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Biomedical subjects

F Gray

Publications and source records attributed to F Gray.

At least 19 recordsLinked to original sources
PubMed1998

Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS.

The chemokine receptors CCR5 and CXCR4 are co-receptors together with CD4 for human immunodeficiency virus (HIV)-1 entry into target cells. Macrophage-tropic HIV-1 viruses use CCR5 as a co-receptor, whereas T-cell-line tropic viruses use CXCR4. HIV-1 infects the brain and causes a progressive encephalopathy in 20 to 30% of infected children and adults. Most of the HIV-1-infected cells in the brain are macrophages and microglia. We examined expression of CCR5 and CXCR4 in brain tissue from 20 pediatric acquired immune deficiency syndrome (AIDS) patients in relation to neuropathological consequences of HIV-1 infection. The overall frequency of CCR5-positive perivascular mononuclear cells and macrophages was increased in the brains of children with severe HIV-1 encephalitis (HIVE) compared with children with mild HIVE or non-AIDS controls, whereas the frequency of CXCR4-positive perivascular cells did not correlate with disease severity. CCR5- and CXCR4-positive macrophages and microglia were detected in inflammatory lesions in the brain of children with severe HIVE. In addition, CXCR4 was detected in a subpopulation of neurons in autopsy brain tissue and primary human brain cultures. Similar findings were demonstrated in the brain of adult AIDS patients and controls. These findings suggest that CCR5-positive mononuclear cells, macrophages, and microglia contribute to disease progression in the central nervous system of children and adults with AIDS by serving as targets for virus replication.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Peripheral neuropathy in human immunodeficiency virus-infected patients with the diffuse infiltrative lymphocytosis syndrome.

A subset of human immunodeficiency virus (HIV)-infected patients develop persistent CD8 hyperlymphocytosis and a Sjogren's syndrome-like syndrome associated with multivisceral CD8 T-cell infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV-infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV-infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA-DR5 and 1 was HLA-DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T-cell lymphoma was observed during follow-up, but 2 patients developed a primary B-cell lymphoma. We conclude that DILS neuropathy represents HIV-associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host-determined and antigen-driven response to HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons.

Detection of apoptotic neurons and microglial cells in the brains of human immunodeficiency virus type 1 (HIV-1)-infected patients has suggested that programmed cell death may be implicated in the physiopathology of HIV-1 encephalopathy. To analyze in vitro the intracellular signals induced by HIV-1 in human neurons and the associated neuronal death, we tested cultured human central nervous system (CNS) cells for apoptosis induced by HIV-1 and gp120 and for signaling pathways activated by gp120. HIV-1 and gp120 induced apoptosis of neurons and microglial cells but not of astrocytes or transformed microglial cells. Gp120 activated c-Jun N-terminal kinase (JNK) and p42 extracellular-regulated kinase (ERK) in primary CNS cells, with an early peak of activation at 2 to 5 minutes that was not present when pure microglial or astrocyte cultures were tested, followed by a late and sustained activation (10 and 60 minutes) in primary and enriched glial cell cultures as well as in transformed microglial cells. This demonstrates that gp120 could be an effector of HIV-1-induced apoptosis in the CNS and act directly on neuronal and glial cells.

AIDS Dementia Complex↗
PubMed1997

Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies.

Giant cell arteritis (GCA) usually manifests as a transmural vascular infiltrate of mononuclear and multinucleated giant cells (MNGC). We describe six patients with GCA associated with severe cerebral amyloid angiopathy (CAA), all with cerebral hemorrhage or varying degrees of cerebral infarct, and histological evidence of Alzheimer's disease (cortical CAA often predominating over senile plaques and neurofibrillary tangles). One case showed mostly cortical involvement (with old microhemorrhages), and the others were primarily leptomeningeal (with involvement of the underlying cortex and extensive encephalomalacia of adjacent brain). Many vessels with CAA exhibited a pronounced adventitial and perivascular infiltrate of lymphocytes, histiocytes, and MNGC. Immunohistochemical staining showed deposition of beta/A4 peptide primarily in the thickened media of CAA vessels, and within the cytoplasm of MNGC--suggesting phagocytosis of insoluble peptide. Cystatin C antibody stained vascular amyloid and diffusely highlighted astrocytic and MNGC cytoplasm. HAM56-positive macrophages were frequently seen around amyloid-laden vessels. Anti-smooth muscle actin immunohistochemistry suggests the occurrence of medial destruction by amyloid, with relative preservation of intimal cells. Ultrastructural studies performed in one case confirmed the presence of intracytoplasmic amyloid in MNGC. The GCA seen in these cases of CAA most likely represents a foreign body response to amyloid proteins, causing secondary destruction of the vessel wall. DNA from brain tissues of five affected patients was examined to assess whether mutations were present in exon 17 of the APP gene or exon 2 of the cystatin C gene, a finding that might explain the foreign body giant cell response to amyloid proteins in these cases. However, restriction fragment mapping of amplified gene segments showed that previously described mutations were not present in these cases.

