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J E Bell

Publications and source records attributed to J E Bell.

At least 55 records · Page 3Linked to original sources
PubMed1998

DNA breaks detected by in situ end-labelling in dorsal root ganglia of patients with AIDS.

Distal sensory axonal polyneuropathy (DSP) is the most frequent HIV-associated peripheral neuropathy. DSPs tend to occur in full-blown AIDS and worsen as CD4 cell counts decrease in blood. To assess a possible role for apoptosis in the pathogenesis of the neuropathy, we used in situ end-labelling (ISEL) detecting DNA strand breaks in DRG neurons of 19 HIV-infected patients, of whom nine had axonal polyneuropathy, and 11 controls. Sensory neurons with ISEL-assessed DNA breaks were observed in 9/19 patients with AIDS, 0/3 patients with pre-AIDS, and 1/11 controls. The prevalence of DNA breaks in neurons was higher in AIDS patients than in controls (P < 0.05). Among AIDS patients, DNA breaks in neurons were more abundant in patients with peripheral neuropathy (P < 0.04). It is possible that DNA breaks of DRG neurons induce the axonopathy and consequently play a role in the pathogenesis of DSP. It cannot be excluded, however, that DNA breaks could represent the result rather than the cause of axonopathy. We suggest that ISEL may detect neurons that were primed to apoptosis before death in relation with the HIV infection, and undergo DNA fragmentation at time of death, rather than neurons that underwent premortem both priming and triggering steps of the apoptotic process. This hypothesis could explain why most ISEL-positive neurons lack typical apoptotic morphology and why normal controls do not show ISEL positive cells.

Acquired Immunodeficiency Syndrome↗
PubMed1998

HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement.

In this consecutive autopsy study, the pathological evidence of HIV encephalitis, which included the presence of giant cells and/or HIV p24 immunopositivity, was found more frequently in drug users (25 of 45; 56%) than in homosexual men (6 of 35; 17%) with AIDS (P < 0.01). Productive infection, as shown by HIV p24 positivity, was found in frontal lobe white matter in 29 of the 31 HIV encephalitis cases, but was also present in grey matter in 50% of the HIV encephalitis cases. Immunopositivity was confined to microglia, monocytes and most but not all giant cells. HIV-1 proviral load was determined by quantitative PCR in 65 of the 80 cases (separately in grey and white matter in 49 of these), and correlated well with the presence of HIV encephalitis (P < 0.001). Twenty-five patients with AIDS (13 male homosexuals, 12 drug users) showed no HIV encephalitis, opportunistic infection or cerebral lymphoma, while 18 (2 male homosexuals, 16 drug users) showed pure HIV encephalitis. Cognitive function had been assessed prospectively in this cohort and graded as normal or mildly, moderately or severely impaired. Because opportunistic infections and lymphomas of the brain may also lead to dementia, patients found to have these conditions at autopsy were excluded from the final analysis of the cases with dementia, so that the precise correlation between cognitive impairment and pure HIV encephalitis could be determined in this cohort without possible confounding variables. Fourteen of 18 patients with pure HIV encephalitis had shown cognitive impairment. Severe dementia correlated better with pure HIV encephalitis in cases in which grey matter involvement was present (7 out of 9) than in those in which only white matter was involved (2 out of 9) (P < 0.05), although milder degrees of cognitive impairment had been present in a further 5 HIV encephalitis cases. No correlation was found between zidovudine therapy and the degree of cognitive impairment. Systemic and cerebral opportunistic infections and lymphoma showed a negative association with HIV encephalitis, being more common in homosexuals than in drug users, despite comparable CD4 counts in the two groups. These findings suggest that neocortical productive HIV infection is a significant factor in AIDS-related dementia, although this may reflect merely a higher overall viral burden in the brain.

AIDS Dementia Complex↗
PubMed1998

Retrospective neuropathological review of prion disease in UK haemophilic patients.

In 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.

Acquired Immunodeficiency Syndrome↗
PubMed1998

The neuropathology of adult HIV infection.

