. Similarly, within the framework of comparable phenotypes, there was no difference in the abundance and distribution of apoptotic neurons according to the aetiology whether sporadic, familial, or iatrogenic, of the disease. The pathogenetic mechanism of neuronal apoptosis remains speculative and several hypothesis have been proposed. The lack of a direct association between neuronal damage and PrPres deposition may support models of neuropathogenesis based on "loss of function" of PrPc, such as withdrawal of defined activation signals inducing programmed cell death, rather than neurotoxicity. It is also possible that PrPres is neurotoxic and the dissociation between neuronal damage and the amount of protein only reflects variations in selective neuronal vulnerability. Finally, neuronal apoptosis might be an indirect consequence of PrPres deposition. PrPres-induced dendritic or axonal damage, perhaps enhanced by consequent microglial activation, might contribute to neuronal apoptosis either due to deafferentation or to retrograde neuronal degeneration.

Animals↗
PubMed1999

[JC virus infection and lympho-plasmocytic infiltration of the central nervous system revealed by a cerebellar syndrome].

We report the case of a 74 year-old woman who had been treated since 8 years for a Waldenström's disease. She also was affected by a progressive multi-focal leukoencephalopathy. The interest of this case lies in two principal features. On the one hand, the clinical and radiological signs were restricted to the cerebellum and to the brainstem, on the other hand, brain examination revealed lymphocytes and plasma cells infiltration suggestive of an associated Bing and Neel syndrome.

Aged↗
PubMed1998

HIV-associated brain pathology: a comparative international study.

Little is known about the frequency and variation of HIV-associated brain pathology in different geographical centres. To assess whether there is an association between the frequency of disease and demographic factors we examined the neuropathological findings in four European and two American cities. The cities included London, Edinburgh, Paris, Budapest, Baltimore and Newark. Information was collected on a total of 1144 cases. HIV encephalitis was the most common observation in all the centres. although its frequency varied between them (P < 0.01). Furthermore, there were significant differences (P < 0.001) between the various categories of exposure and the frequency of HIV encephalitis in Edinburgh and other centres. The occurrence of toxoplasmosis, progressive multifocal leukoencephalolpathy (PML) and cryptococcal infection also differed between the various centres (P < 0.01). None of the findings was attributable to age, sex, or ethnic origin, but the introduction of anti-retroviral treatment, such as Zidovudine, may have been important. Overall, this study highlights geographical variability and the potential importance for group of exposure and anti-retroviral medication as factors affecting the development of various HIV-associated brain lesions.

AIDS Dementia Complex↗