Actins↗
PubMed1997

Pathology of the central nervous system in Chester-Erdheim disease: report of three cases.

Chester-Erdheim disease is a rare form of non-Langerhans cell histiocytosis consisting of disseminated xanthogranulomatous infiltration and fibrosis that primarily involves the bones, visceral organs and systemic fatty spaces. Involvement of the central nervous system is variable, and neuropathological features have seldom been documented. We report the neuropathological findings in 3 autopsy cases. One patient had radiological and pathological bone changes characteristic of Chester-Erdheim disease. Neuropathology revealed multiple characteristic xanthogranulomas disseminated in the cerebral hemispheres, hypothalamus, cerebellum, and brainstem. The second patient presented first with cutaneous lesions characteristic of Langerhans cell histiocytosis. She subsequently developed bone abnormalities suggestive of Chester-Erdheim disease, which was confirmed by autopsy, raising the possibility of a common spectrum of histiocytosis including both diseases. Gross examination of the brain was normal, however, microscopy showed infiltration of the brain by characteristic non-Langerhans cell xanthogranulomas. The third patient presented with systemic features characteristic of Chester-Erdheim disease. Neurological signs included gait disturbance, seizures and confusion. Examination of the brain did not show any histiocytic infiltration, but did show changes suggestive of Hallervorden-Spatz syndrome. Association of Chester-Erdheim disease and Hallervorden-Spatz syndrome has not been previously reported. The relationship between both conditions is unclear.

Adult↗
PubMed1997

Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS.

The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.

Amyloid beta-Protein Precursor↗
PubMed1997

JC virus detection in the cerebrospinal fluid of AIDS patients with progressive multifocal leucoencephalopathy and monitoring of the antiviral treatment by a PCR method.

Twenty-four cerebrospinal fluid (CSF) samples from 19 AIDS patients with neurological signs were analysed by the polymerase chain reaction (PCR) for the presence of JC virus (JCV). Eleven of the 19 patients tested presented with progressive multifocal leucoencephalopathy (PML). Two specific JCV target sequences were used for the PCR analysis: a sequence specific for the T antigen genes from both BK virus (BKV) and JCV (PCR1) and a sequence specific for the large T antigen gene from JCV (PCR2). The JCV genome was detected in 10 of 11 patients with PML by the PCR1 method and in all 11 patients by the PCR2 method. With samples from the eight patients without PML, one positive result was obtained with the PCR1 method and this sample and another gave positive results with PCR2. Multiple CSF samples were collected from three patients with PML at different times, including after intrathecal cytarabine treatment, and were tested by the PCR2 method for the presence of the JCV genome. The PCR result became negative for two of the three patients during the cytarabine treatment. However, the absence of a PCR signal was not associated with clinical improvement in these patients. The PCR method is useful for the detection of JCV in CSF samples and in the diagnosis of PML. However, the application of PCR for monitoring the effect of treatment remains to be established.

AIDS-Related Opportunistic Infections↗
PubMed1997

Bacterial infections.

The organisms that produce bacterial infections of the nervous system in tropical regions are similar to those existing in the rest of the world. However, because of poor socio-economic conditions in the former areas, preventing the implementation of appropriate prophylactic and therapeutic measures, the incidence and course of these diseases may vary. In this paper the neuropathological appearances of the main bacterial diseases are reviewed and the main differences between those occurring in developed and developing countries emphasized. Despite great efforts by governments and communities, tuberculosis still remains a scourge in many countries and leprosy has not been eradicated from earth. Earlier optimism that antibiotics could finally put an end to syphilis have been dashed and the disease still persists. Moreover, the explosion of AIDS not only has produced a recrudescence of many of these diseases, but has also changed their clinical and pathological presentation.

Bacterial Infections↗
PubMed1997

Diagnostic imaging contribution in the early stages of HIV infection of the brain.