Since the onset of the acquired immune deficiency syndrome (AIDS) epidemic fifteen years ago, much has been learned about the effects of the human immunodeficiency virus (HIV) in the nervous system. This review summarizes the pathology findings in the central nervous system (CNS). There is now abundant evidence that HIV can infect the CNS directly, leading to a characteristic HIV encephalitis (HIVE) which occurs in 10-50 p. 100 of AIDS autopsy series. Multinucleated giant cells are the pathognomonic feature of HIVE and are found predominantly in the central white matter and deep grey matter. Evidence of productive HIV infection in the CNS is confined to cells of the microglial/macrophage lineage, from which the giant cells are almost certainly derived. These cells are known to express both CD4 and beta-chemokine receptors, which act in conjunction to permit HIV entry. Restricted infection of astrocytes has also been identified by a variety of methods. HIVE is frequently associated with white matter damage ranging from inflammatory (microglia, macrophages and sparse lymphocytes) to degenerative (myelin loss and axonal damage) pathology. Although giant cells are seen less frequently in neocortical grey matter, significant neuronal loss has been established in a number of studies. Recent investigations using markers of apoptosis, (including TUNEL, Bcl-2 and BAX), have established the presence of DNA damage in some neurons and in other cell types. Axonal damage has also been confirmed by evidence of amyloid precursor protein expression. The CNS is also vulnerable to opportunistic infections and high grade B-cell lymphomas as a result of the immune suppression of advanced HIV infection. Cytomegalovirus (CMV) infection is reported in 10-30 p. 100 of AIDS cases at autopsy, toxoplasma in 10-25 p. 100, progressive multifocal leucoencephalopathy in about 5 p. 100 and lymphomas, usually primary, in up to 10 p. 100. A wide variety of other infections has also been reported. These may coexist with HIVE and may be difficult to diagnose in life. CMV gives rise to microglial nodular encephalitis, ventriculitis, necrotising encephalitis and myelo-radiculitis. Presymptomatic HIV positive patients do not show HIVE or opportunistic infections or lymphomas in the CNS. They frequently display a low-grade T-cell infiltrate in the leptomeninges and parenchyma, particularly around vessels. This lymphocytic infiltrate has been attributed to presumed early invasion of the CNS by HIV although the exact timing of entry is uncertain. It is possible that reported abnormalities in presymptomatic cases such as gliosis, microglial activation and rising proviral load may anticipate the onset of HIVE but most studies show that significant CNS damage and HIV-related pathology is confined to patients with AIDS. HIV-related pathology in the spinal cord includes not only HIV myelitis, opportunistic infections and lymphomas, but also vacuolar myelopathy (VM) which affects predominantly the dorsolateral white matter tracts. The cause of VM is not understood and has not been unequivocally linked with HIV infection. It is noted that none of these neuropathological features (including HIVE) correlates exactly with the clinical expression of AIDS-related dementia (ARD). The exact contribution of macrophage activation and cytokine release, astrocytic infection, neuronal loss and axonal damage to the neuropsychiatric syndromes of advanced HIV infection remain to be determined. While the current understanding of the pathogenesis of HIVE and ARD is beyond the scope of this review it is axiomatic that accurate documentation of neuropathology findings will help to resolve the outstanding dilemmas relating to HIV infection of the CNS. There is considerable optimism that progress in therapeutic regimes for HIV-infected patients will succeed in eliminating the virus from the blood and from lymphoid tissue. (ABSTRACT TRUNCATED)

AIDS-Related Opportunistic Infections↗
PubMed1997

Enhancement of immunohistochemical detection of HIV-1 p24 antigen in brain by tyramide signal amplification.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain has been demonstrated in formalin fixed, paraffin embedded post-mortem brain tissue (PM) by chromogenic immunohistochemistry for the HIV p24 antigen. The sensitivity of antigen detection is increased significantly by tyramide signal amplification (TSA) compared to the conventional peroxidase labelled Avidin-Biotin complex (ABC) technique. The TSA method also permitted the use of a lower concentration of primary antibody than is conventionally used. Sensitivity was enhanced further by microwave irradiation of the paraffin embedded tissues in citrate buffer. HIV-1 p24 antigen was also detected in PM brain tissue by TSA enhanced immunofluorescence and demonstrated increased sensitivity compared to the conventional immunofluorescence technique with a greatly reduced autofluorescence background.

Brain↗
PubMed1997

Investigation of population diversity of human immunodeficiency virus type 1 in vivo by nucleotide sequencing and length polymorphism analysis of the V1/V2 hypervariable region of env.

In this study we have analysed variability in the V1 and V2 regions of human immunodeficiency virus type 1 (HIV-1) proviral sequences amplified from lymphoid tissue, brain and other non-lymphoid tissue collected at autopsy from three HIV-1-infected individuals with giant cell encephalitis. We found no evidence for any tissue-specific grouping of variants in the V1/V2 regions, in contrast to previous comparisons of sequences in the V3 region, but consistent with the existence of evolutionarily distinct lineages previously observed in these study subjects by sequence comparisons of the p17gag gene. Examination of inferred amino acid sequences from V1 and V2 revealed no correlations between tissue origin with overall charge, length or number of glycosylation sites. Length polymorphism analysis is a rapid method to compare whole populations of HIV-1 variants within a sample, and provides information on the length and diversity of the V1 and V2 hypervariable regions. Based upon a comparison of 42 individuals with CD4 counts ranging from 802 to < 1 at time of death, we found no evidence for changes in the length of V2 with development of AIDS. Using the number of length variants in the V1 and V2 hypervariable region as a marker of the overall degree of variability within HIV populations, we found no evidence for an increase or a decrease in diversity between those with and without AIDS defining illness.

Amino Acid Sequence↗
PubMed1997

Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes.

The time of spread of human immunodeficiency virus type 1 (HIV-1) from lymphoid to nonlymphoid tissues in the course of infection was investigated by sequence comparisons of variants infecting a range of lymphoid and nonlymphoid tissues from three individuals with AIDS in the pl7gag gene and regions flanking the V1/V2 hypervariable regions. Phylogenetic analysis in both regions revealed several lineages in each individual that contained sequences from both lymphoid and nonlymphoid tissues such as the brain. This observation contrasts strongly with the previously described organ-specific sequences in the V3 region in this study population and other investigations. Although individual pairwise comparisons of relatively short sequences such as p17gag are subject to considerable stochastic error, we found that the diversity of gag sequences in variants from lymphoid tissue was consistently lower than that found among variants amplified from the brain. By estimating mean synonymous pairwise distances in the p17gag region, we were able to make an approximate calculation of the ages of populations in different tissues. Those from lymphoid tissue ranged from 2.65 to 5.6 years in the three study subjects, compared with 4.1 to 6.2 years for variants in the brain. Indeed, variants infecting the brain were no more closely related to each other than they were to variants infecting other tissues in the body. In two of the three individuals, these times of divergence indicate that infection of the brain may have occurred as an early event in the progression to disease, preceding the onset of AIDS by several years. This study is the first in which it was possible to estimate times of diversification in different tissues in vivo and is of importance in understanding the dynamics of the spread of HIV-1 into nonlymphoid tissues and its possible adaptation for replication in different cell types.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Prion protein immunocytochemistry--UK five centre consensus report.

Creutzfeldt-Jakob disease (CJD) and other prion diseases are associated with the deposition of insoluble prion protein (PrPCJD) in the central nervous system (CNS). Antibodies raised against PrPCJD also react with its precursor protein, a soluble form of PrP (PrPC), which is widely distributed in the normal CNS. This cross-reactivity has in the past raised doubts as to the specificity and diagnostic reliability of PrP immunolocalization, especially in familial cases which are atypical clinically and which lack characteristic pathology findings. Following an MRC-funded workshop which focused on this problem, a multicentre prospective study was set up to identify a reliable protocol for PrPCJD immunocytochemistry. Five UK centres took part in this study and demonstrated consistent staining of plaques, vacuolar deposits in severe spongiform change, and perineuronal deposits using a variety of antibodies and enhancement procedures. A protocol using formic acid, guanidine thiocyanate, and hydrated autoclaving pre-treatment in conjunction with a monoclonal PrPCJD antibody produced the clearest immunochemical results and is presented as the consensus UK recommendation for PrPCJD immunocytochemical procedures.