The neuropathology of full-blown, symptomatic AIDS, established in many large autopsy series, has been described in great detail and is now universally accepted. In contrast, the natural history of the changes occurring in the central nervous system during the earlier states of HIV-1 infection remains poorly understood. With specific regard to MR imaging, structural abnormalities have been reported early in the course of the illness, with variable incidence, making it difficult to appreciate the significance of these findings, in particular for neurologically asymptomatic individuals. This article analyzes successively neuropathologic studies at the early stages of brain involvement by HIV and shows how imaging techniques contribute to the understanding of what is going on during the so-called "asymptomatic" period, lasting from seroconversion to symptomatic AIDS. The complementary use of clinical imaging and new technical modalities, such as proton spectroscopy MR imaging or functional MR imaging, will provide more specific and sensitive analyses. Animal studies also will contribute in the future by providing a better knowledge of the natural history of the illness and providing a means for testing the efficacy of new medication.

Brain↗
PubMed1997

Diagnostic Imaging Contribution in the Early Stages of HIV Infection of the Brain

The neuropathology of full-blown, symptomatic AIDS, established in many large autopsy series, has been described in great detail and is now universally accepted. In contrast, the natural history of the changes occurring in the central nervous system during the earlier states of HIV-1 infection remains poorly understood. With specific regard to MR imaging, structural abnormalities have been reported early in the course of the illness, with variable incidence, making it difficult to appreciate the significance of these findings, in particular for neurologically asymptomatic individuals. This article analyzes successively neuropathologic studies at the early stages of brain involvement by HIV and shows how imaging techniques contribute to the understanding of what is going on during the so-called "asymptomatic" period, lasting from seroconversion to symptomatic AIDS. The complementary use of clinical imaging and new technical modalities, such as proton spectroscopy MR imaging or functional MR imaging, will provide more specific and sensitive analyses. Animal studies also will contribute in the future by providing a better knowledge of the natural history of the illness and providing a means for testing the efficacy of new medication.

Journal Article↗
PubMed1997

[Central nervous system lesions in the early stages of HIV infection].

Early HIV-1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV-1 carriers remain neurologically unimpaired during the so-called "asymptomatic" period lasting from seroconversion to symptomatic AIDS. Therefore, very few neuropathological studies have been conducted in the early pre-AIDS stages, and the natural history of central nervous system changes in HIV-1 infection remains poorly understood. Examination of brains of asymptomatic HIV-1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV-1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T-cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood-brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also be involved. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV-1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV-1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV-1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV-1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T-lymphocytes, continuously inhibit viral replication at this stage.

Acquired Immunodeficiency Syndrome↗
PubMed1997

[Central nervous system mycoses in AIDS with the exception of cryptococcosis. Apropos of 3 anatomo-clinical cases].

Fungal infections of the central nervous system are uncommon in human immunodeficiency virus infected patients. The most frequently encountered is cerebromeningeal cryptococcosis. We report 3 clinicopathological cases of rarer fungal infections of the central nervous system in AIDS patients due to Candida and Aspergillus genders. In most cases, a systemic candida infection or aspergillus pulmonary infection preceded the onset of cerebral granulomas or abscesses. These infections usually occurred at the terminal stage of the disease and were associated with other neuropathologies. Neutropenia associated with lymphopenia represents a frequent risk factor along with intravenous catheter.

AIDS-Related Opportunistic Infections↗
PubMed1997

[Progressive multifocal leukoencephalopathy: virological and neuropathological aspects].

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease of the central nervous system due to an opportunistic infection by a polyomavirus, most often JC virus, which predominantly infects oligodendrocytes. Progressive multifocal leukoencephalopathy used to be a rare condition, usually complicating lymphoproliferative diseases. Since the onset of the AIDS epidemic, its incidence has considerably increased and HIV infection has become, by far, the main risk factor for the disease. In AIDS patients, progressive leukoencephalopathy frequently shows atypical clinical and pathological features. The development of malignant glial tumors, within demyelinating regions, in patients with progressive multifocal leukoencephalopathy, has been reported in exceptional cases. The course of progressive multifocal leukoencephalopathy is invariably fatal. The diagnosis can only be made with certainty by histopathological examination of the brain, on cerebral biopsy or at postmortem. However, neuroradiological features may be extremely suggestive in many cases and PCR seems to be a reliable technique for demonstrating viral genome in the CSF. A few antiviral treatments have been proposed, however their efficacy is difficult to assess due to the low prevalence of the disease and the occurrence of rare cases with spontaneously prolonged survival.