Brain↗
PubMed1997

The neuropathology of HIV-infected African children in Abidjan, Côte d'Ivoire.

In an autopsy study of HIV-infected children in Abidjan, Côte d'Ivoire, the neuropathology of 76 HIV-1- and 2 HIV-2-positive children was compared with that of 77 frequency-matched HIV-negative children, in whom the systemic pathology was also known. Seventy of the 78 HIV-seropositive children were confirmed as HIV-infected, as determined by combined serology, IgA Western blots and clinicopathological criteria. The HIV-negative children showed a high background level (n = 49, 64%) of neuropathological abnormalities, including nonspecific inflammatory infiltrates, micromineralization, and bacterial and lymphocytic meningitis. In the HIV-positive children, HIV encephalitis was found in 4 (6%), cytomegalovirus in 2 (3%), toxoplasmosis in 3 (4%) and measles encephalitis in one (1%). Bacterial meningitis was equally common in both groups, but cerebral malaria was less common (n = 2, 3%) in HIV-positive than in HIV-negative children (n = 11, 14%). The low prevalence of HIV encephalitis may reflect comparatively early death in HIV infection in Africa as compared with our experience in Europe and the US.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Principles and practice of 'high risk' brain banking.

The storage of tissues obtained from patients with clinically documented and neuropathologically validated diseases of the central nervous system (CNS), and from well-chosen control cases, forms a valuable resource for present and future research needs. In particular, it facilitates immediate application of new investigative technology as this becomes available. To maximize their usefulness it is desirable to store tissues in a variety of different forms, including fixed and frozen samples. However, storage of infective dementias poses special problems (including risk to future users) since the infective agent may well survive long-term storage at -70 degrees C. Guidelines for optimal storage of such tissues should conform with safety, but should not be so prescriptive as to deter pathologists who do not have access to sophisticated brain banking resources. This article provides information about tissue storage from infective CNS diseases for pathologists who may require to retain frozen and other samples from such autopsies either occasionally or on a regular basis. Guidelines are offered for banking tissues from cases infected with human immunodeficiency virus (HIV), hepatitis viruses and prions. With detailed description of procedures for acquisition, storage and transparent of high-risk samples. Safety issues and protocols for response to accidental injury involving exposure to these agents are highlighted in this article.

Brain↗
PubMed1996

Protamines of reptiles.

We have characterized for the first time the complete primary structure of the main protamine components of the sperm from four reptiles: Chrysemys picta (turtle), Elaphe obsoleta (snake), Anolis carolinensis (lizard), and Alligator mississipiensis (crocodilian). These species were chosen to represent one of each of the main phylogenetic branches of this taxonomic group. Comparison of these protamine sequences with those already available from other vertebrate groups allows us to define properly the chemical consensus composition of protamines and provides a unique insight into their molecular evolution and classification.

Alligators and Crocodiles↗
PubMed1996

Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1. Edinburgh Heterosexual Transmission Study Group.