AIDS-Related Opportunistic Infections↗
PubMed1997

[Central nervous system infection due to varicella and zoster virus in AIDS].

We have reviewed 23 cases of varicella-zoster virus infection of the central nervous system in patients with the acquired immunodeficiency syndrome, previously reported in the literature, including 11 from our own series. This allowed us to identify 5 clinico-pathological patterns which could occur simultaneously. In most cases, viral proteins or viral genome were identified using immunocytochemistry or in situ hybridization. Multifocal encephalitis involves predominantly the white matter and is likely to be due to haematogenous spread of the infection. Ventriculitis may have variable appearance according to the course of the disease. In one incipient case, the ependymal lining appeared irregular with foci of infected ependymal cells some of which protruded into the ventricular lumen; in other instances, there was acute or chronic necrosis of the ventricular wall with marked vasculitis. Acute haemorrhagic meningo-myelo-radiculitis with necrotising vasculitis may be associated with ventriculitis and results from shedding of infected ependymal cells into the ventricular lumen and secondary seeding of the cerebrospinal fluid. Focal necrotising encephalitis or myelitis usually follows cutaneous herpes zoster in the corresponding dermatoma and is considered to result from neural spread from the diseased trigeminal or dorsal root ganglion. Vasculopathy involving leptomeningeal arteries and causing cerebral infarcts is associated with meningitis in most cases. These findings are in keeping with the observation in other immunocompromised patients, that varicella-zoster virus spread to the central nervous system may follow different routes. Our study tends to show that varicella-zoster virus infection of the central nervous system is more frequent in the acquired immunodeficiency syndrome than previously suspected and suggests this diagnosis must be considered systematically in cases of encephalitis, ventriculitis, focal myelitis, acute myeloradiculitis and cerebral infarcts in these patients, since an efficient treatment is available.

AIDS Dementia Complex↗
PubMed1997

[Central nervous system infection due to Herpes simplex virus in AIDS].

Infections of the central nervous system by Herpes simplex viruses (Herpes simplex type 1 and Herpes simplex type 2) are uncommon in acquired immune deficiency syndrome and are often clinically and pathologically atypical. We have collected 11 cases of herpes simplex encephalomyelitis in AIDS patients reported in the literature. Only 3 of these cases presented with a typical, necrotizing, limbic encephalitis. Other clinicopathological patterns included ventriculitis, rhombencephalitis and myelitis. Ventriculitis and rhombencephalitis were usually due to infection by HSV-1, whereas myelitis was mostly due to HSV-2 infection. Distinction between the 2 types of virus is often difficult by immunohistochemistry due to frequent cross reactivity and usually requires tissue culture, in situ hybridization, or polymerase chain reaction. Association of HSV encephalomyelitis with productive infection of the central nervous system by the human immunodeficiency virus was only found in one case. In contrast, co-infection with cytomegalovirus was found in 9 of the 11 cases. One case also had had varicella zoster virus vasculitis, and another case also had a cerebral malignant non Hodgkin's lymphoma in which Epstein Barr virus genome was identified. This supports the view that concomitant herpes-virus infections of the central nervous system is a characteristic feature of AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1997

[Sequences of human herpes virus type 8 and Epstein-Barr virus in AIDS-related primary central nervous system non-Hodgkin's lymphoma].

Presence of human herpes virus type 8 (HHV8), detected by nested PCR, and expression of Epstein-Barr virus (EBV), as assessed by immunochemistry and in situ hybridization, were evaluated in 20 primary non-Hodgkin immunoblastic lymphomas (NHL) of the central nervous system (CNS) from patients who died from AIDS, and in 10 samples of cerebral tissues from patients who died from AIDS, without cerebral lymphoma or Kaposi's sarcoma, as controls. Six lymphomas (30%) contained HHV8 sequences, and 19 (95%) expressed EBV; detection of HHV8 was more frequent in patients with Kaposi's sarcoma, than in other subjects (4/6 versus 2/14). Three (30%) controls contained HHV8 sequences, whereas none expressed EBV. AIDS-related CNS NHL is therefore clearly associated with EBV expression, while the presence of HHV8 appears occasional, probably associated with a low tissue viral load. The high frequency of HHV8 in AIDS-related primary CNS NHL patients with Kaposi's sarcoma suggests that this virus could play a role in the pathogenesis of some cerebral lymphomas.

AIDS-Related Opportunistic Infections↗