BACKGROUND: Although lymphocytes expressing the CD4 surface receptor for HIV-1 have been identified as the principal target of the virus, the extent to which infection of other cell types of the immune system contributes to immunodeficiency is unknown. We investigated the cell types in peripheral blood infected with HIV and the relation of viral load in different subsets to disease progression. METHODS: The study group consisted of 16 HIV-infected individuals, eight of whom had clinically defined AIDS with CD4 cell counts less than 200/microL blood. The main component subsets of peripheral blood mononuclear cells were purified by magnetic bead separation, and included CD4 and CD8 lymphocytes, B lymphocytes, monocytes, and dendritic cells. HIV proviral sequences within these separate populations were quantified by limiting-dilution nested polymerase chain reaction. FINDINGS: HIV-1 proviral sequences were detected in T-helper cells, cytotoxic T cells, dendritic cells, and monocytes. CD4 T lymphocytes constituted the main reservoir of HIV in all but one of the symptom-free individuals studied (those with CD4 count > 200/microL). However, in all the individuals with CD4 counts of less than 200/microL, most infected cells within the peripheral blood mononuclear cell fraction were either dendritic cells or CD8 lymphocytes. Infection of CD8 cells accounted for between 66% and 97% of total proviral load in five of the eight AIDS patients. A strong inverse relation between total CD8 count and the frequency of CD8 T-lymphocyte infection was found. INTERPRETATION: This study provides evidence for widespread infection of lymphocytes of the CD8 phenotype, indicating that HIV-1 has a broader tropism for different cell types in vivo than described for cultured virus. Infection of CD8 cells may contribute to the decline of this subset upon disease progression in HIV-infected individuals. Infection of CD8 cells may or may not occur by a non-CD4-dependent mechanism of virus entry.

Base Sequence↗
PubMed1996

Deficiency of respiratory chain complex I is a common cause of Leigh disease.

We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.

Blotting, Southern↗
PubMed1996

Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients.

OBJECTIVE: To determine the associations between HIV encephalitis and other central nervous system (CNS) pathology, viral burden, cognitive impairment, zidovudine therapy and risk group in AIDS patients. DESIGN: Planned autopsy study in AIDS patients evaluated prospectively for numerous clinical parameters. SETTING: Regional academic centre for clinical care and pathology examination of patients with HIV infection. PATIENTS: Edinburgh cohort of HIV-positive patients prospectively assessed for cognitive impairment, immunosuppression and clinical course. Unbiased series of consecutive autopsies in 27 homosexual men and 39 drug-using patients with AIDS. INTERVENTIONS: Zidovudine therapy monitored in all patients. MAIN OUTCOME MEASURES: Determination of CNS viral burden and pathology including immunocytochemically confirmed HIV encephalitis in injecting drug users (IDU) versus homosexual AIDS patients with known CD4 counts and cognitive function. RESULTS: HIV encephalitis was present in 59% of IDU and 15% of homosexuals: 88% of patients with encephalitis had displayed cognitive impairment. HIV encephalitis was strongly associated with a high viral load and HIV p24 immunopositivity. Opportunistic infections and lymphomas were more common in homosexuals (63%) than in IDU (31%) and were associated with the degree of immunosuppression before death. Within both groups, prolonged zidovudine treatment was associated with a lower incidence of HIV encephalitis. CONCLUSIONS: This study documents two separate CNS outcomes in AIDS patients in that HIV encephalitis occurs independently of opportunistic infections and lymphomas and shows different associations with risk group, immunosuppression and antiviral treatment before death.

AIDS Dementia Complex↗
PubMed1996

The 'high-risk' neuropathological autopsy in AIDS and Creutzfeldt-Jakob disease: principles and practice.

There is much current clinical, pathological and scientific interest in infective disorders of the central nervous system, particularly those associated with the human immunodeficiency virus (AIDS) and the transmissible human spongiform encephalopathies (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia). To investigate these disorders it is necessary to develop and follow procedures for performing autopsies on known or suspected cases which allow both diagnostic and research investigations to be carried out, while at the same time presenting minimal risk to pathologists, mortuary and laboratory technical staff. This article reviews the objectives for performing 'high-risk' autopsies, and summarizes current guidelines for autopsy procedures and laboratory tissue handling in light of extensive experience in the Neuropathology Laboratory, University of Edinburgh. Neuropathology has a leading role to play in diagnosis and research in this important field; the need for 'high-risk' autopsies is likely to increase into the next century.

Acquired Immunodeficiency Syndrome↗